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Active rheumatoid arthritis (RA) is associated with increased cardiovascular risk and impaired function of high-density lipoprotein (HDL). Previous work suggests that HDL may become dysfunctional through oxidative modifications within the RA joint. The current work evaluates an association of synovial power doppler ultrasound signal (PDUS) with HDL function and structure. Two open-label clinical therapeutic studies using PDUS as a disease outcome measure were included in this analysis, including a 12-month trial of subcutaneous abatacept in 24 RA patients and a 6-month trial of IV tocilizumab in 46 RA patients. Laboratory assays included assessments of HDL function and structure, HDL and total cholesterol levels, and a cytokine/chemokine panel. Patients with the highest baseline PDUS scores in both clinical studies, had worse HDL function, including suppression of paraoxonase 1 (PON1) activity as well as lower HDL-C levels. Associations between other disease assessments (DAS28 and CDAI) and HDL function/structure were noted but were generally of lesser magnitude and consistency than PDUS across the HDL profile. Treatment with tocilizumab for 6 months was associated with increases in cholesterol levels and improvements in the HDL function profile, which correlated with greater decreases in PDUS scores. Similar trends were noted following treatment with abatacept for 3 months. Higher baseline PDUS scores identified patients with worse HDL function. This data supports previous work suggesting a direct association of joint inflammation with abnormal HDL function.

Intravenous immune globulin (IVIG) for the treatment of dermatomyositis has not been extensively evaluated.We conducted a randomized, placebo-controlled trial involving patients with active dermatomyositis. The patients were assigned in a 1:1 ratio to receive IVIG at a dose of 2.0 g per kilogram of body weight or placebo every 4 weeks for 16 weeks. The patients who received placebo and those without confirmed clinical deterioration while receiving IVIG could enter an open-label extension phase for another 24 weeks. The primary end point was a response, defined as a Total Improvement Score (TIS) of at least 20 (indicating at least minimal improvement) at week 16 and no confirmed deterioration up to week 16. The TIS is a weighted composite score reflecting the change in a core set of six measures of myositis activity over time; scores range from 0 to 100, with higher scores indicating greater improvement. Key secondary end points included at least moderate improvement (TIS ≥40) and major improvement (TIS ≥60), and change in score on the Cutaneous Dermatomyositis Disease Area and Severity Index.A total of 95 patients underwent randomization: 47 patients were assigned to the IVIG group, and 48 to the placebo group. At 16 weeks, 79% of the patients in the IVIG group (37 of 47) and 44% of those in the placebo group (21 of 48) had a TIS of at least 20 (difference, 35 percentage points; 95% confidence interval, 17 to 53; P0.001). The results with respect to the secondary end points, including at least moderate improvement and major improvement, were generally in the same direction as the results of the primary end-point analysis, except for the change in creatine kinase level (an individual core measure of the TIS), which did not differ meaningfully between the two groups. Over 40 weeks, 282 treatment-related adverse events occurred in the IVIG group, including headache (in 42% of patients), pyrexia (in 19%), and nausea (in 16%). A total of 9 serious adverse events that were considered to be related to IVIG occurred, including 6 thromboembolic events.In this 16-week trial involving adults with dermatomyositis, the percentage of patients with a response of at least minimal improvement based on a composite score of disease activity was significantly greater among those who received IVIG than among those who received placebo. IVIG was associated with adverse events, including thromboembolism. (Funded by Octapharma Pharmazeutika; ProDERM ClinicalTrials.gov number, NCT02728752.).

Background Rheumatoid arthritis (RA)-associated lung disease (LD) associates with significantly increased morbidity and mortality. Although oxidative stress plays an important role in the inflammatory responses in other forms of lung disease, minimal work has evaluated its role in RA-LD. The current work examines the relationship between the anti-oxidant HDL-associated enzyme paraoxonase-1 (PON1), the PON1 Q192R polymorphism, and a targeted oxylipin panel with RA-LD. Methods This study was conducted as a retrospective chart review of a longitudinal single-center cohort of 250 RA patients. CT scans of the chest were reviewed by the interpreting radiologist and classified as small airways disease (SAD), interstitial lung disease (ILD), and bronchiectasis. PON1 activity was measured by its lactonase, arylesterase, and paraoxonase functions. The PON1 Q192R polymorphism and a targeted lipidomics panel were performed as previously reported. Results 43.2% of the 250 RA patient cohort (n = 108) had available CT scans, including 48 patients (44.4%) with SAD, 27 patients (25.0%) with bronchiectasis, and 16 patients (14.8%) with ILD. Patients with SAD had significantly lower baseline PON1 activity by its arylesterase, and lactonase functions, as well as higher 15-HETE, LTB4, and PGE2 levels compared to those without SAD. These predictors of SAD remained significant after multivariate analysis including known risk factors for RA-LD. Suppressed PON1 activity also correlated with higher levels of 15-HETE and 12-HETE. Conclusion In a single-center RA cohort, suppressed baseline PON1 activity and elevation in the oxylipins 15-HETE, LTB4, and PGE2 predicted the presence of RA-SAD in longitudinal follow-up. Key Points• Small airways disease (SAD) was present in 44.4% of this rheumatoid arthritis (RA) cohort.• Patients with SAD had significantly lower baseline PON1 activity, as well as higher levels of the oxylipins 15-HETE, LTB4, and PGE2 levels compared to those without SAD.• Further work is warranted to confirm these findings and further define the role of PON1 and lipid oxidation in RA lung disease.

Background/Aims The safety profile of filgotinib (FIL), a second-generation oral Janus kinase (JAK) 1 preferential inhibitor approved in Europe, Japan, and the UK for treatment of rheumatoid arthritis (RA) has been reported. In patients (pts) with active RA aged ≥50y with ≥1 cardiovascular (CV) risk factor, treated with the pan-JAK inhibitor tofacitinib, data from an interventional post-marketing study (NCT02092467) suggested a higher risk of major adverse cardiovascular events (MACE) and malignancies compared with TNF inhibitors. No data are available from a similar prospective study with FIL. This post hoc exploratory analysis aimed to describe the incidence of MACE and malignancies in a subgroup of pts with RA from the FINCH and DARWIN clinical trials, receiving FIL 200 mg (FIL200) and FIL 100 mg (FIL100). Methods Exploratory analysis of adverse events of special interest are reported using integrated FIL RA data from phase 2 (NCT01668641, NCT01894516), phase 3 (NCT02889796, NCT02873936, NCT02886728), and the long-term extension (LTE) studies DARWIN 3 (NCT02065700) and FINCH 4 (NCT03025308), in a pt population at higher risk of CV events similar to ORAL-SURVEILLANCE,1 namely, aged ≥50y with ≥1 CV risk factor (history of dyslipidemia, diabetes or CV disease; hypertension, ischemic vascular conditions, peripheral vascular disease, extra-articular manifestations of RA; or current smokers). All pts met ACR criteria for functional class I-III. Censored exposure-adjusted incidence rates (EAIRs)/100 pt-years of exposure for MACE, venous thromboembolism (VTE), malignancies excluding nonmelanoma skin cancer (NMSC), NMSC, (serious) infections, and deaths were determined. Data were as of Jan 11, 2022 (DARWIN 3) and Jan 31, 2022 (FINCH 4). Analyses were performed on an ad hoc interim analysis data set without additional cleaning. Results The higher-risk population included 1484 pts: mean age 62.1y (536 [36.1%] aged ≥65y), 291 (22.5%) current smokers, and 904 (60.9%) received background MTX; baseline (BL) MTX use was higher in the FIL100 vs FIL200 group (66.6% vs 54.6%); other BL demographics were balanced. Numerically higher EAIRs for malignancies (excluding NMSC), NMSC, serious infections, and deaths were observed for pts receiving FIL200 vs FIL100; 95% confidence intervals overlapped. For MACE and VTE, incidence is considered similar for both doses. The risk of experiencing MACE, malignancies excluding NMSC, and NMSC over time with FIL100 or FIL200 will be described. Conclusion In this RA population at higher risk of CV events, the incidence of MACE and VTE was similar for both doses. A numerically higher incidence of malignancies (excluding NMSC), NMSC, serious infections, and deaths was observed in the high- vs low-dose group. Limitations included population selection bias, low event numbers, and the post hoc nature of the analysis. The ongoing LTE and real-world studies in RA will continue to investigate the safety of FIL in these populations. Disclosure M.H. Buch: Honoraria; MHB has recieved funding (Paid to her host institution) fromAbbVie, Galapagos, Gilead, Pfizer, Eli Lilly, Merck-Serono, Roche, UCB. G.R. Burmester: Honoraria; AbbVie, Galapagos, Lilly, MSD, Pfizer, Roche, UCB, Janssen, Gilead Sciences, Inc. X. Mariette: Honoraria; AstraZeneca, Bristol Myers Squibb, Galapagos, GSK, Novartis, Pfizer. C. Charles-Schoeman: Honoraria; AbbVie, Bristol Myers Squibb (BMS), Pfizer, Regeneron-Sanofi, Gilead. V. Rajendran: Other; Employee of Galapagos NV. P. Stiers: Other; Employee of Galapagos NV. A. Cerani: Other; Employee of Galapagos NV. P. Van Hoek: Other; Employee of Galapagos NV. K. Van Beneden: Other; Employee of Galapagos NV. Y. Tanaka: Honoraria; Lilly, AbbVie, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Pfizer, Mitsubishi Tanabe, GlaxoSmithKline, Asahi Kasei, Takeda, Astellas, Janssen, Novartis, Sanofi, UCB, YL Biologics, MSD, Ono, T. H. Schulze-Koops: Honoraria; AbbVie, Galapagos, Lilly, Pfizer. R. Westhovens: Honoraria; Celltrion, Galapagos, Gilead. E. Favalli: Honoraria; AbbVie, BMS, Celltrion, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB.

ObjectiveThe increase in cardiovascular events (CVEs) in systemic lupus erythematosus (SLE) is not fully explained by traditional risk factors. We previously identified four biomarkers (proinflammatory high-density lipoprotein, leptin, soluble TNF-like weak inducer of apoptosis (sTWEAK), and homocysteine) that we combined with age and diabetes to create the predictors of risk for elevated flares, damage progression, and increased cardiovascular diseasein patients with SLE (PREDICTS) risk profile. PREDICTS more accurately identified patients with SLE at risk for progression of subclinical atherosclerosis than any individual variable. We examined whether PREDICTS can also identify patients with SLE at risk for future CVEs.MethodsA total of 342 patients with SLE and 155 matched control subjects participated in this longitudinal prospective study. A high PREDICTS score was defined as three or more predictors or diabetes + one or more predictor. The biomarkers were measured at baseline using published methods. All major adverse CVEs (MACEs) were confirmed by medical record review.ResultsDuring 116 months of follow-up, 5% of patients with SLE died, 12% had a cerebrovascular event, and 5% had a cardiac event. Overall, 20% of patients with lupus experienced any new MACE compared with 5% of control subjects (P < 0.0001). More patients with SLE with a new MACE had high PREDICTS score at baseline (77%) versus patients with no new events (34%) (P < 0.0001). High baseline PREDICTS score also associated with cerebrovascular (P < 0.0001) and cardiac events (P < 0.0001) in SLE. Using Cox regression, a baseline high PREDICTS score associated with a 3.7-fold increased hazard ratio (HR) for a new MACE (P < 0.0001) in SLE. Hypertension (HR = 2.1; P = 0.006) was also a risk.ConclusionA high PREDICTS score and hypertension confer increased risk for new MACEs in patients with SLE.

Paraoxonase 1(PON1) is an HDL-associated protein, which metabolizes inflammatory, oxidized lipids associated with atherosclerotic plaque development. Because oxidized lipid mediators have also been implicated in the pathogenesis of rheumatoid arthritis (RA), we evaluated the role of PON1 in murine inflammatory arthritis. K/BxN serum transfer (STIA) or collagen antibody transfer (CAIA) was used for arthritis induction in B6 mice homozygous for the PON1 human transgene [PON1Tg], PON1 knock-out mice [PON1KO], and wild type littermate control mice [WT]. Experiments were also performed in K/BxN mice with chronic arthritis, and in RA patients and healthy controls. Arthritis activity in K/BxN mice was associated with a marked dyslipidemia, lower PON1 activity and higher bioactive lipid mediators (BLM), as well as a dysregulated hepatic lipid gene expression profile. Higher serum PON1 activity correlated with lower BLM and lower arthritis activity in both K/BxN mice and RA patients. Overexpression of the human PON1 transgene was associated with reduced inflammatory arthritis, which correlated strongly with higher circulating PON1 activity, upregulation of the hepatic glutathione pathway, and reduction of circulating BLM. These results implicate PON1 as a potential novel therapeutic target for joint disease in RA with potential for vascular benefit, which warrants further investigation.

ObjectiveDamage to the vascular endothelium is strongly implicated in the pathogenesis of idiopathic inflammatory myopathies (IIM). Normally, high-density lipoprotein (HDL) protects the vascular endothelium from damage from oxidized phospholipids, which accumulate under conditions of oxidative stress. The current work evaluated the antioxidant function of HDL in IIM patients.MethodsHDL’s antioxidant function was measured in IIM patients using a cell-free assay, which assesses the ability of isolated patient HDL to inhibit oxidation of low-density lipoproteins and is reported as the HDL inflammatory index (HII). Cholesterol profiles were measured for all patients, and subgroup analysis included assessment of oxidized fatty acids in HDL and plasma MPO activity. A subgroup of IIM patients was compared with healthy controls.ResultsThe antioxidant function of HDL was significantly worse in patients with IIM (n = 95) compared with healthy controls (n = 41) [mean (S.d.) HII 1.12 (0.61) vs 0.82 (0.13), P ConclusionThe antioxidant function of HDL is abnormal in IIM patients and may warrant further investigation for its role in propagating microvascular inflammation and damage in this patient population.

ObjectivesTofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within.MethodsThis post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years’ exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed.Results12 410 tofacitinib-treated patients from the development programmes (RA: n=7964; PsO: n=3663; PsA: n=783) were included. IRs (95% CI) of thromboembolic events among the all tofacitinib cohorts’ average tofacitinib 5 mg and 10 mg twice daily treated patients for RA, respectively, were: DVT (0.17 (0.09–0.27) and 0.15 (0.09–0.22)); PE (0.12 (0.06–0.22) and 0.13 (0.08–0.21)); ATE (0.32 (0.22–0.46) and 0.38 (0.28–0.49)). Among PsO patients, IRs were: DVT (0.06 (0.00–0.36) and 0.06 (0.02–0.15)); PE (0.13 (0.02–0.47) and 0.09 (0.04–0.19)); ATE (0.52 (0.22–1.02) and 0.22 (0.13–0.35)). Among PsA patients, IRs were: DVT (0.00 (0.00–0.28) and 0.13 (0.00–0.70)); PE (0.08 (0.00–0.43) and 0.00 (0.00–0.46)); ATE (0.31 (0.08–0.79) and 0.38 (0.08–1.11)). IRs were similar between tofacitinib doses and generally higher in patients with baseline cardiovascular or VTE risk factors. IRs from the overall Corrona populations and in Corrona RA patients (including tofacitinib-naïve/biologic disease-modifying antirheumatic drug-treated and tofacitinib-treated) with baseline cardiovascular risk factors were similar to IRs observed among the corresponding patients in the tofacitinib development programme. No signals of disproportionate reporting of DVT, PE or ATE with tofacitinib were identified in the FAERS database.ConclusionsDVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32–0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13–0.41)).

Background Statins are the most widely used lipid lowering therapies which reduce cardiovascular risk, but are associated with muscular adverse events (AEs). Idiopathic inflammatory myopathies (IIM) are autoimmune diseases of the muscle with higher risk of cardiovascular disease. More data is needed regarding statin safety in patients with intrinsic muscle disease such as IIM. Hypothesis Statins are tolerated in patients with IIM without leading to significant increase in muscular AEs. Methods Statin use was retrospectively examined in a longitudinal IIM cohort. Safety analysis included assessment of muscular and nonmuscular AEs by chart review. IIM patients receiving a statin during the cohort follow‐up period were matched to IIM patients not receiving a statin for comparative analysis of longitudinal outcomes. Results 33/214 patients had a history of statin use. 63% started for primary prevention, while others were started for clinical ASCVD events, vascular surgery, IIM related heart failure, and cardiac transplantation. A high intensity statin was used in nine patients with non‐HMGCR myositis, and tolerated in 8/9 patients. Statin related muscular AE was noted in three patients. There were no cases of rhabdomyolysis, or statin related nonmuscular AEs in a median observation period of 5 years. In patients newly started on statins during cohort follow‐up (n = 7) there was no change in disease activity after statin initiation. Long term outcomes were not different between statin and nonstatin IIM control groups. Conclusion Statins were well tolerated in patients with non‐HMGCR positive IIM. Given the accelerated atherosclerotic risk in IIM patients, further prospective studies of statin safety in IIM patients are warranted.

ObjectivesEvaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic cardiovascular disease (ASCVD) in ORAL Surveillance.MethodsPatients with RA aged ≥50 years with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. Hazard rations (HRs) were evaluated for the overall population and by history of ASCVD (exploratory analysis).ResultsRisk of MACE, myocardial infarction and sudden cardiac death were increased with tofacitinib versus TNFi in ORAL Surveillance. In patients with history of ASCVD (14.7%; 640/4362), MACE incidence was higher with tofacitinib 5 mg two times per day (8.3%; 17/204) and 10 mg two times per day (7.7%; 17/222) versus TNFi (4.2%; 9/214). HR (combined tofacitinib doses vs TNFi) was 1.98 (95% confidence interval (CI) 0.95 to 4.14; interaction p values: 0.196 (for HR)/0.059 (for incidence rate difference)). In patients without history of ASCVD, MACE HRs for tofacitinib 5 mg two times per day (2.4%; 30/1251) and 10 mg two times per day (2.8%; 34/1234) versus TNFi (2.3%; 28/1237) were, respectively, 1.03 (0.62 to 1.73) and 1.25 (0.76 to 2.07).ConclusionsThis post hoc analysis observed higher MACE risk with tofacitinib versus TNFi in patients with RA and history of ASCVD. Among patients without history of ASCVD, all with prevalent CV risk factors, MACE risk did not appear different with tofacitinib 5 mg two times per day versus TNFi. Due to the exploratory nature of this analysis and low statistical power, we cannot exclude differential MACE risk for tofacitinib 5 mg two times per day versus TNFi among patients without history of ASCVD, but any absolute risk excess is likely low.Trial registration numberNCT02092467.

ObjectiveIn the ORAL (Oral Rheumatoid Arthritis triaL) Surveillance study of patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor, incidence of pulmonary embolism was higher with tofacitinib 10 mg two times per day than with tumour necrosis factor inhibitors (TNFi). This exploratory post hoc analysis examined whether biomarkers explained the associations of tofacitinib versus TNFi with venous thromboembolism (VTE).MethodsORAL Surveillance was a prospective, open-label, event-driven, non-inferiority, postauthorisation safety study. Patients were randomised 1:1:1 to receive tofacitinib 5 mg or 10 mg two times per day or a TNFi. For this analysis, 294 soluble, proteomic, genetic and antibody biomarkers (of which 79 had a known role in inflammation, coagulation, vascular biology or Janus kinase signalling) were quantified in serum collected at baseline, month 12 and study end.ResultsOverall, 4362 patients were randomised and treated. The exploratory biomarker data set included 285 patients (57 VTE cases; 228 matched controls). D-dimer was quantified in 3732 patients (54 VTE cases; 3678 controls). No biomarker demonstrated a clear mechanistic association with the increased risk of VTE for tofacitinib versus TNFi. Month 12 D-dimer levels were positively associated with risk of a subsequent VTE within the tofacitinib 5 mg and 10 mg two times per day arms.ConclusionsOverall, this post hoc analysis did not identify biomarkers that explained the increased VTE risk for tofacitinib versus TNFi. Individual VTE risk should be considered when making decisions about initiation or maintenance of tofacitinib treatment.Trial registration numberNCT02092467; ClinicalTrials.gov.

Objectives Patients with idiopathic inflammatory myopathies (IIM) have severe vascular involvement, which contributes to disease morbidity and mortality. Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL) associated protein that protects the vascular endothelium from oxidative injury and damage. The current work assessed the functional and genetic determinants of PON1 activity in IIM patients. Methods A total of 184 IIM patients and 112 healthy controls (HC) were included. PON1 enzyme activity was assessed by paraoxonase, arylesterase and lactonase assays, and the Q192R PON1 single nucleotide polymorphism (SNP) was analysed. Multivariate regression models examined associations of PON1 activity with IIM diagnosis and myositis disease outcomes. Results The arylesterase and lactonase activities of PON1 were significantly lower in IIM patients compared with HC. Higher myositis disease activity, the presence of severe IIM-associated interstitial lung disease (ILD), and the presence of MDA5 or anti-synthetase antibodies were significantly associated with lower PON1 activity. The PON1 Q192R polymorphism was strongly linked to the paraoxonase activity of PON1 in IIM, and patients with the PON1 QQ genotype had better IIM disease outcomes compared with patients with the QR or RR genotypes. Conclusions The arylesterase and lactonase activities of PON1 are significantly impaired in IIM patients compared with HC, and inversely associate with IIM disease activity and the presence of severe ILD. The PON1 QQ genotype associates with more favourable disease outcomes in IIM patients. Large prospective studies are needed to further evaluate the role of PON1 and PON1 genetic polymorphisms in the development and propagation of IIM and IIM-ILD.

Background:Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for rheumatoid arthritis (RA). The safety and efficacy of UPA has been evaluated across a spectrum of patients (pts) with RA in the phase 3 SELECT clinical program.1,2Objectives:To describe long-term laboratory profiles (cutoff date: June 30, 2020) associated with exposure to UPA, adalimumab (ADA), and methotrexate (MTX) in pts with RA treated in the SELECT trials.Methods:Data were analyzed from 6 randomized controlled UPA RA trials.1,2 The proportions of pts experiencing potentially clinically significant laboratory changes at a single time point were summarized for the following groups: pooled UPA 15 mg once daily (QD; UPA15; 6 trials), pooled UPA 30 mg QD (UPA30; 4 trials), ADA 40 mg every other week (EOW; 1 trial), and MTX monotherapy (1 trial). Pts received UPA with/without background conventional synthetic disease-modifying antirheumatic drugs. Treatment-emergent adverse events are reported as exposure-adjusted event rates (events/100 pt-years [E/100 PY]). Toxicity was graded per OMERACT criteria, or NCI CTCAE for creatine phosphokinase (CPK) and creatinine.Results:4413 pts received ≥1 dose of UPA (UPA15, n=3209; UPA30, n=1204). Exposures were comparable between treatment groups (Table). Proportions of pts with Grade (Gr) 3 and 4 decreases in hemoglobin were highest with UPA30 and MTX (Table). Rates of anemia, as reported by the investigator, were comparable between UPA15, ADA, and MTX groups (Figure); the frequency of UPA-treated pts who discontinued due to anemia was low in all arms. Gr 3 and 4 decreases in neutrophils and lymphocytes with UPA were dose-dependent and higher vs ADA or MTX. Discontinuations due to neutropenia and lymphopenia were rare (Table 1.Pts with potentially clinically significant laboratory changesVariable, n (%)MTX monotherapy (n=314; 637.4 PY)ADA 40 mg EOW (n=579; 1051.8 PY)UPA 15 mg QD (n=3209; 7023.8 PY)UPA 30 mg QD (n=1204; 3091.6 PY)Mean (SD) exposure, weeks106 (67)95 (70)114 (64)134 (66)Median (range) exposure, weeks144 (1, 221)118 (2, 231)136 (0, 232)160 (0, 231)Hemoglobin, g/LGr 3 (70–28a (9.0)24b (4.2)254d (7.9)169f (14.2)Gr 4 (16a (5.1)16b (2.8)101d (3.2)78f (6.5)Neutrophils, 109/LGr 3 (0.5–3a (1.0)3b (0.5)40d (1.2)37g (3.1)Gr 4 (1a (0.3)1b (0.2)10d (0.3)5g (0.4)Lymphocytes, 109/LGr 3 (0.5–74a (23.7)53b (9.2)802d (25.1)423g (35.5)Gr 4 (5a (1.6)3b (0.5)75d (2.3)47g (3.9)ALT, U/LGr 3 (3.0–8.0 × ULN)26a (8.3)13c (2.3)152e (4.8)71h (5.9)Gr 4 (>8.0 × ULN)5a (1.6)4c (0.7)26e (0.8)10h (0.8)AST, U/LGr 3 (3.0–8.0 × ULN)15a (4.8)9c (1.6)101e (3.2)36h (3.0)Gr 4 (>8.0 × ULN)1a (0.3)5c (0.9)18e (0.6)8h (0.7)CPK, U/LGr 3 (>5.0–10.0 × ULN)2a (0.6)3c (0.5)65e (2.0)36i (3.0)Gr 4 (>10.0 × ULN)0a (0)3c (0.5)27e (0.8)15i (1.3)Creatinine, μmol/LGr 3 (>3.0–6.0 × ULN)0a (0)1c (0.2)3e (2j (0.2)Gr 4 (>6.0 × ULN)0a (0)4c (0.7)8e (0.3)1j (an=312. bn=576. cn=577. dn=3201. en=3199. fn=1193. gn=1192. hn=1195. in=1196. jn=1197ULN, upper limit of normalConclusion:This long-term analysis of UPA-treated pts with RA showed dose-dependent relationships for several laboratory abnormalities. Incidences of these with UPA15 were typically higher than with ADA but similar to MTX, except for increased CPK elevations. Treatment discontinuations due to laboratory abnormalities were infrequent and similar across all treatment groups.References:[1]Tanaka Y. Mod Rheumatol 2020;30:779–87; 2. Rubbert-Roth A, et al. N Engl J Med 2020;383:1511–21.Acknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Russell Craddock, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Christina Charles-Schoeman Consultant of: AbbVie, Gilead, Pfizer, and Sanofi/Regeneron, Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer, Jon T Giles Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Pfizer, and UCB, Grant/research support from: Pfizer, Nancy Lane Consultant of: Amgen, Mallinckrodt, Pfizer, and Roche, Ernest Choy Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Consultant of: AbbVie, Amgen, Biocon, Biogen, Chugai, Eli Lilly, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regeneron, Roche, R-Pharm, and Sanofi, Grant/research support from: Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi, and UCB, Daniel Furst Speakers bureau: AbbVie, Continuing Medical Education, and Novartis, Consultant of: Actelion, Amgen, Bristol-Myers Squibb, Corbus, Galapagos, Novartis, and Pfizer, Grant/research support from: Actelion, Amgen, Bristol-Myers Squibb, Corbus, Galapagos, GSK, NIH, Novartis, Pfizer, Roche/Genentech, and Sanofi, Jiří Vencovský Speakers bureau: AbbVie, Biogen, MSD, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly, Gilead, and Octapharma, Anthony G Wilson: None declared, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Consultant of: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Tim Shaw Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Jillian Yee Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Samuel Anyanwu Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Celgene, Janssen, Novartis, and UCB, Grant/research support from: Celgene, Janssen, Novartis, Pfizer, Roche, and UCB

Background:Upadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor engineered to have greater selectivity for JAK1 vs JAK2, JAK3, and tyrosine kinase 2, and is approved for the treatment of RA. Across 2 double-blind, placebo (PBO)-controlled Phase 3 studies of UPA in patients with RA, after an initial increase through Week 8, lipid levels remained stable up to Week 24.1,2 Previous studies of JAK or IL-6 receptor inhibitors have reported a negative correlation between changes in lipid levels and RA disease activity.3,4Objectives:To determine the relationship between changes in lipid levels and disease activity outcomes in patients with RA treated with UPA.Methods:Patients with RA and an inadequate response to conventional synthetic/biologic DMARDs (cs/bDMARD-IR) from SELECT-NEXT/SELECT-BEYOND, respectively, were randomized to receive UPA 15 mg once daily (QD), UPA 30 mg QD, or PBO for 12 weeks followed by an extension of up to 5 years; patients randomized to PBO switched to UPA 15 or 30 mg after 12 weeks. Spearman correlations of maximum changes from baseline (BL) through Week 12 in fasting-state lipid levels (low- and high-density lipoprotein cholesterol [LDL-C; HDL-C], and total cholesterol [TC]) with clinical disease activity outcomes measured by change from BL in Clinical Disease Activity Index (CDAI), DAS of 28 joints using CRP (DAS28[CRP]), tender/swollen joint count in 28 joints (TJC28/SJC28), and pain by visual analog scale (VAS) at Weeks 12 and 24, were determined. Spearman correlations of maximum changes from BL in lipid levels and CRP through Week 12 were also determined.Results:Available fasting samples from 1,160 pooled patients (UPA 15 mg, n=386; UPA 30 mg, n=384; PBO, n=390) were included. Modest, but statistically significant, negative correlations were observed between maximum changes from BL in TC through Week 12 and change from BL in CDAI, DAS28(CRP), SJC28, and pain (VAS) at Week 12 with UPA 15 or 30 mg (Figure 1); similar trends were observed at Week 24. Significant correlations between changes in LDL-C and HDL-C and disease activity outcomes were also observed, but were not consistent across UPA doses and time points. No significant correlations were noted between changes in lipid levels and disease activity outcomes in the PBO group. Statistically significant weak negative relationships were observed between maximum changes from BL in lipid levels and CRP levels through Week 12 with UPA 15 mg (HDL-C and TC) or UPA 30 mg (LDL-C and TC) (Table 1).Conclusion:In this large pooled data set of patients receiving UPA, increases in lipid levels showed modest, but statistically significant, correlations with improvement in clinical disease activity outcomes in patients with cs/bDMARD-IR RA. These results add to evidence suggesting a relationship between systemic inflammation and lipid metabolism in patients with RA, which is modifiable with effective interventions, and reinforce the importance of monitoring for hyperlipidemia in these patients.References:[1]Burmester GR, et al. Lancet 2018;391:2503–12.[2]Genovese MC, et al. Lancet 2018;391:2513–24.[3]Kremer JM, et al. Arthritis Rheumatol 2017;69:943–52.[4]Cacciapaglia F, et al. Mediators Inflamm 2018;2018:2453265.Table 1.Spearman correlation of maximum changes from BL in lipid levels through Week 12 with maximum change from BL in CRP through Week 12UPA 15 mg QDUPA 30 mg QDPBOLDL-C-0.099 (n=303)-0.174** (n=302)-0.053 (n=303)HDL-C-0.184** (n=305)-0.087 (n=304)-0.024 (n=303)TC-0.189*** (n=305)-0.236*** (n=304)-0.056 (n=303)**pHDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoproteincholesterol; PBO, placebo; QD, once daily; TC, total cholesterol; UPA, upadacitinibAcknowledgements:AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing assistance was provided by Frances Smith, PhD, of 2 the Nth, which was funded by AbbVie.Disclosure of Interests:Christina Charles-Schoeman Consultant of: AbbVie, Gilead, Pfizer, and Regeneron-Sanofi., Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer, Jon T Giles Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, and Gilead, Grant/research support from: Pfizer, Nancy Lane Speakers bureau: Amgen and Mallinckrodt, Consultant of: Amgen, Mallinckrodt, Pfizer, and Roche, Ernest Choy Speakers bureau: AbbVie, Amgen, AstraZeneca, Bio-Cancer, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai Pharma, Eli Lilly, Ferring Pharmaceuticals, GlaxoSmithKline, Hospira, Janssen, Merck Sharp & Dohme, Napp, Novimmune, Novartis, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, Sanofi, SynAct Pharma, Synovate, Tonix, and UCB, Grant/research support from: AbbVie, Amgen, AstraZeneca, Bio-Cancer, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai Pharma, Eli Lilly, Ferring Pharmaceuticals, GlaxoSmithKline, Hospira, Janssen, Merck Sharp & Dohme, Napp, Novimmune, Novartis, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, Sanofi, SynAct Pharma, Synovate, Tonix, and UCB, Heidi Camp Shareholder of: AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: AbbVie, Employee of: AbbVie, Samuel Anyanwu Shareholder of: AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Celgene, Janssen, Novartis, and UCB, Grant/research support from: Celgene, Janssen, Novartis, Pfizer Inc., Roche, and UCB

Background Circulating lipids have been implicated as important modulators of immune response, and altered lipid levels correlate with the severity of infection. However, long-term prognostic implications of lipid levels regarding future infection risk remain unclear. The current project aims to explore whether baseline lipid levels are associated with risk of future serious infection, measured by hospitalization for pneumonia. Methods A retrospective analysis was performed in 13,478 participants selected from the Atherosclerosis Risk in Communities (ARIC) study, a large community-based longitudinal cohort in the United States with a median follow-up time of >20 years. First incident of hospitalization for pneumonia was identified through hospital discharge records. Cox proportional hazard models were used to assess the association of baseline major lipid levels (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], triglycerides) with time to first pneumonia hospitalization. Results A total of 1969 (14.61%) participants had a pneumonia hospitalization during a median follow-up time of 21.5 years. The hazard ratio (HR) for pneumonia hospitalization was 0.90 (95% confidence interval, 0.87-0.92) for every 10-mg/dL increase in baseline HDL-C, and 1.02 (95% confidence interval, 1.02-1.03) for every 10-mg/dL increase in baseline triglycerides. HDL-C and triglycerides both remained significant predictors of pneumonia hospitalization after multivariable adjustment. Such associations were not seen with baseline LDL-C or total cholesterol levels. Conclusion Lower baseline HDL-C and higher triglyceride levels were strongly associated with increased risk of long-term pneumonia hospitalization in a large longitudinal US cohort.

Introduction: Dermatomyositis (DM) is an inflammatory myopathy characterized by distinct skin manifestations and muscle weakness. Intravenous immunoglobulin (IVIg) has been used off-label as adjuvant therapy in DM, but is not indicated for DM, due to lack of proven efficacy in a large randomized controlled trial. The objective of the ProDERM (Progress in DERMatomyositis) study was to evaluate the efficacy, safety and long-term tolerability of IVIg (Octagam 10%) in patients with DM in a randomized, placebo-controlled, double-blind, Phase III study. Methods: Adult patients with active DM who were continuing standard therapy at a stable dose were eligible for this study. Patients were randomized 1:1 to receive either 2 g/kg of IVIg or placebo, administered every 4 weeks until week 16 (First Period). Patients were switched to the alternate treatment if they showed clinical deterioration in the First Period. After response assessment at week 16, all patients on placebo and those without deterioration on IVIg entered the open-label Extension Period, receiving 2 g/kg IVIg every 4 weeks for 24 weeks. Results: The primary efficacy endpoint was the proportion of responders in the IVIg vs placebo arm at week 16, where response was defined per 2016 ACR/EULAR Myositis Response Criteria of at least minimal improvement [Total Improvement Score (TIS) ≥20] and without deterioration at 2 consecutive visits up to week 16. TIS consists of composite response criteria, combining weighted improvement in 6 core set measures (CSMs), Global Disease Activity (Physician and Patient), manual muscle testing-8 (MMT-8), Health Assessment Questionnaire, extra-muscular disease activity, and muscle enzymes. Secondary endpoints included the mean change in individual CSMs, time to improvement in TIS, time to confirmed deterioration in the First Period, and the overall proportion of patients with deteriorations. Adverse events, including infusion reactions and thromboembolic events, were recorded. Conclusions: The ProDERM study was the first to assess the long-term efficacy and safety of IVIg (Octagam 10%) in a placebo-controlled, blinded, randomized trial in DM. The study aimed to inform on the use of IVIg in the treatment of DM, and results are expected in Q3 2020. ClinicalTrials.gov Identifier: NCT02728752.

ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). We report the largest integrated safety analysis of tofacitinib, as of March 2017, using data from phase I, II, III, IIIb/IV and long-term extension studies in adult patients with RA.MethodsData were pooled for patients with RA who received ≥1 tofacitinib dose. Incidence rates (IRs; patients with events/100 patient-years [PY]; 95% CIs) of first-time occurrences were obtained for adverse events (AEs) of interest.Results7061 patients received tofacitinib (total exposure: 22 875 PY; median [range] exposure: 3.1 [0 to 9.6] years). IRs (95% CI) for serious AEs, serious infections, herpes zoster (all), opportunistic infections (excluding tuberculosis [TB]) and TB were 9.0 (8.6 to 9.4), 2.5 (2.3 to 2.7), 3.6 (3.4 to 3.9), 0.4 (0.3 to 0.5) and 0.2 (0.1 to 0.2), respectively. IRs (95% CI) for malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC and lymphomas were 0.8 (0.7 to 0.9), 0.6 (0.5 to 0.7) and 0.1 (0.0 to 0.1), respectively. IRs (95% CI) for gastrointestinal perforations, deep vein thrombosis, pulmonary embolism, venous thromboembolism, arterial thromboembolism and major adverse cardiovascular events were 0.1 (0.1 to 0.2), 0.2 (0.1 to 0.2), 0.1 (0.1 to 0.2), 0.3 (0.2 to 0.3), 0.4 (0.3 to 0.5) and 0.4 (0.3 to 0.5), respectively. IR (95% CI) for mortality was 0.3 (0.2 to 0.3). IRs generally remained consistent across 6-month intervals to >78 months.ConclusionThis represents the largest clinical dataset for a JAK inhibitor in RA to date. IRs remained consistent with previous reports from the tofacitinib RA clinical development programme, and stable over time.Trial registration numbersNCT01262118;NCT01484561;NCT00147498;NCT00413660;NCT00550446;NCT00603512;NCT00687193;NCT01164579;NCT00976599;NCT01059864;NCT01359150;NCT02147587;NCT00960440;NCT00847613;NCT00814307;NCT00856544;NCT00853385;NCT01039688;NCT02187055;NCT00413699;NCT00661661.For summary of phase I, phase II, phase III, phase IIIb/IV and LTE studies included in the integrated safety analysis, see online supplemental table 1.

The reported incidence of cardiac involvement in patients with idiopathic inflammatory myopathies (IIM) is increasing, and cardiovascular events are recognized as one of the major causes of morbidity and mortality. Histopathologic analyses suggest that immune-mediated inflammation is the major cause of damage in the heart muscle as well as the cardiac conduction system, which may lead to congestive heart failure and arrhythmias. Subclinical cardiac involvement is reported much more commonly than clinically evident cardiac manifestations, and the incidence varies between 13% and 72% of IIM patients dependent on the diagnostic modalities. A threefold to fivefold increased risk of myocardial infarction (MI) has been reported in patients with polymyositis and dermatomyositis compared to nonmyositis controls. All patients with a diagnosis of IIM should undergo a detailed cardiac history at initial evaluation and, if required, a screening EKG and echocardiogram. Tailored cardiac therapy should be used in conjunction with immunosuppression as indicated. IIM patients require continued cardiac “vigilance” even when the skeletal muscle disease is in remission.

Objective.Tofacitinib has been investigated for the treatment of rheumatoid arthritis (RA) in phase III studies in which concomitant glucocorticoids (GC) were allowed. We analyzed the effect of GC use on efficacy outcomes in patients with RA receiving tofacitinib and/or methotrexate (MTX) or conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in these studies.Methods.Our posthoc analysis included data from 6 phase III studies (NCT01039688; NCT00814307; NCT00847613; NCT00853385; NCT00856544; NCT00960440). MTX-naive patients or patients with inadequate response to csDMARD or biological DMARD received tofacitinib 5 or 10 mg twice daily alone or with csDMARD, with or without concomitant GC. Patients receiving GC (≤ 10 mg/day prednisone or equivalent) before enrollment maintained a stable dose throughout. Endpoints included the American College of Rheumatology (ACR) 20/50/70 response rates, rates of Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA; CDAI ≤ 10) and remission (CDAI ≤ 2.8), and changes from baseline in CDAI, 28-joint count Disease Activity Score (DAS28-4)–erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire–Disability Index (HAQ-DI), pain visual analog scale (VAS), and modified total Sharp score.Results.Of 3200 tofacitinib-treated patients, 1258 (39.3%) received tofacitinib monotherapy and 1942 (60.7%) received tofacitinib plus csDMARD; 1767 (55.2%) received concomitant GC. ACR20/50/70 response rates, rates of CDAI LDA and remission, and improvements in CDAI, DAS28-4-ESR, HAQ-DI, and pain VAS with tofacitinib were generally similar with or without GC in monotherapy and combination therapy studies. GC use did not appear to affect radiographic progression in tofacitinib-treated MTX-naive patients. MTX plus GC appeared to inhibit radiographic progression to a numerically greater degree than MTX alone.Conclusion.Concomitant use of GC with tofacitinib did not appear to affect clinical or radiographic efficacy. MTX plus GC showed a trend to inhibit radiographic progression to a greater degree than MTX alone.

The objective of this study was to evaluate oxidation products of arachidonic acid and linoleic acid in lipoproteins and synovial fluid (SF) from patients with active rheumatoid arthritis (RA) compared to non-RA controls. High-density lipoproteins (HDL) and low-density lipoproteins (LDL) were isolated from plasma using fast protein liquid chromatography and HDL was isolated from SF using dextran sulfate precipitation. 5-Hydroxyeicosatetraenoic acid (HETE), 12-HETE, 15-HETE, 9 hydroxyoctadecadienoic (HODE), and 13-HODE levels were measured in HDL, LDL, and SF by liquid chromatography-tandem mass spectrometry. HDL's anti-inflammatory function, cholesterol levels, myeloperoxidase (MPO) and paraoxonase 1 (PON1) activities were determined as previously. 5-HETE, 15-HETE, 9-HODE, and 13-HODE levels were significantly increased in HDL and LDL from patients with active RA (n=10) compared to healthy controls (n=8) and correlated significantly with measures of systemic inflammation, particularly in HDL (r=0.65-0.80, p values

Background:Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme with paraoxonase, lactonase and arylesterase activities.1 PON1 contributes to the antioxidant properties of HDL, and is being investigated for its atheroprotective properties.1 Patients (pts) with rheumatoid arthritis (RA) who are homozygous for the RR genotype of the Q192R gene polymorphism on PON1 (rs662) have increased paraoxonase activity, and lower risk of carotid plaques, vs those with QQ or QR genotypes.2 Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA.Objectives:To investigate the relationship between PON1 genotype/activity and risk of major adverse cardiovascular events (MACE) in the tofacitinib RA clinical programme.Methods:In this post hoc analysis, data were pooled from pts enrolled in nine Phase 2/3 studies of tofacitinib in RA. Enzyme activities in pt plasma samples were measured at individual study baseline (BL) and at follow-up visits using three substrates: paraoxon (paraoxonase activity), dihydrocoumarin (lactonase activity) and phenylacetate (arylesterase activity). The effect of the PON1 Q192R genotype (QQ, QR or RR) on BL paraoxonase/lactonase/arylesterase activity was assessed using linear regression for each study, with age and sex as covariates, and then fixed-effect meta-analysis assessed effects across studies. The risk of MACE by enzyme activity was determined using Cox proportional hazards regression stratified by clinical studies. Univariate regression against BL enzyme activity and other risk factors, as well as both minimally and fully adjusted multivariable regressions against time-varying enzyme activity, are presented.Results:The analysis included 1969 pts with RA who received ≥1 dose of tofacitinib and had PON1 activity measures available at BL; 39 pts had ≥1 MACE event. Compared with the QQ genotype, the RR genotype had a highly significant positive association with BL paraoxonase activity, and a highly significant negative association with BL lactonase and arylesterase activity (Table 1). A univariate analysis identified several BL covariates significantly associated with risk of MACE (Figure 1a). Time-varying models found a highly significant association of increased paraoxonase activity over time with lower risk of future MACE, even after controlling for low-density lipoprotein or HDL cholesterol levels, and other traditional cardiovascular (CV) risk factors identified in univariate analysis (Figure 1b), with similar findings for lactonase and arylesterase (data not shown).Table 1.Effect of PON1 genotype (RR vs QQ) on BL enzyme activitynEstimate95% CIp valueCochran’s Q testParaoxonase12291.0350.93, 1.1410.209Lactonase1188-0.375-0.505, -0.2460.025Arylesterase1231-1.016-1.382, -0.6490.251Fixed-effects model; estimate >0 favours RR genotype and BL, baseline; CI, confidence intervalConclusion:Higher activity of the HDL-associated protein PON1 over time was associated with a significantly reduced risk of future MACE in pts with RA receiving tofacitinib, after controlling for traditional CV risk factors and cholesterol levels. Further investigation of PON1 as a novel functional lipid biomarker to assess CV risk in pts with RA is warranted.References:[1]Mackness & Mackness. Gene 2015; 567: 12-21.[2]Charles-Schoeman et al. Arthritis Rheum 2013; 65: 2765-2772.Acknowledgements:Study sponsored by Pfizer Inc. Medical writing support was provided by Jennifer Higginson, CMC Connect, and funded by Pfizer Inc.Disclosure of Interests:Christina Charles-Schoeman Consultant of: AbbVie, Gilead, Pfizer Inc, Regeneron-Sanofi, Grant/research support from: AbbVie, Bristol-Myers Squibb, Pfizer Inc, Craig Hyde Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Shunjie Guan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Neil Parikh: None declared, Jennifer Wang: None declared, Ani Shahbazian: None declared, Lori Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Andrews Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Objectives Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We report an integrated safety summary of tofacitinib from two phase I, nine phase II, six phase III and two long-term extension studies in adult patients with active RA. Methods Data were pooled for all tofacitinib-treated patients (data cut-off: 31 March 2015). Incidence rates (IRs; patients with event/100 patient-years) and 95% CIs are reported for adverse events (AEs) of interest. Results 6194 patients received tofacitinib for a total 19 406 patient-years' exposure; median exposure was 3.4 patient-years. IR (95% CI) for serious AEs was 9.4 (9.0 to 9.9); IR for serious infections was 2.7 (2.5 to 3.0). IR for (all) herpes zoster was 3.9 (3.6 to 4.2); IR for disseminated or multidermatomal herpes zoster was 0.3 (0.2 to 0.4). IR for opportunistic infections (excluding tuberculosis) was 0.3 (0.2 to 0.4) and was 0.2 (0.1 to 0.3) for tuberculosis. IR for malignancies (excluding non-melanoma skin cancer (NMSC)) was 0.9 (0.8 to 1.0); NMSC IR was 0.6 (0.5 to 0.7). IR for gastrointestinal perforations was 0.1 (0.1 to 0.2). Analysis of IR for serious infections, herpes zoster and malignancies by 6-month intervals did not reveal any notable increase in IR with longer-duration tofacitinib exposure. Conclusion This analysis of tofacitinib exposure up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. AEs were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports. Trial registration numbers NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT00413699, NCT00661661; Results.

Objective Abnormal function of high-density lipoprotein (HDL) has been implicated as a potential mechanism for the increased incidence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). This study was undertaken to evaluate changes in HDL function and HDL-associated proteins over 2 years of follow-up in patients with early RA receiving either methotrexate (MTX) monotherapy, MTX + etanercept (ETN) combination therapy, or MTX + sulfasalazine (SSZ) + hydroxychloroquine (HCQ) triple therapy in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial. Methods The antioxidant capacity of HDL, paraoxonase 1 (PON-1) activity, and levels of HDL-associated haptoglobin (Hp), HDL-associated apolipoprotein A-I (Apo A-I), and myeloperoxidase (MPO) were measured in 550 TEAR participants at 4 time points (time 0 [pretreatment] and at 24, 48, and 102 weeks of treatment). Repeated-measures analysis using mixed-effects linear models with an autoregressive covariate structure was performed to model the within-subject covariance over time. Results Mixed-effects models, which were controlled for traditional CV risk factors, treatment regimen, prednisone use, and statin use, demonstrated significant associations between RA disease activity, measured using the Disease Activity Score in 28 joints, erythrocyte sedimentation rate, or C-reactive protein level, and the profile of HDL function over time. Specifically, decreases in RA disease activity over time were associated with increases in PON-1 activity and levels of HDL-associated Apo A-I, and decreases in the HDL inflammatory index and levels of MPO and HDL-associated Hp. Conclusion Reduced disease activity in patients with early RA treated with MTX monotherapy, MTX + ETN combination therapy, or MTX + SSZ + HCQ triple therapy in the TEAR trial was associated with improvements in the HDL function profile. Additional studies are warranted to evaluate abnormal HDL function as a potential mechanism and therapeutic target for CV risk in patients with RA.

Background Rheumatoid arthritis (RA) is a systemic inflammatory condition associated with increased rates of atherosclerotic morbidity and mortality. One mechanism by which inflammation may increase atherosclerotic progression is via pathogenic remodeling of high-density lipoprotein (HDL)-associated proteins with resultant reduction in HDL function.1 Upadacitinib (UPA), a selective JAK1 inhibitor, has demonstrated efficacy in patients with moderate-to-severe RA. Objectives To assess the effect of UPA treatment on cholesterol efflux capacity (CEC) and evaluate the association of CEC with changes in inflammation and serum lipids. Methods A subset of patients from the Phase 2 BALANCE II study2 and the Phase 3 SELECT-NEXT study3 were selected from the pool of patients with serum samples available at baseline and Week 12. Patients were matched for age and sex, and selected based on level of response to UPA therapy (BALANCE II, UPA 6 mg BID: 39 responders [mean change in DAS28-CRP at Week 12 -3.22] and 30 non-responders [mean change in DAS28-CRP -0.33]; SELECT-NEXT, UPA 15 mg QD: 20 responders [mean change in DAS28-CRP -3.78] and 20 non-responders [mean change in DAS28-CRP -0.67]). A demographically similar placebo (PBO) group without selection based on degree of response was also included (20 patients from each study). J774 macrophages labeled with [3H]-cholesterol (treated with cAMP to express ABCA1 or left untreated) were exposed to patient sera. The difference between cholesterol efflux from serum-exposed and unexposed cells provided a measurement of CEC. Results were compared between the responder, non-responder, and PBO groups using Tukey’s mean comparison method; correlations were calculated using the Pearson method; and all statistical analyses were performed in JMP 13.10 (SAS Institute). Results In both studies, changes in global and ABCA1-dependent CEC, and to a lesser extent non-ABCA1-dependent CEC, were significantly higher in the UPA-treated group compared with the PBO group (Figure). In the BALANCE II study, there was a significant increase in CEC among UPA responders relative to PBO and a numerically apparent difference observed between UPA non-responders and PBO. Notably, in the SELECT-NEXT study, a similar and highly significant improvement in CEC was observed for both UPA-treated groups relative to PBO (without a significant difference between the responder and non-responder groups). Despite the lack of a consistent association between change in CEC and change in clinical disease activity, observed increases in CEC correlated significantly with reductions in CRP levels in all groups across all active treatment groups. Additionally, increases in CEC at Week 12 correlated well with changes in total blood cholesterol and HDL levels, but weakly with changes in blood low-density lipoprotein (LDL) levels. Conclusion UPA treatment is associated with significant improvement in CEC. This effect was observed even among those demonstrating minimal clinical response (but not in those treated with PBO). The effect seems to be primarily driven by ABCA1-dependent cholesterol efflux and is strongly correlated with a rise in HDL cholesterol as well as reduction in systemic inflammation as measured by change in CRP. References [1] Charles-Schoeman C, et al. Arthritis Rheumatol2017;69:46–57; [2] Genovese MC, et al. Arthritis Rheumatol2016;68:2857–66; [3] Burmester GR, et al. Lancet2018;391:2503–12 Acknowledgement AbbVie, Inc was the study sponsor, contributed to the study design, data collection, analysis & interpretation, and to writing, reviewing, and approval of the final version. Medical writing support was provided by John Ewbank, PhD, of 2 the Nth. Disclosure of Interests Christina Charles-Schoeman Grant/research support from: Bristol-Myers Squibb, AbbVie, and Pfizer, Consultant for: Regeneron-Sanofi, Pfizer, and Gilead, Thierry Sornasse Shareholder of: AbbVie, Employee of: AbbVie, Jeremy Sokolove Shareholder of: AbbVie, Employee of: AbbVie

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 risk of cardiovascular disease (CVD) is higher in patients with psoriatic arthritis (PsA) compared to the general population. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Because tofacitinib increases circulating lipid levels in some patients, we evaluated CVD risk factors and major adverse cardiovascular events (MACE) in patients with active PsA receiving tofacitinib 5 or 10 mg twice daily plus conventional synthetic disease‐modifying antirheumatic drugs. Methods: Data were pooled from 2 phase III studies (Efficacy and Safety of Tofacitinib in Psoriatic Arthritis [OPAL Broaden] and Tofacitinib in Patients with Psoriatic Arthritis With Inadequate Response to TNF Inhibitors [OPAL Beyond]) and 1 ongoing long‐term extension (Open‐Label Extension Study of Tofacitinib in Psoriatic Arthritis [OPAL Balance], data cutoff January 2017; database not locked). Outcomes included fasting lipid levels, blood pressure, hypertension‐related adverse events (AEs; including hypertension, high blood pressure, and increased blood pressure), and MACE. Results: Overall, 783 tofacitinib‐treated patients were included. Percentage increases from baseline in low‐density lipoprotein cholesterol (LDL‐c) and high‐density lipoprotein cholesterol (HDL‐c) levels ranged from 9% to 14% for tofacitinib 5 mg and 10 mg at 3 and 6 months; no meaningful changes in LDL‐c:HDL‐c or total cholesterol:HDL‐c ratios were observed. Blood pressure remained stable for 24 months. Fifty‐eight patients (7.4%) had hypertension‐related AEs; none were fatal (incidence rate [IR] per 100 patient‐years 4.81 [95% confidence interval (95% CI) 3.65–6.22]). Five patients (0.6%) had MACE (IR 0.24 [95% CI 0.05–0.70]); 2 were fatal. Conclusion: Serum lipid level increases at month 3 following tofacitinib treatment in PsA were consistent with observations in rheumatoid arthritis and psoriasis. The IR of hypertension‐related AEs and MACE was low; long‐term follow‐up is ongoing.

Cardiovascular (CV) morbidity and mortality are increased in patients with active, untreated rheumatoid arthritis (RA), despite lower levels of total and low-density lipoprotein cholesterol reported in individuals with active RA compared with those without RA. Alterations in non-traditional lipid assessments, such as high-density lipoprotein (HDL) function and HDL-associated proteins, have been described in patients with active RA, including elevated HDL-associated serum amyloid A and decreased paraoxonase-1 activity. We review changes in both traditional lipoprotein concentrations and non-traditional lipoprotein assessments in multiple studies of treatment with disease-modifying antirheumatic drugs (DMARDs), including non-biologic and biologic DMARDs and tofacitinib. In addition, data from a recently published clinical trial with tofacitinib that describe a potential mechanism for suppression of cholesterol levels in active RA patients are reviewed. Finally, CV event data from various studies of DMARDs are presented, and the current management of RA patients with regard to the CV risk is reviewed.

Patients with rheumatoid arthritis (RA) suffer significantly increased cardiovascular (CV) morbidity and mortality when compared to the general population (1–3). Both traditional CV risk factors such as dyslipidemia as well as RA disease activity contribute to this increased CV risk (4;5). High levels of systemic inflammation have been associated with the suppression of circulating cholesterol levels in disease states such as endotoxemia as well as RA (6). Previous studies have suggested that cholesterol levels may increase after RA treatment; however, a wide range of cholesterol changes has been reported by different studies with different drug treatments, study designs, durations, and patient populations (7–10). Few studies have been able to analyze long-term follow up of a large group of early RA patients randomized to biologic and non-biologic disease modifying therapies. It remains unclear whether serum cholesterol increases over time are related solely to specific drug mechanisms, suppression of inflammation, or a combination of these and other patient factors. The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial enrolled 755 patients with very early, active RA in which 90% of patients had disease duration less than one year and 75% of patients had received no disease modifying anti-rheumatic drug (DMARD) therapy prior to study entry. These patients were randomized to methotrexate (MTX) monotherapy versus MTX combination therapy with etanercept (MTX+ETA) or triple therapy (TT) including MTX, sulfasalazine (SSZ), and hydroxychloroquine (HCQ) and followed for two years (11). We previously reported that marked increases in total, low-density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol occurred after 6 months of treatment in the TEAR trial (12). We now describe the cholesterol changes over two years of follow-up with specific evaluation of relationships to disease activity, systemic inflammation, and the treatments received.

Background and aimsTo evaluate changes in the high-density lipoprotein (HDL) proteome and HDL function in active rheumatoid arthritis (RA) patients initiating therapy with abatacept or adalimumab in the Abatacept Versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) study.MethodsUltra high-pressure liquid chromatography (UHPLC) coupled with ion mobility mass spectrometry (LC-IM-MS) was used to analyze proteins associated with immunoaffinity-captured HDL from plasma of 30 patients with RA randomized to either abatacept (n = 15) or adalimumab (n = 15) therapy. Paraoxonase 1 (PON1) activity, HDL anti-oxidant capacity, cholesterol profiles, and homocysteine levels were also measured at baseline and following treatment. Repeated-measures analyses were performed using mixed-effect linear models to model the within-subject covariance over time.ResultsIn models controlling for age, sex and treatment group, improvement in inflammation measured by decreases in CRP was associated with improvement in HDL function and changes in several HDL-associated proteins including significant decreases in lipopolysaccharide-binding protein, serum amyloid A-I (SAA-I) and inter-alpha-trypsin inhibitor heavy chain H4 (p values

Background Cardiovascular (CV) disease and cardiometabolic syndrome are common comorbidities/causes of mortality in patients (pts) with psoriatic arthritis (PsA). Tofacitinib is an oral JAK inhibitor for the treatment of PsA. Objectives To investigate changes in lipid levels and incidence of CV events in pts with PsA treated with tofacitinib in Phase (P) 3 and long-term extension (LTE) studies. Methods Data were analysed for pts who received ≥1 dose of tofacitinib 5 or 10 mg BID or placebo (PBO), integrated across 2 P3 studies (OPAL Broaden [12 months (m); NCT01877668, including adalimumab control]; OPAL Beyond [6 m; NCT01882439]) and 1 LTE study (OPAL Balance [data cut-off May 2016; ongoing, database not locked; NCT01976364]). Lipid levels were assessed throughout P3 and LTE studies; this analysis included data from the PBO-controlled period (M0–3) of P3 studies. Blood pressure, hypertension events (standardised MedDRA query [narrow]) and adjudicated (independent/blinded to treatment) major adverse cardiovascular events (MACE) are reported for all pts who received ≥1 dose of tofacitinib (pooled across doses for hypertension and MACE). Incidence rates (IR; pts with events/100 pt-years [PY]) and 95% CI are reported. Results Overall, 783 pts (776 PY of tofacitinib exposure) were included in P3 and LTE studies; treatment duration was 1–927 days. After 3 m of tofacitinib treatment in P3 studies, dose-dependent increases in lipid levels were observed with tofacitinib; minimal changes were observed with PBO, except for triglycerides (figure 1). Concurrent increases in high-density and low-density lipoprotein (HDL/LDL) and no change in the total cholesterol/HDL ratio were shown. Across P3 and LTE studies, no clinically significant changes in mean systolic or diastolic blood pressure were seen to 24 m. Hypertension events were reported in 38 (4.9%) pts: IR 4.93 [95% CI 3.49, 6.77]. Of these events, 4 led to pt discontinuation and 2 were serious adverse events. MACE were reported for 3 (0.4%) pts receiving tofacitinib (IR 0.38 [95% CI 0.08, 1.11]) and included sudden cardiac death (57 days of exposure at time of event), myocardial infarction (197 days) and ischaemic stroke (80 days). This is within the range reported in tofacitinib studies in pts with psoriasis (IR 0.24 [0.15, 0.37]; 8,759 PY of exposure) and rheumatoid arthritis (RA) (IR 0.38 [0.30, 0.47]; 21,286 PY of exposure). No dose-dependent effects on blood pressure were apparent. Conclusions In pts with PsA, the magnitude and dose dependency of increases in lipid levels to M3 were consistent with findings in tofacitinib studies in pts with psoriasis and RA. In P3 and LTE studies, no clinically significant changes were seen in blood pressure or incidence of hypertension. Incidence of MACE was within the range reported in prior tofacitinib studies in psoriasis and RA; however, the long latency of MACE requires longer-term observation. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by A MacLachlan of CMC and funded by Pfizer Inc. Disclosure of Interest D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, C. Charles-Schoeman Grant/research support from: AbbVie, Bristol-Myers Squibb, Pfizer Inc, Consultant for: Amgen, Gilead, Pfizer Inc, Regeneron-Sanofi, I. McInnes Grant/research support from: Celgene, Janssen, Novartis, Pfizer Inc, Roche, UCB, Consultant for: AbbVie, Celgene, Janssen, Novartis, Pfizer Inc, Roche, UCB, D. Veale Grant/research support from: AbbVie, Actelion, Bristol-Myers Squibb, Janssen, MSD, Novartis, Pfizer Inc, Roche, UCB, Speakers bureau: AbbVie, Actelion, Bristol-Myers Squibb, Janssen, MSD, Novartis, Pfizer Inc, Roche, UCB, B. Thiers Consultant for: Pfizer Inc, Valeant Pharmaceuticals, D. Graham Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Jones Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Wolk Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background: Tofacitinib is an oral Janus kinase (JAK) inhibitor that preferentially inhibits signalling by JAK3 and JAK1, with functional selectivity over JAK2. Potential increased risk of venous thromboembolic events (VTE) in patients (pts) with rheumatoid arthritis (RA) has been reported for a JAK 1/2 inhibitor.1 Objectives: To assess VTE risk with tofacitinib in pts with RA, psoriasis (PsO), psoriatic arthritis (PsA) and ulcerative colitis (UC). Methods: Data from Phase (P)2 (RA, PsO, UC) and P3 (RA, PsO, PsA, UC) randomised clinical studies of tofacitinib as monotherapy or in combination with conventional synthetic (cs)DMARDs were reviewed. Two cohorts were defined; 1) the placebo (PBO)-controlled cohort: pts randomised to tofacitinib 5 or 10 mg BID, or PBO up to Month (M)3 in RA, PsO and PsA studies, and pts randomised to tofacitinib 10 mg BID or PBO for the 9-week induction period in UC studies; 2) the dose-comparison cohort: pts randomised to tofacitinib 5 or 10 mg BID, adalimumab (ADA) 40 mg SC Q2W (RA and PsA only) or methotrexate (MTX) 20 mg QW (RA only) throughout the P2/3 studies for RA (up to M24), PsO (up to M12) and PsA (up to M12), and for the 12-month P3 UC maintenance study. First deep vein thrombosis (DVT) and pulmonary embolism (PE) events were identified using the MedDRA embolic and thrombotic SMQ preferred terms restricted to the respiratory, thoracic, mediastinal and vascular disorder System Organ Classes; incidence rates (IRs; pts with events/100 pt-years) were based on single events occurring during treatment or ≤28 days after the last dose or up to the cohort cut-off date. IRs for PE in RA pts were compared with Corrona Registry data (May 2017 cut-off). Results: Up to M3 in the PBO-controlled cohort, DVT and PE each occurred in 2 pts receiving PBO (1 RA pt and 1 UC pt per event); no tofacitinib-treated pts had DVT or PE events (Table). In the dose-comparison cohort 2 DVT events occurred in tofacitinib-treated pts with RA (5 mg BID, n=1; 10 mg BID, n=1) and 1 DVT event in a pt with PsA (tofacitinib 10 mg BID) (Table). IRs (95% CI) were 0.1 (0.0, 0.3) for both tofacitinib doses in RA and 0.5 (0.0, 2.8) for tofacitinib 10 mg BID in PsA. Two DVT events occurred with MTX; none with ADA. Five PE events occurred in the dose comparison cohort, all in RA (5 mg BID, n=2; 10 mg BID, n=3). IRs were 0.1 (0.0, 0.4) for tofacitinib 5 mg BID and 0.2 (0.0, 0.4) for 10 mg BID. IRs for PE with tofacitinib in RA were similar to those reported by the Corrona Registry in RA pts treated with tofacitinib (0.1 [0.0, 0.4]), biologic DMARDs (0.2 [0.1, 0.3]) and csDMARDs (0.2 [0.0, 0.5]). Conclusions: Analysis of DVT and PE across randomised clinical studies for RA, PsO, PsA and UC showed no evidence of an increased risk of these events with tofacitinib vs other therapies. Reference [1]Weinblatt M, et al. Arthritis Rheumatol2017;69(suppl 10):2352. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by A MacLachlan of CMC and funded by Pfizer Inc. Disclosure of Interest: P. Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, Sun, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, Sun, UCB, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Novartis, Pfizer Inc, UCB, J. Kremer Shareholder of: Corrona LLC, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Genentech, Novartis, Pfizer Inc, Regeneron, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Genentech, Novartis, Pfizer Inc, Regeneron, Employee of: Corrona LLC, S. Cohen Grant/research support from: Pfizer Inc, Consultant for: AbbVie, Amgen, Boehringer Ingelheim, Gilead, Merck, Pfizer Inc, J. Curtis Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona LLC, Crescendo Bio, Eli Lilly, Janssen, Myriad, Pfizer Inc, Roche, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Corrona LLC, Crescendo Bio, Eli Lilly, Janssen, Myriad, Pfizer Inc, Roche, UCB, C. Charles-Schoeman Grant/research support from: AbbVie, Bristol-Myers Squibb, Pfizer Inc, Consultant for: Amgen, Gilead, Pfizer Inc, Regeneron-Sanofi, E. Loftus Jr Grant/research support from: AbbVie, Allergan, Amgen, Celgene, Celltrion, CVS Caremark, Eli Lilly, Genentech, Gilead, Janssen, MedImmune, Mesoblast, Napo Pharmaceuticals, Pfizer Inc, Receptos, Robarts Clinical Trials, Salix, Seres Therapeutics, Takeda, UCB, Consultant for: AbbVie, Allergan, Amgen, Celgene, Celltrion, CVS Caremark, Eli Lilly, Genentech, Gilead, Janssen, MedImmune, Mesoblast, Napo Pharmaceuticals, Pfizer Inc, Receptos, Robarts Clinical Trials, Salix, Seres Therapeutics, Takeda, UCB, J. Greenberg Consultant for: Eli Lilly, Genentech, Janssen, Novartis, Pfizer Inc, Employee of: Corrona LLC, N. Palmetto Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Graham Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, P. Biswas Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, G. Chan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Valdez Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Hendrikx Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Jones Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

To describe the use of oral cyclophosphamide (PO CYC) in a single center longitudinal cohort of patients with idiopathic inflammatory myopathies (IIM). Patients using PO CYC were identified through a retrospective chart review of a myositis cohort at a single academic center. PO CYC dose, duration, adverse events, and disease activity measures before and after CYC were analyzed. Disease activity measures included muscle enzymes, manual muscle testing (MMT8), 100-mm visual analog scale (VAS), and 1-4 Likert scale for physician global assessment. Fourteen patients were treated with PO CYC within the cohort between 2008 and 2017; 9 dermatomyositis (DM), 3 polymyositis (PM), and 2 with immune-mediated necrotizing myopathy (IMNM). Age was 51.1 (40-72) years and the cumulative dose of PO CYC was 41 (2-131) grams over duration of 12.4 (0.5-43) months, mean (range) for all. All patients had severe refractory IIM, 10 (72%) with ILD, 3 (21%) with cardiac involvement and 4 (29%) were dependent in most activities of daily living. Median number of prior failed therapies was 4.5 (range 3-6) including intravenous CYC in 5 patients. Disease activity measures significantly improved following CYC use and concomitant daily prednisone dose decreased. The most common adverse events during CYC therapy were infections. We report the first cohort study of PO CYC use in IIM patients with severe, treatment refractory disease. Further trials are needed to verify these results as well as to evaluate long-term safety outcomes.

Objective: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). This study was undertaken to evaluate the risk of major adverse cardiovascular events (MACE) in patients with RA receiving tofacitinib. Methods: Data were pooled from patients with moderately to severely active RA receiving ≥1 tofacitinib dose in 6 phase III and 2 long‐term extension studies over 7 years. MACE (myocardial infarction, stroke, cardiovascular death) were independently adjudicated. Cox regression models were used to evaluate associations between baseline variables and time to first MACE. Following 24 weeks of tofacitinib, changes in variables and time to future MACE were evaluated after adjusment for age, baseline values, and time‐varying tofacitinib dose. Hazard ratios and 95% confidence intervals were calculated. Results: Fifty‐two MACE occurred in 4,076 patients over 12,873 patient‐years of exposure (incidence rate 0.4 patients with events per 100 patient‐years). In univariable analyses of baseline variables, traditional cardiovascular risk factors and glucocorticoid and statin use were associated with MACE risk; disease activity and inflammation measures were not. In subsequent multivariable analyses, baseline age, hypertension, and the total cholesterol to high‐density lipoprotein (HDL) cholesterol ratio remained significantly associated with risk of MACE. After 24 weeks of treatment, an increase in HDL cholesterol and a decrease in the total to HDL cholesterol were associated with decreased MACE risk; changes in total cholesterol, low‐density lipoprotein (LDL) cholesterol, and disease activity measures were not. Increased erythrocyte sedimentation rates trended with increased future MACE risk. Conclusion: In this post hoc analysis, after 24 weeks of tofacitinib treatment, increased HDL cholesterol, but not increased LDL cholesterol or total cholesterol, appeared to be associated with lower future MACE risk. Further data are needed to test the cardiovascular safety of tofacitinib.

Objectives Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR). Methods Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed. Results 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs). Conclusions Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations. Trial registration numbers (NCT00413660, NCT0050446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385).

Objective Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Systemic inflammation is proposed to play a fundamental role in the altered lipid metabolism associated with RA; however, the underlying mechanisms are unknown. We undertook this study to compare cholesterol and lipoprotein kinetics in patients with active RA with those in matched healthy volunteers. Methods This was a phase I open-label mechanism-of-action study. Cholesterol and lipoprotein kinetics were assessed with 13C-cholesterol and 13C-leucine infusions. RA patients were reevaluated after receiving oral tofacitinib 10 mg twice daily for 6 weeks. Results Levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and apolipoprotein A-I (Apo A-I) as well as HDL cholesterol particle number were lower in RA patients (n = 36) than in healthy volunteers (n = 33). In contrast, the cholesterol ester fractional catabolic rate was higher in RA patients, but no differences were observed in cholesterol ester transfer protein, cholesterol ester production rate, HDL-associated Apo A-I fractional catabolic rate, or LDL-associated Apo B fractional catabolic rate. Following tofacitinib treatment in RA patients, the cholesterol ester fractional catabolic rate decreased and cholesterol levels increased. The decrease in cholesterol ester fractional catabolic rate correlated significantly with the increase in HDL cholesterol. Additionally, HDL cholesterol particle number increased and markers of HDL cholesterol function improved. Conclusion This is the first study to assess cholesterol and lipoprotein kinetics in patients with active RA and matched healthy volunteers. The data suggest that low cholesterol levels in patients with active RA may be driven by increases in cholesterol ester catabolism. Tofacitinib treatment reduced cholesterol ester catabolism, thereby increasing cholesterol levels toward those in healthy volunteers, and markers of antiatherogenic HDL function improved.