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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.

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.

Background and objectives: Cardiac involvement has been well recognized in patients with dermatomyositis (DM) and polymyositis (PM) with a variable frequency between 9 and 72%. However, clinically significant heart involvement in DM/PM is relatively infrequent and there have been rare reports of cardiac transplantation in DM. Our aims were to describe a case of severe cardiac involvement in DM requiring heart transplantation and review the literature of cardiac disease in DM and PM. Methods: A patient with dermatomyositis who was referred to our institution with severe heart failure is described. Pathology of the patient's skeletal and cardiac muscle is reviewed. A MEDLINE database search of reports of cardiac involvement in DM and PM was also conducted. Results: A 36 year-old man with DM presented with severe heart failure to our institution for evaluation of heart transplantation. After a three month hospitalization he underwent successful cardiac transplantation. Pathological examination of his explant heart revealed a pattern of inflammation and damage similar to DM in skeletal muscle. The patient is currently doing well, 20 months post-transplant, and is maintained on tacrolimus, cellcept, rituximab, and low dose prednisone. To our knowledge, this is the first case report of heart transplantation in dermatomyositis in which the muscle pathology is similar in both heart and skeletal muscle. Conclusions: Severe cardiac involvement requiring transplantation is rare in dermatomyositis but does occur and appears to be related to a similar inflammatory process as noted in the skeletal muscle. Keywords: Dermatomyositis, Inflammatory myopathy, Cardiomyopathy, Cardiac transplantation, Orthotopic heart transplant

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

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.

Background Patients (pts) with RA have increased risk of myocardial infarction (MI) and stroke that cannot be completely explained by traditional cardiovascular (CV) risk factors. Tofacitinib is an oral JAK inhibitor for the treatment of RA. Treatment with tofacitinib may increase total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c) and high-density lipoprotein-cholesterol (HDL-c), without affecting TC/HDL-c ratio. Objectives To evaluate major adverse CV event (MACE) risk factors in tofacitinib-treated pts with RA in the clinical development programme. Methods Data were pooled from pts with moderately to severely active RA receiving ≥1 tofacitinib dose in 6 Phase 3 and 2 long-term extension (LTE) studies (1 LTE study ongoing, data cut-off: April 2015). MACE was any MI, stroke or CV death (coronary, cerebrovascular, cardiac). Cox regression models evaluated associations between baseline (BL) values and time (BL to first tofacitinib dose) to first MACE. Changes (BL to Week [wk] 24) in MACE predictors and time to future MACE (first occurrence after 24 wks) were evaluated after adjusting for age, BL values and time-varying tofacitinib dose. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Results 52 MACE cases occurred over 12,873 pt-years (py) of exposure in 4076 pts (incidence rate: 0.4 pts with events/100 py). At BL, compared with pts without MACE, pts with MACE were older (mean age 60.2 vs 52.7 years) with a higher mean BMI (29.2 vs 27.0 kg/m2) and longer mean RA disease duration (10.1 vs 7.7 years), and were more likely to have a history of diabetes (15.4% vs 7.6%) and hypertension (57.7% vs 33.7%). Pts with MACE had higher mean TC (208.2 vs 198.3 mg/dL), LDL-c (123.3 vs 114.0 mg/dL), TC/HDL-c ratio (4.0 vs 3.5) and triglycerides (152.1 vs 125.3 mg/dL) at BL, and lower HDL-c (55.3 vs 59.4 mg/dL) vs pts without MACE. In univariate analyses, traditional CV risk factors and corticosteroid and statin use at BL were associated with MACE risk (Table). BL disease activity and inflammation measures were not associated with MACE risk (Table). In multivariate analysis, BL age, hypertension and the TC/HDL-c ratio were significantly associated with MACE risk. Increases in HDL-c (p Conclusions In pooled analyses of tofacitinib-treated pts (age and BL value adjusted), increases in LDL-c and TC after 24 wks of tofacitinib therapy were not associated with future MACE risk. Increases in HDL-c and decreases in the TC/HDL-c ratio after 24 wks of tofacitinib therapy were associated with reduced future MACE risk. Increases in ESR after 24 wks may be associated with increased future MACE risk. More data are needed to confirm these findings. Acknowledgements Previously presented at ACR 2016 and reproduced with permission. This study was sponsored by Pfizer Inc. Editorial support was provided by C Viegelmann of CMC and was funded by Pfizer Inc. Disclosure of Interest C. Charles-Schoeman Grant/research support from: AbbVie, Bristol-Myers Squibb, Pfizer Inc, Consultant for: Amgen, Pfizer Inc, Regeneron-Sanofi, H. Valdez Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Hwang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Boy Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, I. McInnes Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Pfizer Inc, Roche

Background Tofacitinib is an oral JAK inhibitor for the treatment (tx) of rheumatoid arthritis (RA). Studies have shown diminishing response to tx in RA patients (pts) when cycling through TNF inhibitors. Prior analyses assessed tofacitinib in csDMARD-inadequate response (IR) pts vs overall bDMARD-IR pts. Objectives To compare tofacitinib safety and efficacy in RA pts who have previously failed tx (lack of efficacy and/or safety reasons) with csDMARDs, with pts who failed tx with either 1 or ≥2 prior bDMARDs. Methods Data from pts who received ≥1 dose of tofacitinib in 19 RA studies up to 96 months (2 Phase [P] 1; 9 P2; 6 P3; 2 LTE studies [1 LTE ongoing; data as of March 2015]) were used in this analysis. Data were pooled across all 19 studies for safety assessments in the All RA population: csDMARD-IR, n=4377; bDMARD-IR, n=838 (1 bDMARD-IR, n=533; ≥2 bDMARD-IR n=305). Safety was also assessed up to 24 months in pts randomised to tofacitinib 5 or 10 mg BID or placebo (PBO) in a pooled P2/P3 randomised controlled trial (RCT) population (8 P2, 6 P3 studies; csDMARD-IR, n=3328; bDMARD-IR, n=782). Incidence rates (pts with events/100 pt-years) were calculated for serious AEs (SAEs), serious infections (SIs) and herpes zoster (HZ). Efficacy was assessed by pts achieving ACR20 response and DAS28-4(ESR) ≤3.2 at Month 3 in a pooled P3 RCT population (csDMARD-IR, n=2375; bDMARD-IR, n=664). Results Prior to tofacitinib tx, bDMARD-IR pts had longer RA duration, greater disease burden and more corticosteroid use vs csDMARD-IR pts. SAEs were more common among bDMARD-IR vs csDMARD-IR pts in both the P2/P3 RCT and the All RA populations; SAE rates were not higher in pts failing ≥2 bDMARDs vs 1 bDMARD (Table). Incidence rates for SIs were generally greater in pts with IR to bDMARDs vs csDMARDs in the All RA population, but generally lower in pts with IR to 1 or ≥2 bDMARDs vs csDMARDs in the P2/P3 RCT population; incidence with 5 mg BID was lower for 1 vs ≥2 bDMARDs in the P2/P3 RCT population. Incidence rates for HZ were similar between pts with IR to csDMARDs or 1 bDMARD, but appeared numerically greater in pts with IR to ≥2 bDMARDs in both the P2/P3 RCT and the All RA populations. A similar pattern was observed across tofacitinib and PBO groups. Efficacy at Month 3 in the P3 RCT population was greater with both tofacitinib doses vs PBO. Although absolute response was smaller in pts with IR to bDMARDs vs csDMARDs, generally similar efficacy was observed in pts with IR to 1 or ≥2 bDMARDs (Table). Conclusions SAEs and SIEs were more common in tofacitinib- and PBO-treated pts with IR to bDMARDs vs csDMARDs; increased risk was generally not observed with increasing number of prior bDMARDs. HZ risk appeared greater with ≥2 bDMARDs vs 1 bDMARD. Efficacy was greater with tofacitinib vs PBO for csDMARD-IR and bDMARD-IR pts, with similar response observed in pts with IR to ≥2 or 1 bDMARD. These data support the use of tofacitinib in different lines of therapy, although the analysis is limited by smaller sample size in some groups. Acknowledgements This study was sponsored by Pfizer Inc. Editorial support was provided by N Jones of CMC and was funded by Pfizer Inc. Disclosure of Interest C. Charles-Schoeman Grant/research support from: AbbVie, Bristol-Myers Squibb, Pfizer Inc, Consultant for: Amgen, Pfizer Inc, Regeneron-Sanofi, J. Kremer Shareholder of: Corrona, LLC, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Eli Lilly, Pfizer Inc, Employee of: Corrona, LLC, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Geier Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Zhang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Strengholt Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, G. Burmester Grant/research support from: UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Hexal, Janssen, Medimmune, MSD, Novartis, Pfizer Inc, Roche, Sanofi, Speakers bureau: AbbVie, Bristol-Myers Squibb, Hexal, MSD, Novartis, Pfizer Inc, Roche

Objective An increased frequency of atherosclerosis (ATH) in systemic lupus erythematosus (SLE) is well-documented but not fully explained by the presence of traditional cardiac risk factors. Several nontraditional biomarkers, including proinflammatory high-density lipoprotein (piHDL) and leptin, have been individually associated with subclinical ATH in SLE. The aim of this study was to examine whether these and other biomarkers can be combined into a risk profile, the Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular Disease in Patients with SLE (PREDICTS), that could be used to better predict future progression of ATH. Methods In total, 210 patients with SLE and 100 age-matched healthy control subjects (all women) participated in this prospective cohort study. The longitudinal presence of carotid plaque and intima-media thickness (IMT) were measured at baseline and followup (mean ± SD 29.6 ± 9.7 months). Results At followup, carotid plaque was present in 29% of SLE patients. Factors significantly associated with plaque, determined using Salford Predictive Modeling and multivariate analysis, included age ≥48 years (odds ratio [OR] 4.1, P = 0.002), high piHDL function (OR 9.1, P < 0.001), leptin levels ≥34 ng/dl (OR 7.3, P = 0.001), plasma soluble TWEAK levels ≥373 pg/ml (OR 28.8, P = 0.004), and history of diabetes (OR 61.8, P < 0.001). Homocysteine levels ≥12 μmoles/liter were also a predictor. However, no single variable demonstrated an ideal combination of good negative predictive values (NPVs), positive predictive values (PPVs), sensitivity, and specificity. A high-risk PREDICTS profile was defined as ≥3 positive biomarkers or ≥1 positive biomarker plus a history of diabetes; for high-risk SLE patients, the PPV was 64%, NPV was 94%, sensitivity was 89%, and specificity was 79%. In multivariate analysis, SLE patients with the high-risk profile had 28-fold increased odds for the longitudinal presence of plaque (P < 0.001) and increased progression of IMT (P < 0.001). Conclusion A high-risk PREDICTS score confers 28-fold increased odds of the presence of any current, progressive, or acquired carotid plaque, both in patients with SLE and in control subjects, and is significantly associated with higher rates of IMT progression.

To the Editor: We thank Professor Boers for his interest1 in our study2 and are grateful for the opportunity to respond to his queries. Our posthoc analysis investigated the effect of concomitant glucocorticoid (GC) use on clinical and radiographic outcomes in phase III studies of methotrexate (MTX)-naive patients receiving tofacitinib or MTX as monotherapy (ORAL Start), disease-modifying antirheumatic drug (DMARD)–inadequate responder (IR) patients receiving tofacitinib or placebo as monotherapy (ORAL Solo), and MTX-IR and DMARD-IR patients receiving tofacitinib or placebo in combination with background conventional synthetic DMARD (ORAL Sync, ORAL Standard, ORAL … Address correspondence to E. Bananis, 235 E. 42nd St., New York, New York 10017, USA. E-mail: stratis.bananis{at}pfizer.com.

Objective To investigate the relationship of genetic and biochemical determinants of paraoxonase 1 activity to carotid plaque as a surrogate marker of cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). Methods The relationships between paraoxonase 1 activity, PON1 genotype (for the functional polymorphism at position 192), and carotid plaque presence were determined in 168 RA patients. After an overnight fast, blood was collected for lipoprotein analysis, and paraoxonase 1 activity was measured using paraoxon as the substrate. The PON1 Q192R genotype was determined for all patients. Lipoprotein cholesterol levels, traditional CV risk factors, medication use, and RA disease characteristics were assessed for all patients. Results Paraoxonase 1 activity values in the RA patients were highest for the RR genotype, intermediate for the QR genotype, and lowest for the QQ genotype (P < 0.0001). Compared to patients with either the QQ genotype or the QR genotype, patients with the RR genotype demonstrated decreased risk of carotid plaque on multivariate analysis, controlling for traditional CV risk factors, high-sensitivity C-reactive protein levels, prednisone use, and cholesterol-lowering medication use (P < 0.05). Additional multivariate logistic regression analysis controlling for the above factors also revealed a significant association of plasma paraoxonase 1 activity with carotid plaque in RA patients. Lower plasma paraoxonase 1 activity was associated with increased risk of carotid plaque (P < 0.05). Conclusion The current findings suggest a relationship of the genetic determinants and activity of paraoxonase 1 to CV risk in RA patients, as assessed by the presence or absence of carotid plaque. Further CV outcome studies are warranted to validate the utility of paraoxonase 1 as a biomarker of CV risk in patients with RA.

Summary Background Rheumatoid arthritis is a heterogeneous chronic disease, and no therapeutic agent has been identified which is universally and persistently effective in all patients. We investigated the effectiveness of tofacitinib (CP-690,550), a novel oral Janus kinase inhibitor, as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. Methods We did a 6-month, double-blind, parallel-group phase 3 study at 82 centres in 13 countries, including North America, Europe, and Latin America. 399 patients aged 18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors (TNFi) were randomly assigned in a 2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with: tofacitinib 5 mg (n=133); tofacitinib 10 mg (n=134); or placebo (n=132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n=66) or 10 mg twice a day (n=66). Primary endpoints included American College of Rheumatology (ACR)20 response rate, mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI), and rates of disease activity score (DAS)28-4(ESR) less than 2·6 (referred to as DAS28 Findings At month 3, ACR20 response rates were 41·7% (55 of 132 [95% CI vs placebo 6·06–28·41]; p=0·0024) for tofacitinib 5 mg twice a day and 48·1% (64 of 133; [12·45–34·92]; p Interpretation In this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi. Funding Pfizer.

Objectives Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The implications of treatment with tofacitinib on cardiovascular (CV) risk in RA are unknown. Therefore, CV adverse events (AEs), and blood pressure and lipid level changes, in tofacitinib-treated patients with RA were evaluated. Methods Data were pooled from six Phase (P)3 studies (24 months) and two open-label long-term extension (LTE) studies (60 months) of tofacitinib in patients with RA and inadequate response to DMARDs. Tofacitinib was administered alone or with non-biologic DMARDs. CV events, including major adverse CV events (MACE: CV death and non-fatal CV events) and congestive heart failure (CHF), were assessed by a blinded adjudication committee. Results Overall, 4271 patients from P3 studies and 4827 enrolled from P2/P3 studies into LTE studies were evaluated, representing 3942 and 8699 patient-years of exposure to tofacitinib, respectively. Blood pressure remained stable over time across studies. The number of investigator-reported hypertension-related AEs in tofacitinib-treated patients was low in P3 studies (Months 0?3: 2.8%; Months 3?6: 1.4%; >6 months: 2.8%). Across studies, lipid level increases were generally observed within 1?3 months of treatment and stabilized thereafter. Patients with events (incidence rate [IR]/100 patient-years) for MACE and CHF, respectively, were: 23 (0.58) and 9 (0.23) in P3 studies, and 32 (0.37) and 8 (0.09) in LTE studies; IRs were comparable with placebo (P3) and did not increase over time (LTE). Conclusions Tofacitinib was associated with a low incidence of CV events in a large Phase 3 program, including LTE studies. Further long-term studies are underway.

Patients with rheumatoid arthritis (RA) suffer significantly increased cardiovascular (CV) morbidity and mortality, when compared with the general population. Both traditional CV risk factors and high levels of systemic inflammation have been linked to the increased CV risk in RA patients, but significant uncertainty remains regarding the mechanisms through which these factors contribute to CV disease (CVD). In addition, ongoing questions remain regarding how best to identify RA patients at high risk for CVD and what primary and secondary prevention strategies are effective at influencing CV outcome. The present review summarizes recent research in this field.

Patients with RA have a significantly increased risk of cardiovascular disease (CVD) including myocardial infarction and sudden cardiac death which is not explained by traditional CVD risk factors (1). Previous work has suggested that systemic inflammation contributes to CVD in RA, and patients with active disease and high inflammatory burden are at significantly increased risk (2–4). Although some studies have suggested that RA mortality rates may be falling in response to new therapies (5), survival trends are not keeping pace with the general population and CVD remains the leading cause of death (6). The investigation of novel mechanisms for accelerated atherosclerosis in patients with RA therefore becomes important both for appropriate treatment and for aggressive primary prevention. The inverse relationship between HDL cholesterol and the risk of CVD is well established (7, 8). However, a significant number of CVD events occur in patients with normal HDL and LDL cholesterol levels (9, 10). Previous work has suggested that the inflammatory nature of HDL may be a more sensitive marker of CVD than HDL cholesterol levels. Thus, there is a need for further investigation of biomarkers with better predictive value based on HDL function (11–13). HDL plays numerous anti-inflammatory and athero-protective roles by promoting reverse cholesterol transport and preventing the oxidation of LDL (14, 15). However, HDL protective function is impaired and becomes pro-inflammatory during pathologic processes that accelerate CVD events (16–18). The molecular changes and mechanisms that promote the conversion of anti-inflammatory HDL to pro-inflammatory HDL are currently unknown. The knowledge of molecular profiles that distinguish pro-inflammatory and anti-inflammatory HDL may facilitate better understanding of the alterations in HDL’s protein cargo, which adversely affect its normal antioxidant and anti-inflammatory functions. Pro-inflammatory HDL is increased in RA patients compared to healthy controls (19). We recently reported that levels of pro-inflammatory HDL are positively correlated with disease activity in RA patients (20). However, how pro-inflammatory HDL is involved in RA activity and its relationship to CVD is unknown. In this report, we evaluated HDL carrying distinct (anti-or pro-) inflammatory properties from plasma of RA patients. HDL was isolated using immunocapture columns and further subjected to our newly developed Offgel electrophoresis and LC-MS/MS method to identify protein markers that distinguish the inflammatory nature of HDL. Multiple proteins were identified in HDL including several proteins significantly associated with pro-inflammatory HDL. Four of these HDL-associated proteins were validated in a second RA cohort by HDL capturing ELISA. Since the inflammatory nature of HDL has previously been directly linked to CVD, and is also significantly correlated with disease activity in RA, characterization of the biomarkers reported here may identify novel molecular connections that contribute to the higher risk of CVD in RA patients.

Recent data suggest that atherosclerotic disease is increased in patients with idiopathic inflammatory myositis (IIM) and that dyslipidemia is a significant risk factor for cardiovascular events. Lipid-lowering agents may be associated with myopathic side effects. The current work evaluates the use of lipid-lowering therapy in patients with IIM treated by IIM specialists belonging to the International Myositis Assessment and Clinical Studies (IMACS) Group. The IMACS Group is a multidisciplinary coalition of experts with significant interest and experience in IIM. IMACS members were asked to complete an 18-item online survey detailing their clinical practice on monitoring and treating hypercholesterolemia in IIM patients. Specific questions regarding the types of lipid-lowering therapies used in IIM patients and any side effects associated with treatment were asked. Sixty-three IMACS members representing 23 countries and a minimum of 1,641 IIM patients participated in the online survey. Seventy-six percent of these specialists treating adult IIM patients use lipid-lowering therapies in their patients. HMG co-enzymeA reductase inhibitors (statins) were the most commonly used agents (93 %). Thirty-six cases of worsening myositis associated with statin use were reported in over 300 patients using lipid-lowering therapies. Seven of eight responders who reported worsening in myositis with lipid-lowering therapies reported cases in which the myositis improved after holding therapy. This survey suggests that statins are commonly used by physicians specializing in the treatment of patients with IIM and that some myositis patients worsen with statin use and may improve on dechallenge. More research regarding the safety of lipid-lowering agents in patients with IIM is warranted.

Reverse cholesterol transport (RCT) is a major antiatherogenic function of high density lipoprotein (HDL). In the current work, the authors evaluated whether the RCT capacity of HDL from rheumatoid arthritis (RA) patients is impaired when compared to healthy controls.HDL was isolated from 40 patients with RA and 40 age and sex matched healthy controls. Assays of cholesterol efflux, HDL's antioxidant function and paraoxanase-1 (PON-1) activity were performed as described previously. Plasma myeloperoxidase (MPO) activity was assessed by a commercially available assay.Mean cholesterol efflux capacity of HDL was not significantly different between RA patients (40.2% ± 11.1%) and controls (39.5% ± 8.9%); p=0.75. However, HDL from RA patients with high disease activity measured by a disease activity score using 28 joint count (DAS285.1), had significantly decreased ability to promote cholesterol efflux compared to HDL from patients with very low disease activity/clinical remission (DAS282.6). Significant correlations were noted between cholesterol efflux and the DAS28 (r=-0.39, p=0.01) and erythrocyte sedimentation rate, (r=-0.41, p=0.0009). Higher plasma MPO activity was associated with worse HDL function (r=0.41/p=0.009 (antioxidant capacity); r=0.35, p=0.03 (efflux)). HDL's ability to promote cholesterol efflux was modestly but significantly correlated with its antioxidant function (r=-0.34, p=0.03).The cholesterol efflux capacity of HDL is impaired in RA patients with high disease activity and is correlated with systemic inflammation and HDL's antioxidant capacity. Attenuation of HDL function, independent of HDL cholesterol levels, may suggest a mechanism by which active RA contributes to increased cardiovascular (CV) risk.

Background: Patients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors. High levels of leptin and low levels of adiponectin are associated with both atherosclerosis and immunomodulatory functions in the general population. Objective: To examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis. Methods: Carotid ultrasonography was performed in 250 women with SLE and 122 controls. Plasma leptin and adiponectin levels were measured. Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed. Results: Leptin levels were significantly higher in patients with SLE than in controls (23.7±28.0 vs 13.3±12.9 ng/ml, p

Accumulating evidence has demonstrated that exercise and physical activity decreases cardiovascular morbidity and mortality in the general population (1, 2). Data from the Framingham Heart Study indicate that in the population aged 50 years or older, high physical activity is associated with an increased life expectancy of 3.7 years in men and 3.5 years in women (3). Moreover, low physical activity appears to be an independent predictor of coronary heart disease (4). Suggested mechanisms for the cardiac benefits of increased physical activity include enhanced glucose regulation and insulin sensitivity, fat redistribution/loss, improved endothelial function, decreased blood pressure and lipid levels, anti-thrombotic effects, and modification of novel cardiovascular risk factors (e.g. inflammatory cytokines) (5). While the cardiovascular benefits of exercise are well recognized, few studies have examined the relationship between physical activity and subclinical markers of atherosclerosis, such as carotid intima-media thickness (IMT) and plaque. A systematic review of cross-sectional, interventional, retrospective or prospective clinical studies demonstrated that physical inactivity is associated with increased IMT (5). However, the same study reported inconsistent associations between structured lifestyle interventions and progression of IMT. Other studies have found no relationship between physical activity and IMT (6, 7), while some have demonstrated an inverse association between physical activity in men, but not in women (8). A recent report from the Multi-Ethnic Study of Atherosclerosis found that walking pace was favorably associated with common carotid IMT; however, this association was no longer significant after controlling for traditional cardiac risk factors (9). Differences in physical activity assessment techniques may contribute to the disparities in these findings. In addition, the majority of studies have evaluated these relationships within the general population. The use of heterogeneous study cohorts may also contribute to result discrepancies. To address this issue, the present study examined the relationships between physical activity and subclinical atherosclerosis in patients with systemic lupus erythematosus (SLE), a patient population with a predilection for premature cardiovascular disease (10). Patients with SLE have an increased risk of coronary artery disease (10) and stroke (11) compared with the general population. Myocardial infarction (MI), the leading cause of death in SLE patients, occurs on average at 49 years of age, 20 years earlier than the general population (12). SLE patients also have significantly increased subclinical atherosclerosis compared with healthy controls, measured as carotid artery plaque or coronary artery calcification (13, 14). Furthermore, the rate of plaque progression over a short period (mean of 4.19 years) is significantly higher than in healthy controls (15). Research suggests that the pathogenesis of SLE-related enhanced atherosclerosis is multi-factorial, involving abnormalities of lipids, inflammation, and autoimmune reactions (16). With regard to lipids, recent studies have demonstrated that dysfunction of high-density lipoproteins (HDL) contributes to atherosclerotic plaque formation in SLE patients (17). Specifically, dysfunctional, proinflammatory HDL (piHDL) is associated with increased IMT and plaque on carotid ultrasound (18). To our knowledge, no studies have assessed whether factors such as diet and lifestyle interventions may improve HDL function in SLE patients. However, a study of obese men exposed to a three-week intensive diet and exercise intervention found a substantial decrease in piHDL levels after the intervention (19). The purpose of the present study was to investigate the relationship between physical activity and subclinical atherosclerosis in patients with SLE. A secondary goal was to examine the relationship between physical activity and piHDL in patients with SLE.

Objective To characterize the antiinflammatory function of high-density lipoprotein (HDL) in patients with rheumatoid arthritis (RA) and to identify specific differences in HDL-associated proteins and enzymes that distinguish proinflammatory HDL from normal, antiinflammatory HDL. Methods We studied 132 RA patients. The antiinflammatory function of HDL was assessed by a cell-free assay, and proinflammatory HDL was defined by an HDL inflammatory index ≥1. Plasma and HDL-associated protein levels of apolipoprotein A-I (Apo A-I), haptoglobin, hemopexin, hemoglobin, and myeloperoxidase (MPO) were measured by direct and sandwich enzyme-linked immunosorbent assays, respectively. Lecithin:cholesterol acyltransferase (LCAT) activity was measured by a commercially available assay. Results Age, disease activity, the presence of erosive disease, non-Caucasian race, and smoking were significantly associated with proinflammatory HDL on multivariate analysis. Patients with proinflammatory HDL had higher measures of systemic inflammation, and a significant correlation was observed between RA disease activity (using the Disease Activity Score in 28 joints) and the HDL inflammatory index (r = 0.54, P < 0.0001). Compared with patients with antiinflammatory HDL, patients with proinflammatory HDL had significantly higher levels of haptoglobin, hemoglobin, Apo A-I, and MPO associated with HDL (P < 0.05 for all comparisons except MPO, which was P = 0.05). LCAT activity was lowest in patients with proinflammatory HDL, but was also significantly reduced in RA patients with antiinflammatory HDL as compared with healthy controls (P = 0.001). Conclusion Proinflammatory HDL in this RA patient cohort was associated with active disease and an altered protein cargo as compared with antiinflammatory HDL in RA patients and in healthy controls. The antiinflammatory function of HDL was inversely correlated with systemic inflammation in RA patients and may warrant further investigation as a mechanism by which active RA increases cardiovascular morbidity and mortality.

Objective.Previous work has suggested involvement of the muscle microvasculature in the pathogenesis of dermatomyositis (DM). Our study evaluates whether standard histochemical reactions can identify microvascular changes in muscle biopsies from patients with DM compared to myopathic and nonmyopathic controls.Methods.Muscle biopsies were obtained from 111 patients, including 45 patients with DM. Microvascular quantitation was performed on transversely oriented 1-μm toluidine blue-stained plastic sections. Histoenzymatic procedures included alkaline phosphatase (AP), nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR), succinate dehydrogenase (SDH), cytochrome C oxidase (COX), and myosin ATPase reactions.Results.Capillary density was significantly lower in DM muscle biopsies compared to biopsies from patients with noninflammatory myopathies (NIM; n = 26) and healthy control muscle (n = 27; mean ± SD: 252 ± 114 vs 402 ± 56 and 325 ± 109 capillaries/mm2, respectively; p values < 0.05). In contrast, a marked increase in the number of capillaries staining with NADH-TR was noted in DM compared to other idiopathic inflammatory myopathies (IIM; n = 13), NIM, and controls (49.8 ± 50.7 vs 8.0 ± 7.1, 6.7 ± 7.2, and 3.6 ± 2.8 capillaries/mm2; p < 0.05 compared to DM). DM capillaries also demonstrated mildly increased staining with AP compared to controls; however, no increased SDH or COX reactivity was observed.Conclusion.DM muscle capillaries are highly reactive with NADH-TR compared to myopathic and nonmyopathic controls. The lack of staining of DM capillaries with mitochondrial SDH and COX reactions suggests that NADH-TR reactivity may be secondary to activation of the microvascular endoplasmic reticulum, rather than mitochondrial hyperplasia.

Patient overall satisfaction with health (PSH) was measured by a subset of questions from the Arthritis Impact Measurement Scales II. Based on longitudinal observations for 267 early rheumatoid arthritis (RA) patients of the United States Western Consortium (WC) cohort receiving first non-biologic DMARD treatment, we estimated the 1-year change in PSH ( $$\Updelta$$ PSH). Logistic regression analysis was used to estimate the association of improvement in $$\Updelta$$ PSH with the core set of clinical and patient-reported components of disease activity scores (DAS). Most patients were more satisfied with health after 1 year of treatment (80%); few achieved DAS28-ESR minimal disease activity (27%) or remission (7%). Laboratory and joint count measures were not associated with improved 12-month PSH. Patients with greater HAQ-DI (P = 0.0473) and self-reported stiffness (P = 0.0669) were more likely to have a perceived overall health benefit from treatment. Regardless of objective disease status, patients are generally satisfied with first-line treatment, which could present a challenge to implementing DAS-guided treatment change. Patients with greater self-reported functional limitations might have lower expectations for treatment benefit and be less willing to modify their current therapy; subjective assessments of function and stiffness could be particularly useful in identifying these patients.

Background Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Phase (P) 2, P3, and open-label long-term extension (LTE) studies described the safety profile of tofacitinib and demonstrated that tofacitinib is effective as monotherapy and in combination with non-biologic disease-modifying antirheumatic drugs (DMARDs). Objectives This analysis describes safety data for tofacitinib in patients (pts) from the integrated RA clinical trial database based on cumulative exposure in P2, P3, and LTE studies, with a focus on safety events of special interest according to duration of tofacitinib exposure. Methods The analysis was performed on pts who received ≥1 dose of tofacitinib (doses pooled), as monotherapy or with background DMARDs, integrated across 6 P2, 6 P3 trials, and in 2 LTE studies (ongoing; database not locked) up to April 10, 2013. Pts switching from placebo, adalimumab or methotrexate to tofacitinib contributed data following their first dose of tofacitinib. Incidence rates (IR; events/100 patient-years [py] and 95% confidence intervals [CI]) are listed. The IR for opportunistic infections (OI) included herpes zoster (HZ) events that were described as disseminated or multidermatomal and excluded events of tuberculosis (TB), which are reported separately. Results The analysis includes 5,671 pts and represents an overall 12,664 py of tofacitinib exposure, with a median exposure of 2.4 years. The numbers of pts receiving tofacitinib for at least 12, 24, 36 and >48 months were 4,204 (74%), 3,804 (54%), 1,948 (34%), and 555 (10%) respectively. Overall 926 (16.3%) discontinued due to adverse events (AEs). The IR for mortality (within 30 days of last dose) was 0.28 (0.20, 0.39). IRs across discrete 6-month periods of exposure for serious AEs (SAEs) and AEs of interest, were stable across time intervals (Table 1). Serious infections were the most common SAEs (IR 2.93 [2.65, 3.25]). IRs for OI and TB were 0.25 (0.18, 0.36) and 0.21 (0.14, 0.30), respectively. Of all HZ AEs (overall IR 4.22 [3.87, 4.61]), 93% were non-serious; disseminated and multidermatomal cases were rare. Rates of all malignancies, excluding non-melanoma skin cancer (NMSC), and of lymphoma/lymphoproliferative disorders, were similar across time intervals (Table 1). US Surveillance, Epidemiology, and End Results Program (SEER) standardised incidence ratios (95% CI) were 1.08 (0.89, 1.31) for malignancies excluding NMSC and 2.58 (1.24, 4.74) for lymphoma, and were comparable to those reported from cohorts of RA pts treated with tumour necrosis factor inhibitors. Conclusions The pattern and rate of SAEs, and AEs of special interest observed following >12,000 py of overall exposure was stable across time intervals. No new risks were identified compared to previous reports. Longer term follow-up, observational research, and pharmacovigilance activities will further characterise the safety profile of tofacitinib in RA. Acknowledgements All studies were sponsored by Pfizer Inc. Editorial support was provided by Claire Cridland, of Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest S. Cohen Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, Y. Tanaka Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, X. Mariette Grant/research support: Pfizer Inc, J. Curtis Grant/research support: Pfizer Inc, K. Kwok Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Lee Consultant for: Pfizer Inc, P. Nash Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, K. Winthrop Grant/research support: Pfizer Inc, C. Charles-Schoeman Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, K. Thirunavukkarasu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Anisfeld Shareholder of: Pfizer Inc, Consultant for: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Riese Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Wollenhaupt Grant/research support: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.5656

Background Tofacitinib is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis (RA). Objectives To evaluate the cardiovascular (CV) event rates and changes in blood pressure (BP) in the tofacitinib Phase 3 (P3) and long-term open-label extension (LTE) studies. Methods Five P3 studies in patients (pts) with inadequate response to nonbiologic/biologic disease-modifying anti-rheumatic drugs (DMARDs) and 2 LTE studies were included. Tofacitinib was administered as monotherapy or with background nonbiologic DMARDs, predominantly methotrexate. One P3 study included adalimumab (ADA) as active control. An independent CV Safety Endpoint Adjudication Committee performed blinded adjudication of deaths, potential major adverse CV events (MACE), and events of congestive heart failure (CHF). MACE was defined as CV death and non-fatal CV events. Results: MACE IRs (per 100 pt-y) in placebo (PBO) and tofacitinib groups in P3 were low. IR in the LTE studies in the tofacitinib All Dose group (0.19) was lower than in P3 (0.57). IRs of CHF in tofacitinib were low. In P3, mean changes from baseline at Month 3 for systolic and diastolic BP, respectively, were -0.1 mmHg and -0.8 mmHg for PBO and -0.2 and 0.3 mmHg for tofacitinib. Mean BP changes at Months 6 and 12 and in the LTE studies remained stable. Conclusions Incidence rates of MACE were similar across groups in P3 with lower rates in LTE, suggesting no increased risk over 3 years of follow up. Tofacitinib was not associated with clinically meaningful increases in BP. Although the number of events have been fewand longer observation periods are warranted, CV risk does not appear to be increased with tofacitinib treatment and rates of CV events are consistent with those observed among patients with RA of similar disease severity.1-3 References Solomon DH et al. Circulation 2003; 107: 1303-1307; Solomon DH et al. Ann Rheum Dis 2006; 65: 1608-1612; 3. Nicola PJ et al. Arthritis Rheum 2006; 54: 60-67. Disclosure of Interest C. Charles-Schoeman Grant/Research support from: Pfizer Inc., Consultant for: Pfizer Inc., P. Wicker Consultant for: Pfizer Inc., U. Sechtem Consultant for: Pfizer Inc., M. Gonzalez-Gay Consultant for: Pfizer Inc., S. Wood Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., M. Boy Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Geier Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., K. Soma Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Riese Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.