Risk of extended major adverse cardiovascular event endpoints with tofacitinib versus TNF inhibitors in patients with rheumatoid arthritis: a post hoc analysis of a phase 3b/4 randomised safety study.

OBJECTIVES: Compare the risk of extended major adverse cardiovascular (CV) event (MACE) composite outcomes and component events in patients with rheumatoid arthritis (RA) treated with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in Oral Rheumatoid Arthritis Trial (ORAL) Surveillance. METHODS: Patients with RA aged ≥50 years and with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. MACE (non-fatal myocardial infarction (MI), non-fatal stroke or CV death (MACE-3)) was extended by sequential addition of CV events (hospitalisation for unstable angina (MACE-4), coronary revascularisation (MACE-5), transient ischaemic attack (MACE-6), peripheral vascular disease (MACE-7)), heart failure (HF) hospitalisation (MACE-8) and venous thromboembolism (VTE; (MACE-8 plus VTE)). HRs (tofacitinib vs TNFi) were evaluated for MACE and individual components. RESULTS: HRs for MACE-4 to MACE-8 with combined and individual tofacitinib doses versus TNFi were similar. Risk of MACE-8 plus VTE appeared similar with tofacitinib 5 mg two times per day versus TNFi (HR 1.12 (0.82 to 1.52)), but higher with tofacitinib 10 mg two times per day versus TNFi (HR 1.38 (1.02 to 1.85)). Risk of MI was higher with tofacitinib versus TNFi, but difference in risk of other individual CV events was not suggested. Across extended MACE definitions, risk appeared higher with tofacitinib versus TNFi in those with atherosclerotic CV disease or age ≥65 years. CONCLUSION: In ORAL Surveillance, risk of composite CV endpoints combining all ischaemic CV events and HF did not appear different with tofacitinib versus TNFi. The totality of CV risk was higher with tofacitinib 10 mg two times per day versus TNFi, driven by an increase in VTE. TRIAL REGISTRATION NUMBER: NCT02092467.

Risk of Venous Thromboembolism With Tofacitinib Versus Tumor Necrosis Factor Inhibitors in Cardiovascular Risk-Enriched Rheumatoid Arthritis Patients.

OBJECTIVE: The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. METHODS: Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient-years) by 6-month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. RESULTS: Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6-month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m2, older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. CONCLUSION: Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

Assessing the Performance of a Nutrition Knowledge Questionnaire With a Low Socioeconomic Status Population Using Rasch Analysis.

Parents and preschool teachers play a key role in shaping children's dietary behaviors. Knowledge of nutrition and healthy dietary choices is a key component to improve dietary habits and reduce the prevalence of obesity and associated co-morbidities. Using valid and reliable instruments is necessary for accurate assessment of knowledge to tailor interventions and measure effectiveness specific to the population of interest. The objectives of this paper are to (1) identify potential gaps in the baseline nutrition knowledge among parents and teachers using a previously validated questionnaire prior to a preschool obesity prevention intervention; and (2) assess the instrument's reliability and construct validity for a low socioeconomic status population using a post hoc Rasch analysis. Participants included 177 parents and 75 teachers who participated in a Head Start intervention study. Knowledge scores, instrument reliability, and item fit and difficulty were assessed using a Rasch analysis; t-tests were used to determine differences in scores between parents and teachers. Parents answered 38% of questions correctly while teachers correctly answered 46% of the questions. Adequate item fit and reliability were indicated for Sections 1 and 2 of the Nutrition Knowledge Questionnaire (NKQ). Section 3 demonstrated less adequate reliability. The items were found to adequately and reliably define the unidimensional measures of the three components of knowledge represented in this instrument, providing evidence of construct validity. However, Rasch measures indicated the NKQ overall was difficult for participants. Recommendations for improving the instrument for nutrition education/intervention and research practice areas related to obesity and obesity-related conditions are addressed.

Rheumatoid arthritis disease activity and adverse events in patients receiving tofacitinib or tumor necrosis factor inhibitors: a post hoc analysis of ORAL Surveillance.

Background: In patients with rheumatoid arthritis (RA), persistent inflammation and increasing disease activity are associated with increased risk of adverse events (AEs). Objectives: To assess relationships between RA disease activity and AEs of interest in patients treated with tofacitinib or tumor necrosis factor inhibitors (TNFi). Design: This was a post hoc analysis of a long-term, postauthorization safety endpoint trial of tofacitinib versus TNFi. Methods: In ORAL Surveillance, 4362 patients aged ⩾50 years with active RA despite methotrexate, and ⩾1 additional cardiovascular (CV) risk factor, were randomized 1:1:1 to tofacitinib 5 or 10 mg twice daily or TNFi for up to 72 months. Post hoc time-dependent multivariable Cox analysis evaluated the relationships between disease activity [Clinical Disease Activity Index (CDAI)], inflammation [C-reactive protein (CRP)], and AEs of interest. The AEs included major adverse CV events (MACE), malignancies excluding nonmelanoma skin cancer (NMSC), venous thromboembolism (VTE), serious infections, herpes zoster (HZ), nonserious infections excluding HZ (NSI), and death. Results: Across treatments, risk for NSI was higher when patients had CDAI-defined active disease versus remission; MACE and VTE risks trended higher, but did not reach significance. Hazard ratios for MACE, malignancies excluding NMSC, VTE, infections, and death rose by 2-9% for each 5-mg/L increment in serum CRP. The interaction terms evaluating the impact of treatment assignment on the relationship between disease activity and AEs were all p > 0.05. Conclusion: In ORAL Surveillance, higher NSI risk was observed in the presence of active RA versus remission. The risk of MACE and VTE directionally increased in active disease versus remission, although statistical power was limited due to small event numbers in these categories. The relationship between active disease and AEs was not impacted by treatment with tofacitinib versus TNFi. Registration: NCT02092467.

The link between disease activity and adverse medical events in people with rheumatoid arthritis taking tofacitinib or tumor necrosis factor inhibitors. Why was the study done? • People with rheumatoid arthritis (RA) who have uncontrolled symptoms (high disease activity) have a higher chance of having adverse medical events (medical problems that occur during treatment with a medication) than people who have mild symptoms (low disease activity). • We looked at the link between levels of disease activity and the risk of having adverse medical events in people with RA who took tofacitinib or a tumor necrosis factor inhibitor (TNFi) medication. What did the researchers do? • We used the results of ORAL Surveillance, a long-term safety trial in people with RA. ○ In this study, people with RA were 50 years or older and at high risk of a major cardiovascular event such as heart attack or stroke. • For up to 6 years, people took tofacitinib 5 or 10mg tablets two times a day or TNFi injections. • We used statistical tests to examine the link between different levels of RA disease activity or inflammation and different adverse medical events, such as: ○ major cardiovascular events (such as heart attack, stroke, or death due to heart failure) ○ cancers ○ blood clots ○ infections ○ deaths. What did the researchers find? • In people who took tofacitinib or TNFi: ○ People with active disease (those with RA symptoms) had a higher risk of infections that did not lead to hospitalization (nonserious infections) than people in remission (those with very mild symptoms or no symptoms at all). ○ People with active disease also had a slightly higher risk of major cardiovascular events and blood clots than those in remission. ○ Higher levels of inflammation led to increased risk of major cardiovascular events, cancers, blood clots, infections, and deaths. What do the findings mean? • Active RA disease leads to higher risk of adverse medical events. • The medication used (tofacitinib or TNFi) did not affect the link between levels of RA disease activity and adverse medical events. • This study was limited by the low number of adverse medical events recorded.

Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial.

OBJECTIVES: To evaluate malignancies and their associations with baseline risk factors and cardiovascular risk scores with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA). METHODS: In an open-label, randomised controlled trial (ORAL Surveillance; NCT02092467), 4362 patients with RA aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 (N=1455) or 10 mg two times per day (N=1456) or TNFi (N=1451). Incidence rates (IRs; patients with first events/100 patient-years) and HRs were calculated for adjudicated malignancies excluding non-melanoma skin cancer (NMSC), NMSC and subtypes. Post hoc analyses for malignancies excluding NMSC, lung cancer and NMSC included risk factors identified via simple/multivariable Cox models and IRs/HRs categorised by baseline risk factors, history of atherosclerotic cardiovascular disease (HxASCVD) and cardiovascular risk scores. RESULTS: IRs for malignancies excluding NMSC and NMSC were higher with tofacitinib (combined and individual doses) versus TNFi. Risk of lung cancer (most common subtype with tofacitinib) was higher with tofacitinib 10 mg two times per day versus TNFi. In the overall study population, the risk of malignancies excluding NMSC was similar between both tofacitinib doses and TNFi until month 18 and diverged from month 18 onwards (HR (95% CIs) for combined tofacitinib doses: 0.93 (0.53 to 1.62) from baseline to month 18 vs 1.93 (1.22 to 3.06) from month 18 onwards, interaction p=0.0469). Cox analyses identified baseline risk factors across treatment groups for malignancies excluding NMSC, lung cancer and NMSC; interaction analyses generally did not show statistical evidence of interaction between treatment groups and risk factors. HxASCVD or increasing cardiovascular risk scores were associated with higher malignancy IRs across treatments. CONCLUSIONS: Risk of malignancies was increased with tofacitinib versus TNFi, and incidence was highest in patients with HxASCVD or increasing cardiovascular risk. This may be due to shared risk factors for cardiovascular risk and cancer. TRIAL REGISTRATION NUMBERS: NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661.

Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance.

OBJECTIVES: Evaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic cardiovascular disease (ASCVD) in ORAL Surveillance. METHODS: Patients with RA aged ≥50 years with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. Hazard rations (HRs) were evaluated for the overall population and by history of ASCVD (exploratory analysis). RESULTS: Risk of MACE, myocardial infarction and sudden cardiac death were increased with tofacitinib versus TNFi in ORAL Surveillance. In patients with history of ASCVD (14.7%; 640/4362), MACE incidence was higher with tofacitinib 5 mg two times per day (8.3%; 17/204) and 10 mg two times per day (7.7%; 17/222) versus TNFi (4.2%; 9/214). HR (combined tofacitinib doses vs TNFi) was 1.98 (95% confidence interval (CI) 0.95 to 4.14; interaction p values: 0.196 (for HR)/0.059 (for incidence rate difference)). In patients without history of ASCVD, MACE HRs for tofacitinib 5 mg two times per day (2.4%; 30/1251) and 10 mg two times per day (2.8%; 34/1234) versus TNFi (2.3%; 28/1237) were, respectively, 1.03 (0.62 to 1.73) and 1.25 (0.76 to 2.07). CONCLUSIONS: This post hoc analysis observed higher MACE risk with tofacitinib versus TNFi in patients with RA and history of ASCVD. Among patients without history of ASCVD, all with prevalent CV risk factors, MACE risk did not appear different with tofacitinib 5 mg two times per day versus TNFi. Due to the exploratory nature of this analysis and low statistical power, we cannot exclude differential MACE risk for tofacitinib 5 mg two times per day versus TNFi among patients without history of ASCVD, but any absolute risk excess is likely low. TRIAL REGISTRATION NUMBER: NCT02092467.

Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial.

OBJECTIVES: To characterise infections in patients with rheumatoid arthritis (RA) in ORAL Surveillance. METHODS: In this open-label, randomised controlled trial, patients with RA aged≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg two times per day or a tumour necrosis factor inhibitor (TNFi). Incidence rates (IRs; patients with first events/100 patient-years) and hazard ratios (HRs) were calculated for infections, overall and by age (50-<65 years; ≥65 years). Probabilities of infections were obtained (Kaplan-Meier estimates). Cox modelling identified infection risk factors. RESULTS: IRs/HRs for all infections, serious infection events (SIEs) and non-serious infections (NSIs) were higher with tofacitinib (10>5 mg two times per day) versus TNFi. For SIEs, HR (95% CI) for tofacitinib 5 and 10 mg two times per day versus TNFi, respectively, were 1.17 (0.92 to 1.50) and 1.48 (1.17 to 1.87). Increased IRs/HRs for all infections and SIEs with tofacitinib 10 mg two times per day versus TNFi were more pronounced in patients aged≥65 vs 50-<65 years. SIE probability increased from month 18 and before month 6 with tofacitinib 5 and 10 mg two times per day versus TNFi, respectively. NSI probability increased before month 6 with both tofacitinib doses versus TNFi. Across treatments, the most predictive risk factors for SIEs were increasing age, baseline opioid use, history of chronic lung disease and time-dependent oral corticosteroid use, and, for NSIs, female sex, history of chronic lung disease/infections, past smoking and time-dependent Disease Activity Score in 28 joints, C-reactive protein. CONCLUSIONS: Infections were higher with tofacitinib versus TNFi. Findings may inform future treatment decisions. TRIAL REGISTRATION NUMBER: NCT02092467.

Assessment of the Effects of Inhibition or Induction of CYP2C19 and CYP2C9 Enzymes, or Inhibition of OAT3, on the Pharmacokinetics of Abrocitinib and Its Metabolites in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is a Janus kinase 1-selective inhibitor for the treatment of moderate-to-severe atopic dermatitis. Abrocitinib is eliminated primarily by metabolism involving cytochrome P450 (CYP) enzymes. Abrocitinib pharmacologic activity is attributable to the unbound concentrations of the parent molecule and 2 active metabolites, which are substrates of organic anion transporter 3 (OAT3). The sum of potency-adjusted unbound exposures of abrocitinib and its 2 active metabolites is termed the abrocitinib active moiety. We evaluated effects of CYP inhibition, CYP induction, and OAT3 inhibition on the pharmacokinetics of abrocitinib, its metabolites, and active moiety. METHODS: Three fixed-sequence, open-label, phase I studies in healthy adult volunteers examined the drug-drug interactions (DDIs) of oral abrocitinib with fluvoxamine and fluconazole, rifampin, and probenecid. RESULTS: Co-administration of abrocitinib with fluvoxamine or fluconazole increased the area under the plasma concentration-time curve from time 0 to infinity (AUCinf) of the unbound active moiety of abrocitinib by 91% and 155%, respectively. Co-administration with rifampin decreased the unbound active moiety AUCinf by 56%. The OAT3 inhibitor probenecid increased the AUCinf of the unbound active moiety by 66%. CONCLUSIONS: It is important to consider the effects of DDIs on the abrocitinib active moiety when making dosing recommendations. Co-administration of strong CYP2C19/2C9 inhibitors or CYP inducers impacted exposure to the abrocitinib active moiety. A dose reduction by half is recommended if abrocitinib is co-administered with strong CYP2C19 inhibitors, whereas co-administration with strong CYP2C19/2C9 inducers is not recommended. No dose adjustment is required when abrocitinib is administered with OAT3 inhibitors. CLINICAL TRIALS REGISTRATION IDS: NCT03634345, NCT03637790, NCT03937258.

Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis.

BACKGROUND: Increases in lipid levels and cancers with tofacitinib prompted a trial of major adverse cardiovascular events (MACE) and cancers in patients with rheumatoid arthritis receiving tofacitinib as compared with a tumor necrosis factor (TNF) inhibitor. METHODS: We conducted a randomized, open-label, noninferiority, postauthorization, safety end-point trial involving patients with active rheumatoid arthritis despite methotrexate treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor. Patients were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a TNF inhibitor. The coprimary end points were adjudicated MACE and cancers, excluding nonmelanoma skin cancer. The noninferiority of tofacitinib would be shown if the upper boundary of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor. RESULTS: A total of 1455 patients received tofacitinib at a dose of 5 mg twice daily, 1456 received tofacitinib at a dose of 10 mg twice daily, and 1451 received a TNF inhibitor. During a median follow-up of 4.0 years, the incidences of MACE and cancer were higher with the combined tofacitinib doses (3.4% [98 patients] and 4.2% [122 patients], respectively) than with a TNF inhibitor (2.5% [37 patients] and 2.9% [42 patients]). The hazard ratios were 1.33 (95% confidence interval [CI], 0.91 to 1.94) for MACE and 1.48 (95% CI, 1.04 to 2.09) for cancers; the noninferiority of tofacitinib was not shown. The incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor. Efficacy was similar in all three groups, with improvements from month 2 that were sustained through trial completion. CONCLUSIONS: In this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk-enriched population, risks of MACE and cancers were higher with tofacitinib and did not meet noninferiority criteria. Several adverse events were more common with tofacitinib. (Funded by Pfizer; ORAL Surveillance ClinicalTrials.gov number, NCT02092467.).

Fracture in clinical studies of tofacitinib in rheumatoid arthritis.

Background: Preclinical data suggest that tofacitinib would protect bone health in patients with rheumatoid arthritis (RA). Objective: To assess fracture risk in tofacitinib RA clinical trials. Design: Post hoc analysis. Methods: We analyzed pooled data of phase I/II/III and long-term extension studies ('P123LTE cohort'), pooled data of placebo-controlled portions of phase III studies (phase III placebo-controlled cohort), and data from ORAL Surveillance [phase IIIb/IV randomized, open-label trial evaluating tofacitinib 5/10 mg twice daily (BID) vs tumor necrosis factor inhibitor (TNFi) in patients ⩾ 50 years with ⩾ 1 additional cardiovascular risk factor]. Results: In the phase III placebo-controlled cohort, incidence rates (IRs) [95% confidence interval (CI)] of fracture were 2.11 (1.09-3.68), 2.56 (1.23-4.71), and 4.43 (1.78-9.12) per 100 patient-years (PYs) for tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo, respectively [tofacitinib 5 mg BID vs placebo: hazard ratio (HR) (95% CI) = 0.55(0.18-1.65); tofacitinib 10 mg BID vs placebo: HR (95% CI) = 0.72 (0.26-2.01)]. In P123LTE, IRs (95% CI) were 2.62 (2.29-2.99) and 2.26 (2.02-2.52) per 100 PY for average tofacitinib 5 and 10 mg BID, respectively. In ORAL Surveillance, IRs (95% CI) were 2.79 (2.34-3.30), 2.87 (2.40-3.40), and 2.27 (1.87-2.74) per 100 PY for tofacitinib 5 mg BID, tofacitinib 10 mg BID, and TNFi, respectively. In ORAL Surveillance, the risk of fracture was numerically higher than TNFi for tofacitinib 5 mg BID [HR (95% CI) = 1.23 (0.96-1.58)] and tofacitinib 10 mg BID [HR (95% CI) = 1.26 (0.97-1.62)]. In ORAL Surveillance, independent predictors of all and osteoporotic fractures with tofacitinib or TNFi included age ⩾ 65, female sex, history of fracture/osteoporosis, and baseline oral corticosteroid use. Conclusion: This post hoc analysis showed numerically lower fracture risk with tofacitinib versus placebo and numerically greater risk versus TNFi. We did not identify any tofacitinib-specific predictors of fractures, and predictors of fracture were generally aligned with prior literature in the general population and patients with RA. Patients with fracture risk factors should be adequately monitored and treated. Clinical trial registration: NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02187055, NCT02831855, NCT00413699, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT00661661, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT01262118, NCT01484561, NCT02281552, NCT02147587, NCT02092467.

Postapproval Comparative Safety Study of Tofacitinib and Biological Disease-Modifying Antirheumatic Drugs: 5-Year Results from a United States-Based Rheumatoid Arthritis Registry.

OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared 5-year adverse event (AE) incidence rates (IRs) between patients initiating tofacitinib and those initiating new biological disease-modifying antirheumatic drugs (bDMARDs) within the United States (US) Corrona RA registry. METHODS: IRs (number of first events/100 patient-years) of major adverse cardiovascular events (MACE), serious infection events (SIEs), herpes zoster (HZ), malignancies, and death were estimated among tofacitinib and bDMARD initiators, regardless of dose/schedule, between November 6, 2012 (US Food and Drug Administration tofacitinib approval), and July 31, 2018 (follow-up through January 31, 2019). Propensity score (PS) methods were used to control for nonrandom prescribing practices. Hazard ratios (HRs) were calculated to compare rates using multivariable-adjusted Cox regression. Different risk windows were used for acute (MACE, SIEs, HZ, and venous thromboembolic events [VTEs]) and long-term (malignancy and death) events. VTEs were assessed descriptively. RESULTS: For MACE, SIEs, and HZ, 1999 (3152.1 patient-years) and 8358 (12 869.4 years) tofacitinib and bDMARD initiators were included, respectively; for malignancy/death, 1999 (4505.6 patient-years) and 6354 (16 670.8 patient-years) initiators were included, respectively. AE rates were similar across cohorts, except for HZ, which was significantly higher with tofacitinib versus bDMARDs (PS-trimmed adjusted HR 2.32; 95% confidence interval [CI] 1.43-3.75). There were 45 (zero serious) and 88 (five serious) HZ events with tofacitinib and bDMARDs, respectively. Sensitivity analyses demonstrated similar results. VTE IRs (95% CI) were 0.29 (0.13-0.54) and 0.33 (0.24-0.45) for tofacitinib and bDMARDs, respectively. CONCLUSION: In this registry analysis, both cohorts had similar MACE, SIE, malignancy, death, and VTE rates; HZ rates were higher for tofacitinib initaitors than for bDMARD initiators.

Development of the Impact of a Preschool Obesity Prevention Intervention Enhanced With Positive Behavioral Supports for Mississippi Head Start Centers.

OBJECTIVE: To describe the methodology of the Impact of a Preschool Obesity Prevention intervention enhanced with positive behavioral supports. DESIGN: The social ecological model serves as the conceptual framework for this study, which has a within- and between-subjects design with an intervention group and a delayed intervention control group. This 3-year project will use formative methods to pretest materials in Year 1, collect data pre- and postintervention with a follow-up at 4 months in Years 2 and 3, and conduct summative and process evaluation in Year 3. SETTING: Head Start centers in Southern and East-Central Mississippi counties. PARTICIPANTS: Three hundred parents with 3-year-old children enrolled in 9 Head Start centers (53 classrooms) and 75 Head Start teachers. INTERVENTIONS: During Year 2, Hip Hop to Health Jr., Parent-Child Interaction Therapy, and Positive Behavior Interventions and Supports will be implemented. MAIN OUTCOME MEASURES: Primary outcomes include changes in parenting and teacher practices. Secondary outcomes include parent feeding styles as well as weight status and dietary intake. Variables will be measured using anthropometrics and validated surveys. ANALYSIS: The primary analysis will be a multilevel 2 × 3 mixed ANOVA.

Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data.

OBJECTIVES: Tofacitinib 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. METHODS: This 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. RESULTS: 12 410 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. CONCLUSIONS: DVT, 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)).

Tofacitinib in combination with methotrexate in patients with rheumatoid arthritis: patient-reported outcomes from the 24-month Phase 3 ORAL Scan study.

OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we present data from the completed Phase 3 randomised controlled trial (RCT) ORAL Scan (NCT00847613), which evaluated the impact of tofacitinib on patient-reported outcomes (PROs) through 24 months in patients with active RA and inadequate responses to methotrexate (MTX-IR). METHODS: Patients were randomised 4:4:1:1 to receive tofacitinib 5 or 10 mg twice daily (BID), or placebo advanced to tofacitinib 5 or 10 mg, plus background MTX. Patients receiving placebo advanced to tofacitinib at month 3 (non-responders) or month 6 (remaining patients). Mean changes from baseline in PROs, assessed at months 1-24, included Health Assessment Questionnaire-Disability Index, Patient Global Assessment of disease activity (visual analogue scale [VAS]), Patient Assessment of Arthritis Pain (VAS), health-related quality of life (Short Form-36 version 2), Functional Assessment of Chronic Illness Therapy-Fatigue and Medical Outcomes Study-Sleep. RESULTS: Overall, 539/797 (67.6%) patients completed 24 months' treatment. At month 3, tofacitinib-treated patients reported signi cant (p<0.05) mean changes from baseline versus placebo across all PROs, and significantly more patients reported improvements ≥ minimum clinically important differences versus placebo. Improvements in PROs with tofacitinib were sustained to month 24. Following advancement to tofacitinib, placebo-treated patients generally reported changes of similar magnitude to tofacitinib-treated patients. CONCLUSIONS: Patients with RA and MTX-IR receiving tofacitinib 5 or 10 mg BID plus MTX reported significant and clinically meaningful improvements in PROs versus placebo at month 3, which were sustained through 24 months.

Expenditure, Coping, and Academic Behaviors among Food-Insecure College Students at 10 Higher Education Institutes in the Appalachian and Southeastern Regions.

BACKGROUND: A number of studies have measured college student food insecurity prevalence higher than the national average; however, no multicampus regional study among students at 4-y institutions has been undertaken in the Appalachian and Southeast regions of the United States. OBJECTIVES: The aims of this study were to determine the prevalence of food insecurity among college students in the Appalachian and Southeastern regions of the United States, and to determine the association between food-insecurity status and money expenditures, coping strategies, and academic performance among a regional sample of college students. METHODS: This regional, cross-sectional, online survey study included 13,642 college students at 10 public universities. Food-insecurity status was measured through the use of the USDA Adult Food Security Survey. The outcomes were associations between food insecurity and behaviors determined with the use of the money expenditure scale (MES), the coping strategy scale (CSS), and the academic progress scale (APS). A forward-selection logistic regression model was used with all variables significant from individual Pearson chi-square and Wilcoxon analyses. The significance criterion α for all tests was 0.05. RESULTS: The prevalence of food insecurity at the universities ranged from 22.4% to 51.8% with an average prevalence of 30.5% for the full sample. From the forward-selection logistic regression model, MES (OR: 1.47; 95% CI: 1.40, 1.55), CSS (OR: 1.19; 95% CI: 1.18, 1.21), and APS (OR: 0.95; 95% CI: 0.91, 0.99) scores remained significant predictors of food insecurity. Grade point average, academic year, health, race/ethnicity, financial aid, cooking frequency, and health insurance also remained significant predictors of food security status. CONCLUSIONS: Food insecurity prevalence was higher than the national average. Food-insecure college students were more likely to display high money expenditures and exhibit coping behaviors, and to have poor academic performance.

Treatment outcomes in patients with seropositive versus seronegative rheumatoid arthritis in Phase III randomised clinical trials of tofacitinib.

Objectives: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We examined response to tofacitinib 5 or 10 mg two times a day in patients with seropositive vs seronegative RA. Methods: Data were pooled from five Phase III studies of conventional synthetic disease-modifying antirheumatic drug (csDMARD)- or biological DMARD-inadequate responders (ORAL Step [NCT00960440]; ORAL Scan [NCT00847613]; ORAL Solo [NCT00814307]; ORAL Sync [NCT00856544]; ORAL Standard [NCT00853385]). 'Serotype' subgroups were: anticyclic citrullinated peptide (CCP) and rheumatoid factor (RF) positive (anti-CCP+/RF+); anti-CCP+/RF negative (-); anti-CCP-/RF+; anti-CCP-/RF-. At month 3, ACR20/50/70 response rates, Disease Activity Score (DAS28-4[ESR])-defined remission (DAS28-4[ESR]<2.6) and low disease activity (LDA; DAS28-4[ESR]≤3.2), changes from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 Health Survey (SF-36) physical functioning and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Safety endpoints were compared. Results: Baseline demographics/characteristics were similar across subgroups. Tofacitinib significantly improved ACR20/50/70 response rates, DAS28-4(ESR) LDA rates and CFB in HAQ-DI and FACIT-F vs placebo across subgroups. More anti-CCP+/RF+ than anti-CCP-/RF- patients had ACR20/50/70 responses (ACR20/50: both tofacitinib doses; ACR70: 10 mg two times a day). SF-36 physical functioning improved in anti-CCP+/RF+, anti-CCP+/RF- and anti-CCP-/RF+ patients (both tofacitinib doses) and anti-CCP-/RF- patients (10 mg two times a day) vs placebo. More anti-CCP+/RF+ and anti-CCP+/RF- than anti-CCP-/RF- patients achieved DAS28-4(ESR) remission and LDA with tofacitinib 10 mg two times a day. Frequency of adverse events (AEs), serious AEs and discontinuations due to AEs were similar across subgroups. Conclusion: Generally, tofacitinib efficacy (ACR20/50/70 responses) and safety were similar across subgroups. DAS28-4(ESR) remission rates and SF-36 physical functioning appeared lower in anti-CCP- patients.