Changes in Lipid Levels and Incidence of Cardiovascular Events Following Tofacitinib Treatment in Patients With Psoriatic Arthritis: A Pooled Analysis Across Phase III and Long-Term Extension Studies

Dafna D Gladman, Christina Charles-Schoeman, Iain B McInnes, Douglas J Veale, Bruce Thiers, Mike Nurmohamed, Dani Graham, Cunshan Wang, Thomas Jones, Robert Wolk, Ryan DeMasi, Dafna D Gladman, Christina Charles-Schoeman, Iain B McInnes, Douglas J Veale, Bruce Thiers, Mike Nurmohamed, Dani Graham, Cunshan Wang, Thomas Jones, Robert Wolk, Ryan DeMasi

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01877668 NCT01882439 NCT01976364.

© 2019, Pfizer Inc. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Figures

Figure 1
Figure 1
Mean percentage change from baseline in lipids at A, month 3 and B, month 6 (pooled phase III data), based on patients with a baseline and ≥1 postbaseline measurement. Patients randomized to placebo were advanced to tofacitinib 5 or 10 mg twice daily (BID) at month 3. LDL‐c = low‐density lipoprotein cholesterol; HDL‐c = high‐density lipoprotein cholesterol; N = number of patients with value at the given time point.
Figure 2
Figure 2
Mean lipid ratios at baseline, month 3, and month 6 for A, low‐density lipoprotein cholesterol (LDL‐c):high‐density lipoprotein cholesterol (HDL‐c) and B, total cholesterol:HDL‐c (pooled phase III data), based on patients with a baseline and ≥1 postbaseline measurement. Patients randomized to placebo were advanced to tofacitinib 5 or 10 mg twice daily (BID) at month 3. N = number of patients with value at the given time point.
Figure 3
Figure 3
Least squares (LS) mean change from baseline in C‐reactive protein (CRP) level over time (pooled phase III data). Two separate analyses were performed. A mixed model for repeated measures (MMRM) was used to generate results with data from week 2 to month 3, as well as results from week 2 to month 6. Each analysis was based on an MMRM with the fixed effects of treatment, visit, treatment‐by‐visit interaction, geographic location, study, and baseline value; an unstructured covariance matrix was used. BID = twice daily; N = number of patients with value at the given time point; *** = P < 0.001 versus placebo.
Figure 4
Figure 4
A, Mean systolic, and B, mean diastolic sitting blood pressure (BP) over 24 months (pooled phase III and long‐term extension data). Includes all tofacitinib‐exposed patients who had both a baseline and ≥1 postbaseline observation; baseline values are from the OPAL Broaden and OPAL Beyond studies. Average tofacitinib 5 mg twice daily (BID) comprised patients with an average total daily dose of <15 mg from day 1 using tofacitinib. Average tofacitinib 10 mg BID comprised patients with an average total daily dose of ≥15 mg from day 1 using tofacitinib. N = number of patients with value at the given time point.

References

    1. Coates LC, Kavanaugh A, Mease PJ, Soriano ER, Acosta‐Felquer ML, Armstrong AW, et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 treatment recommendations for psoriatic arthritis. Arthritis Rheumatol 2016;68:1060–71.
    1. Gladman DD, Ang M, Su L, Tom BD, Schentag CT, Farewell VT. Cardiovascular morbidity in psoriatic arthritis. Ann Rheum Dis 2009;68:1131–5.
    1. Juneblad K, Rantapää‐Dahlqvist S, Alenius GM. Disease activity and increased risk of cardiovascular death among patients with psoriatic arthritis. J Rheumatol 2016;43:2155–61.
    1. Ahlehoff O, Gislason GH, Charlot M, Jørgensen CH, Lindhardsen J, Olesen JB, et al. Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J Intern Med 2011;270:147–57.
    1. Jamnitski A, Visman IM, Peters MJ, Boers M, Dijkmans BA, Nurmohamed MT. Prevalence of cardiovascular diseases in psoriatic arthritis resembles that of rheumatoid arthritis. Ann Rheum Dis 2011;70:875–6.
    1. Van Halm VP, Peters MJ, Voskuyl AE, Boers M, Lems WF, Visser M, et al. Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross‐sectional study, the CARRE Investigation. Ann Rheum Dis 2009;68:1395–400.
    1. Peters MJ, van Halm VP, Voskuyl AE, Smulders YM, Boers M, Lems WF, et al. Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum 2009;61:1571–9.
    1. Agca R, Heslinga SC, Rollefstad S, Heslinga M, McInnes IB, Peters MJ, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2017;76:17–28.
    1. Johnsson H, McInnes IB, Sattar N. Cardiovascular and metabolic risks in psoriasis and psoriatic arthritis: pragmatic clinical management based on available evidence. Ann Rheum Dis 2012;71:480–3.
    1. Shrestha A, Bahce‐Altuntas A, Mowrey W, Broder A. Active peripheral inflammation is associated with pro‐atherogenic lipid profile in psoriatic arthritis. Semin Arthritis Rheum 2016;46:286–90.
    1. Smolen JS, Schöls M, Braun J, Dougados M, FitzGerald O, Gladman DD, et al. Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force. Ann Rheum Dis 2018;77:3–17.
    1. Mease P, Hall S, Fitzgerald O, van der Heijde D, Merola JF, Avila‐Zapata F, et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med 2017;377:1537–50.
    1. Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba A, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N Engl J Med 2017;377:1525–36.
    1. Nash P, Coates LC, Kivitz AJ, Mease PJ, Gladman DD, Covarrubias‐Cobos JA, et al. Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, up to 24 months in patients with active psoriatic arthritis: interim data from OPAL Balance, an open‐label, long‐term extension study [abstract]. Ann Rheum Dis 2017;76:682.
    1. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006;54:2665–73.
    1. Helliwell PS, FitzGerald O, Fransen J, Gladman DD, Kreuger GG, Callis‐Duffin K, et al. The development of candidate composite disease activity and responder indices for psoriatic arthritis (GRACE project). Ann Rheum Dis 2013;72:986–91.
    1. Mumtaz A, Gallagher P, Kirby B, Waxman R, Coates LC, Veale JD, et al. Development of a preliminary composite disease activity index in psoriatic arthritis. Ann Rheum Dis 2011;70:272–7.
    1. Schoels M. Psoriatic arthritis indices. Clin Exp Rheumatol 2014;32:S109–12.
    1. Daly L. Simple SAS macros for the calculation of exact binomial and Poisson confidence limits. Comput Biol Med 1992;22:351–61.
    1. Daly L, Bourke GJ, McGilvray J. Interpretation and use of medical statistics, 4th ed Oxford: Blackwell Scientific Publications; 1991.
    1. Charles‐Schoeman C, Gonzalez‐Gay MA, Kaplan I, Boy M, Geier J, Luo Z, et al. Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: implications for the rheumatologist. Semin Arthritis Rheum 2016;46:71–80.
    1. Wu JJ, Strober BE, Hansen PR, Ahlehoff O, Egeberg A, Qureshi A, et al. Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long‐term extension data in patients with plaque psoriasis. J Am Acad Dermatol 2016;75:897–905.
    1. Wolk R, Armstrong EJ, Hansen PR, Thiers B, Lan S, Tallman AM, et al. Effect of tofacitinib on lipid levels and lipid‐related parameters in patients with moderate to severe psoriasis. J Clin Lipidol 2017;11:1243–56.
    1. Charles‐Schoeman C, Wicker P, Gonzalez‐Gay MA, Boy M, Zuckerman A, Soma K, et al. Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor. Semin Arthritis Rheum 2016;46:261–71.
    1. Eder L, Wu Y, Chandran V, Cook R, Gladman DD. Incidence and predictors for cardiovascular events in patients with psoriatic arthritis. Ann Rheum Dis 2016;75:1680–6.
    1. Boers M, Nurmohamed MT, Doelman CJ, Lard LR, Verhoeven AC, Voskuyl AE, et al. Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis. Ann Rheum Dis 2003;62:842–5.
    1. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, et al. C‐reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004;350:1387–97.
    1. Franklin SS, Wong ND. Hypertension and cardiovascular disease: contributions of the Framingham Heart Study. Glob Heart 2013;8:49–57.
    1. Ogdie A, Yu Y, Haynes K, Love TJ, Maliha S, Jiang Y, et al. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population‐based cohort study. Ann Rheum Dis 2015;74:326–32.
    1. Mease PJ, McInnes IB, Gottlieb AB, Widmer A, Pricop L, Mpofu S. Secukinumab safety and tolerability in patients with active psoriatic arthritis and psoriasis: results from a pooled safety analysis [abstract]. Arthritis Rheumatol 2015;67 Suppl 10:2886.
    1. Savage LJ, Wittmann M, McGonagle D, Helliwell PS. Ustekinumab in the treatment of psoriasis and psoriatic arthritis. Rheumatol Ther 2015;2:1–16.
    1. Kitas GD, Gabriel SE. Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives. Ann Rheum Dis 2011;70:8–14.
    1. Toms TE, Panoulas VF, Kitas GD. Dyslipidaemia in rheumatological autoimmune diseases. Open Cardiovasc Med J 2011;5:64–75.
    1. Hudgins LC, Parker TS, Levine DM, Gordon BR, Saal SD, Jiang XC, et al. A single intravenous dose of endotoxin rapidly alters serum lipoproteins and lipid transfer proteins in normal volunteers. J Lipid Res 2003;44:1489–98.
    1. Miller IM, Skaaby T, Ellervik C, Jemec GB. Quantifying cardiovascular disease risk factors in patients with psoriasis: a meta‐analysis. Br J Dermatol 2013;169:1180–7.
    1. Labitigan M, Bahče‐Altuntas A, Kremer JM, Reed G, Greenberg JD, Jordan N, et al. Higher rates and clustering of abnormal lipids, obesity, and diabetes mellitus in psoriatic arthritis compared with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2014;66:600–7.
    1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–95.
    1. Husni ME, Wilson Tang WH, Lucke M, Chandrasekharan UM, Brennan DM, Hazen SL. Correlation of high‐density lipoprotein‐associated paraoxonase 1 activity with systemic inflammation, disease activity, and cardiovascular risk factors in psoriatic disease. Arthritis Rheumatol 2018;70:1240–50.
    1. Pfizer Inc . XELJANZ prescribing information. 2017. URL: .
    1. Pfizer Inc . XELJANZ summary of product characteristics. 2017. URL: .
    1. McInnes IB, Kim HY, Lee SH, Mandel D, Song YW, Connell CA, et al. Open‐label tofacitinib and double‐blind atorvastatin in rheumatoid arthritis patients: a randomised study. Ann Rheum Dis 2014;73:124–31.
    1. Kremer J, Cappelli LC, Etzel CJ, Greenberg J, Geier J, Madsen A, et al. Real‐world data from a post‐approval safety surveillance study of tofacitinib vs biologic DMARDS and conventional synthetic DMARDS: five‐year results from a US‐based rheumatoid arthritis registry [abstract]. Arthritis Rheumatol 2018;70 Suppl 10:1542.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj