The effects of the spleen tyrosine kinase inhibitor fostamatinib on ambulatory blood pressure in patients with active rheumatoid arthritis: results of the OSKIRA-ABPM (ambulatory blood pressure monitoring) randomized trial

Kitas, George D.; Abreu, Gabriel; Jedrychowicz-Rosiak, Krystyna; Miller, Jeffrey L.; Nakov, Roumen; Panfilov, Seva; Vencovský, Jiří; Wang, Millie; Weinblatt, Michael E.; White, William Β.

doi:10.1016/j.jash.2014.08.013

Cited by 10 publications

(7 citation statements)

References 40 publications

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“…Disease modifying drugs, especially methotrexate, may exhibit adverse effects on lipid profile and similar observations have been recently reported for IL-6 inhibitors [Souto et al 2015]. It is worth noting that even emerging treatments for RA including small molecules, such as spleen tyrosine kinase inhibitors, have been associated with high blood pressure in randomized controlled trials [Kitas et al 2014]. Given the wide variety of CV side effects related to the administration of broadly used conventional and biologic disease modifying drugs, the appreciation of unfavorable effects of individual regimens on traditional and disease-related CV risk factors represents an important element of CV prevention and physicians treating RA patients should be aware of this additional risk.…”

Section: Antirheumatic Drug-related Cardiotoxicitysupporting

confidence: 63%

Cardiovascular risk in rheumatoid arthritis: assessment, management and next steps

Zegkos

Kitas

Dimitroulas

2016

Therapeutic Advances in Musculoskeletal

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Rheumatoid arthritis (RA) is associated with increased cardiovascular (CV) morbidity and mortality which cannot be fully explained by traditional CV risk factors; cumulative inflammatory burden and antirheumatic medication-related cardiotoxicity seem to be important contributors. Despite the acknowledgment and appreciation of CV disease burden in RA, optimal management of individuals with RA represents a challenging task which remains suboptimal. To address this need, the European League Against Rheumatism (EULAR) published recommendations suggesting the adaptation of traditional risk scores by using a multiplication factor of 1.5 if two of three specific criteria are fulfilled. Such guidance requires proper coordination of several medical specialties, including general practitioners, rheumatologists, cardiologists, exercise physiologists and psychologists to achieve a desirable result. Tight control of disease activity, management of traditional risk factors and lifestyle modification represent, amongst others, the most important steps in improving CV disease outcomes in RA patients. Rather than enumerating studies and guidelines, this review attempts to critically appraise current literature, highlighting future perspectives of CV risk management in RA.

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Section: Antirheumatic Drug-related Cardiotoxicitysupporting

confidence: 63%

Cardiovascular risk in rheumatoid arthritis: assessment, management and next steps

Zegkos

Kitas

Dimitroulas

2016

Therapeutic Advances in Musculoskeletal

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“…In a study measuring ambulatory blood pressure over 24 h in patients with RA, fostamatinib reproducibly elevated blood pressure to a similar extent as to that observed in the phase II and III trials (Kitas et al. ). To date, there have been little or no signals of any associated side effects that may precede hypertensive changes (e.g., inhibition of renal function) leading to the hypothesis that the blood pressure increase may relate directly to the drug pharmacology rather than being a response to another initiating effect.…”

Section: Introductionsupporting

confidence: 56%

Prevention of fostamatinib‐induced blood pressure elevation by antihypertensive agents

Lengel

Bergström

Barthlow

et al. 2015

Pharmacology Res & Perspec

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Fostamatinib is a tyrosine kinase inhibitor with activity against spleen tyrosine kinase which has completed clinical trials for patients with rheumatoid arthritis. In clinical studies fostamatinib treatment was associated with a small elevation of systemic arterial blood pressure (BP), a similar finding to that seen with other kinase inhibitors, especially those that inhibit VEGFR2 signaling. We have investigated the link between fostamatinib-induced blood pressure elevation and plasma levels of the fostamatinib-active metabolite R940406 in conscious rats and found the time course of the BP effect correlated closely with changes in R940406 plasma concentration, indicating a direct pharmacological relationship. Free plasma levels of R940406 produced in these studies (up to 346 nmol/L) span the clinically observed mean peak free plasma concentration of 49 nmol/L. We have demonstrated that the blood pressure elevation induced by fostamatinib dosing can be successfully controlled by a variety of methods, notably simple drug withdrawal or codosing with a range of standard antihypertensive agents such as atenolol, captopril, and nifedipine. These findings support potential methods of maintaining patient safety while on fostamatinib therapy. Furthermore, we have demonstrated, using nifedipine as an example agent, that this blood pressure control was not achieved by reduction in plasma exposure of R940406, suggesting that potential benefits from the pharmacology of the investigational drug can be maintained while blood pressure control is managed by use of standard comedications.

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“…Prior investigations in animal models and in vitro have shown that fostamatinib reduces vascular endothelial growth factor receptor 2–mediated endothelial nitric oxide availability, resulting in impaired vasorelaxation, which in turn leads to increased vascular resistance and increases in BP (). A separate report that addresses the effect of fostamatinib on 24‐hour ambulatory systolic BP in patients in the OSKIRA study program (the ambulatory BP monitoring [ABPM] trial) has recently been published ().…”

Section: Discussionmentioning

confidence: 99%

Effects of Fostamatinib, an Oral Spleen Tyrosine Kinase Inhibitor, in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate: Results From a Phase III, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Study

Weinblatt

Genovese

et al. 2014

Arthritis & Rheumatology

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Objective. This phase III, 52-week study compared fostamatinib with placebo (for 24 weeks) in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) therapy.Methods. Patients taking MTX were randomized(1:1:1) to receive fostamatinib 100 mg twice daily for 52 weeks (group A), fostamatinib 100 mg twice daily for 4 weeks and then 150 mg once daily (group B), or placebo for 24 weeks and then fostamatinib 100 mg twice daily (group C). At week 24, the co-primary end points were change from baseline in the American College of Rheumatology 20% (ACR20) improvement response rates and change in the modified total Sharp/van der Heijde score of radiographic damage (SHS).Results. In this study, 918 patients were randomized and received >1 dose of study drug (fostamatinib or placebo); the demographic and baseline clinical characteristics were well balanced. Following treatment with both fostamatinib regimens, a statistically significant difference in the ACR20 improvement response was achieved at week 24 as compared with that in patients receiving placebo (49.0% [group A] and 44.4%, [group B] versus 34.2%; P < 0.001 and P ‫؍‬ 0.006, respectively), but there was no statistically significant difference in the SHS between either fostamatinib group and placebo (P ‫؍‬ 0.25 and P ‫؍‬ 0.17, respectively). The most common adverse events in patients in groups A, B, and C were hypertension (15.8%, 15.1%, and 3.9%, respectively) and diarrhea (13.9%, 15.1%, and 3.9%, respectively). Elevated blood pressure (>140/90 mm Hg) occurred at >1 visit in 44.2%, 41.6%, and 19.3% of patients in each respective group.Conclusion. With the use of either fostamatinib regimen in patients with RA, statistically significant, but not clinically significant, improvements in the ACR20 improvement response over placebo were achieved at ClinicalTrials.gov identifier: NCT01197521.

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The effects of the spleen tyrosine kinase inhibitor fostamatinib on ambulatory blood pressure in patients with active rheumatoid arthritis: results of the OSKIRA-ABPM (ambulatory blood pressure monitoring) randomized trial

Cited by 10 publications

References 40 publications

Cardiovascular risk in rheumatoid arthritis: assessment, management and next steps

Cardiovascular risk in rheumatoid arthritis: assessment, management and next steps

Prevention of fostamatinib‐induced blood pressure elevation by antihypertensive agents

Effects of Fostamatinib, an Oral Spleen Tyrosine Kinase Inhibitor, in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate: Results From a Phase III, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Study

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