Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study

Valenzuela, Fernando; Korman, Neil J.; Bissonnette, Robert; Bakos, Noémi; Tsai, Tsen‐Fang; Harper, Melanie; Ports, William C.; Tan, Huaming; Tallman, Anna M.; Valdez, Hernán; Gardner, Annie

doi:10.1111/bjd.16798

Cited by 53 publications

(50 citation statements)

References 27 publications

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“…In the present report, infections were found to be generally mild to moderate in severity and seldom led to study discontinuation. The IR of severe infections (1.4/100 p-y) did not increase over time and was comparable to that reported in pooled safety data for up to 5 years of treatment with the anti-IL-12 and anti-IL-23 agent ustekinumab (1.1/100 p-y) [25], in pooled safety data primarily for 3 years for the tumor necrosis factor (TNF) inhibitor adalimumab (1.8/100 p-y) [26] and in data for up to 66 months in a single study of the Janus kinase inhibitor tofacitinib (1.2/100 p-y) [27]. There were no reports of Grade 4 (\ 0.5 9 10 9 /L) neutropenia associated with infections; an infection temporally associated with Grade 3 (\ 1.0-0.5 9 10 9 /L) neutropenia was reported for three patients (0.1%; influenza [n = 1], otitis externa [n = 1] and nasopharyngitis [n = 1]) and infections associated with Grade 2 neutropenia (\ 1.5-1.0 9 10 9 /L) were reported for 27 (0.5%) patients.…”

Section: Discussionmentioning

confidence: 99%

Safety of Ixekizumab Treatment for up to 5 Years in Adult Patients with Moderate-to-Severe Psoriasis: Results from Greater Than 17,000 Patient-Years of Exposure

Armstrong

Paul

Puig

et al. 2019

Dermatol Ther (Heidelb)

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Introduction: Long-term safety data are critical for evaluating therapies for psoriasis. Ixekizumab has demonstrated efficacy and is well tolerated for the treatment of moderate-to-severe plaque psoriasis. We examined the safety and tolerability of up to 5 years of ixekizumab therapy in patients with psoriasis. Methods: Integrated safety data were analyzed from 13 ixekizumab clinical studies. Rates of treatment-emergent adverse events (TEAEs), serious AEs (SAEs) and AEs of special interest were analyzed for the 12-week induction period in the combined pivotal studies, and for all pooled studies by year(s) of therapy and overall, reported as exposure-adjusted incidence rates (IRs) per 100 patient-years (p-y) and/or frequencies. Results: Total ixekizumab exposure was 17,003.4 p-y (N = 5898); 2749 patients had C 4 years of exposure. When compared across years of exposure, rates for AEs remained largely stable or declined, including TEAEs leading to discontinuation (3.8/100 p-y in year 1, declining to 2.0/100 p-y in year 5); SAEs (range 6.2-7.0/100 p-y); serious infections (range 1.3-1.7/100 p-y); nonmelanoma skin cancer (ranging from 0.5/100 p-y in year 1 to Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.10067021.

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Section: Discussionmentioning

confidence: 99%

Safety of Ixekizumab Treatment for up to 5 Years in Adult Patients with Moderate-to-Severe Psoriasis: Results from Greater Than 17,000 Patient-Years of Exposure

Armstrong

Paul

Puig

et al. 2019

Dermatol Ther (Heidelb)

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“…Tofacitinib 10 mg was found to be non-inferior to etanercept, but tofacitinib 5 mg was not shown to be non-inferior to etanercept. 32 Although study results demonstrated that both the 5 mg and 10 mg doses were effective in treating plaque psoriasis, [33][34][35] the 10 mg dose was proven to be more efficacious. 36 However, this higher dose is associated with increased safety concerns, leading the FDA to decline approval of tofacitinib for moderate-to-severe plaque psoriasis.…”

Section: Psoriasis Clinical Trialsmentioning

confidence: 99%

<p>Tofacitinib in the management of active psoriatic arthritis: patient selection and perspectives</p>

Ly¹,

Beck²,

Smith³

et al. 2019

PTT

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Tofacitinib is an oral Janus kinase inhibitor approved for the treatment of psoriatic arthritis (PsA). It provides an alternative option for patients who have had an inadequate response and tolerance to other disease modifying antirheumatic drugs (DMARDs). It has demonstrated comparable efficacy to biologics, is effective in the management of treatment resistant disease, and is reported to improve enthesitis, dactylitis, and radiographic progression. Tofacitinib is also associated with an increased risk of serious infections, malignancy, and laboratory abnormalities. There is currently a large armamentarium of therapies for psoriatic arthritis, and choosing among treatments can be challenging. Due to this wide selection, a thorough assessment of psoriatic disease phenotype, patient preference, disease presentation, and comorbidities is critical. This review addresses key considerations in patient selection for the treatment of PsA with tofacitinib.

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“…Although phase III clinical trials for Tofacitinib showed an increased risk of cellulitis, herpes zoster, a decrease in neutropenia and increased levels of low- and high-density lipoproteins, this drug is still used due to lack of novel agents available to block the deleterious effects of IL-6 [110]. There are no cardiovascular risks reportedly associated with tofacitinib [111, 112], although trials examining specific benefits under pathological cardiovascular conditions are yet to be reported. Ruxolitinib is another orally bioavailable first-generation JAK inhibitor.…”

Section: Opportunities For Therapeutic Applicationsmentioning

confidence: 99%

Therapeutic Targeting of the Proinflammatory IL-6-JAK/STAT Signalling Pathways Responsible for Vascular Restenosis in Type 2 Diabetes Mellitus

Moshapa

Riches-Suman

Palmer

2019

Cardiology Research and Practice

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Type 2 diabetes mellitus (T2DM) is increasing worldwide, and it is associated with increased risk of coronary artery disease (CAD). For T2DM patients, the main surgical intervention for CAD is autologous saphenous vein grafting. However, T2DM patients have increased risk of saphenous vein graft failure (SVGF). While the mechanisms underlying increased risk of vascular disease in T2DM are not fully understood, hyperglycaemia, insulin resistance, and hyperinsulinaemia have been shown to contribute to microvascular damage, whereas clinical trials have reported limited effects of intensive glycaemic control in the management of macrovascular complications. This suggests that factors other than glucose exposure may be responsible for the macrovascular complications observed in T2DM. SVGF is characterised by neointimal hyperplasia (NIH) arising from endothelial cell (EC) dysfunction and uncontrolled migration and proliferation of vascular smooth muscle cells (SMCs). This is driven in part by proinflammatory cytokines released from the activated ECs and SMCs, particularly interleukin 6 (IL-6). IL-6 stimulation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT) pathway is a key mechanism through which EC inflammation, SMC migration, and proliferation are controlled and whose activation might therefore be enhanced in patients with T2DM. In this review, we investigate how proinflammatory cytokines, particularly IL-6, contribute to vascular damage resulting in SVGF and how suppression of proinflammatory cytokine responses via targeting the JAK/STAT pathway could be exploited as a potential therapeutic strategy. These include the targeting of suppressor of cytokine signalling (SOCS3), which appears to play a key role in suppressing unwanted vascular inflammation, SMC migration, and proliferation.

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Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study

Abstract: In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).

Cited by 53 publications

References 27 publications

Safety of Ixekizumab Treatment for up to 5 Years in Adult Patients with Moderate-to-Severe Psoriasis: Results from Greater Than 17,000 Patient-Years of Exposure

Safety of Ixekizumab Treatment for up to 5 Years in Adult Patients with Moderate-to-Severe Psoriasis: Results from Greater Than 17,000 Patient-Years of Exposure

<p>Tofacitinib in the management of active psoriatic arthritis: patient selection and perspectives</p>

Therapeutic Targeting of the Proinflammatory IL-6-JAK/STAT Signalling Pathways Responsible for Vascular Restenosis in Type 2 Diabetes Mellitus

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