Baricitinib Safety for Events of Special Interest in Populations at Risk: Analysis from Randomised Trial Data Across Rheumatologic and Dermatologic Indications

Taylor, Peter C; Bieber, Thomas; Alten, Rieke; Witte, Torsten; Galloway, James; Deberdt, Walter; Issa, Maher; Haładyj, Ewa; Torre, Inmaculada de la; Grond, Susanne; Wollenberg, Andreas

doi:10.1007/s12325-023-02445-w

Cited by 19 publications

(9 citation statements)

References 63 publications

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“…JAK inhibitors are broad-acting therapeutics, but may be associated with significant safety concerns including the boxed warning related to cardiovascular and cancer risks [ 46 , 48 , 69 ] based on studies in rheumatoid arthritis [ 46 , 70 , 71 ]. In patients with AD, however, both risk factors and cardiovascular adverse events are less prevalent compared with rheumatoid arthritis [ 72 ]. The European Medicines Agency has published risk factors for patients using JAK inhibitors, but not changed the dermatological indications for the substance class [ 73 ].…”

Section: Need For Improved Therapeutic Options For Atopic Dermatitismentioning

confidence: 99%

OX40 in the Pathogenesis of Atopic Dermatitis—A New Therapeutic Target

Croft,

Esfandiari,

Chong

et al. 2024

Am J Clin Dermatol

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Atopic dermatitis (AD) is a chronic, heterogeneous, inflammatory disease characterized by skin lesions, pruritus, and pain. Patients with moderate-to-severe AD experience chronic symptoms, intensified by unpredictable flares, and often have comorbidities and secondary complications, which can result in significant clinical burden that impacts the patient’s overall quality of life. The complex interplay of immune dysregulation and skin barrier disruption drives AD pathogenesis, of which T-cell-dependent inflammation plays a critical role in patients with AD. Despite new targeted therapies, many patients with moderate-to-severe AD fail to achieve or sustain their individual treatment goals and/or may not be suitable for or tolerate these therapies. There remains a need for a novel, efficacious, well-tolerated therapeutic option that can deliver durable benefits across a heterogeneous AD patient population. Expression of OX40 [tumor necrosis factor receptor superfamily, member 4 (TNFRSF4)], a prominent T-cell co-stimulatory molecule, and its ligand [OX40L; tumor necrosis factor superfamily, member 4 (TNFSF4)] is increased in AD. As the OX40 pathway is critical for expansion, differentiation, and survival of effector and memory T cells, its targeting might be a promising therapeutic approach to provide sustained inhibition of pathogenic T cells and associated inflammation and broad disease control. Antibodies against OX40 [rocatinlimab (AMG 451/KHK4083) and telazorlimab (GBR 830)] or OX40L [amlitelimab (KY1005)] have shown promising results in early-phase clinical studies of moderate-to-severe AD, highlighting the importance of OX40 signaling as a new therapeutic target in AD. Graphical Abstract

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Section: Need For Improved Therapeutic Options For Atopic Dermatitismentioning

confidence: 99%

OX40 in the Pathogenesis of Atopic Dermatitis—A New Therapeutic Target

Croft,

Esfandiari,

Chong

et al. 2024

Am J Clin Dermatol

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“…Post hoc analyses of ORAL Surveillance found that rates of MACE with JAK inhibitors primarily occurred in patients with preexisting atherosclerotic cardiovascular disease and that the risk of VTE and MACE was higher for those with active RA . Another study found that the incidence rates of MACE and VTE with JAK inhibitors were lower for patients with fewer cardiovascular risk factors across conditions, including RA. It is likely that the patients included in the dermatology RCTs had fewer cardiovascular comorbidities than the patients enrolled in the rheumatology RCTs.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular and Venous Thromboembolic Risk With JAK Inhibitors in Immune-Mediated Inflammatory Skin Diseases

Ingrassia,

Maqsood,

Gelfand

et al. 2024

JAMA Dermatol

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ImportanceJanus kinase (JAK) inhibitors are an effective treatment option for patients with certain skin-related conditions, such as atopic dermatitis, alopecia areata, and vitiligo, but there is a current US Food and Drug Administration (FDA) boxed warning label for oral and topical JAK inhibitors regarding increased risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), serious infections, malignant neoplasm, and death. However, this boxed warning was precipitated by results of the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance study, which only included patients with rheumatoid arthritis, and the same association may not be observed in dermatologic conditions.ObjectiveTo determine the risk of all-cause mortality, MACE, and VTE with JAK inhibitors in patients with dermatologic conditions.Data SourcesPubMed and ClinicalTrials.gov were searched from database inception to April 1, 2023.Study SelectionThis review included phase 3 randomized clinical trials with a placebo/active comparator group of JAK inhibitors used for a dermatologic indication with FDA approval or pending approval or with European Union or Japanese approval. Studies without a comparison group, case reports, observational studies, and review articles were excluded.Data Extraction and SynthesisThis study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Adverse events using odds ratios (ORs) and 95% CIs were calculated using a random-effects model and the DerSimonian-Laird method. Studies were screened, data abstracted, and quality assessed by 2 independent authors. The protocol was prospectively registered with PROSPERO.Main Outcomes and MeasuresPrimary outcomes were a composite of adjudicated MACE and all-cause mortality, and VTE.ResultsThe analysis included 35 randomized clinical trials with 20 651 patients (mean [SD] age, 38.5 [10.1] years; male, 54%) and a mean (SD) follow-up time of 4.9 (2.68) months. Findings did not show a significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (OR, 0.83; 95% CI, 0.44-1.57) or VTE (OR, 0.52; 95% CI, 0.26-1.04).Conclusions and RelevanceIn this systematic review and meta-analysis, use of JAK inhibitors was not associated with increased risk of all-cause mortality, MACE, and VTE compared to the placebo/active comparator groups. Additional trials with long-term follow-up are needed to better understand the safety risks of JAK inhibitors used for dermatologic indications.

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“…66 These warnings include the risks of serious cardiovascular-related events, cancer, blood clots, of the JAK inhibitor-related adverse events of special interest. 67 Overall, JAK inhibitors can cause off-target harm, but their longer-term adverse effects remain to be fully clarified. 61,68 Therefore, a fully informed and responsible treatment decision requires a sober risk-cost-benefit calculation.…”

Section: Risks For the Treatment Of Aamentioning

confidence: 99%

“…They were based on a study comparing the side effects in 1450 patients with rheumatoid arthritis receiving 5–10 mg twice daily oral tofacitinib or tumor necrosis factor (TNF)‐α inhibitor injections for about 40 months. An analysis of pooled data from clinical trials and long‐term extensions in patients with RA, AD, and AA including baricitinib exposure up to 9.3 years revealed that populations with low risk have low incidence of the JAK inhibitor‐related adverse events of special interest 67 …”

Section: Jak In Aamentioning

confidence: 99%

Alopecia areata: What's new in the diagnosis and treatment with JAK inhibitors?

Dainichi,

Iwata,

Kaku

2023

The Journal of Dermatology

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Alopecia areata (AA) affects individuals of all ages and is intractable in severe relapsing cases. Dermatologists and other healthcare providers should consider AA in the medical context and prioritize treatment. Several randomized controlled clinical studies on Janus kinase (JAK) inhibitors with different specificities for the treatment of AA are ongoing. These studies have encouraged us to appreciate the importance of a definitive diagnosis and accurate evaluation of AA before and during treatment. Following our previous review article in 2017, here we provide the second part of this two‐review series on the recent progress in the multidisciplinary approaches to AA from more than 1800 articles published between July 2016 and December 2022. This review focuses on the evaluation, diagnosis, and treatment of AA. We also provide the latest information on the safety and efficacy of JAK inhibitors for the treatment of AA and describe their mechanisms of action.

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Baricitinib Safety for Events of Special Interest in Populations at Risk: Analysis from Randomised Trial Data Across Rheumatologic and Dermatologic Indications

Cited by 19 publications

References 63 publications

OX40 in the Pathogenesis of Atopic Dermatitis—A New Therapeutic Target

OX40 in the Pathogenesis of Atopic Dermatitis—A New Therapeutic Target

Cardiovascular and Venous Thromboembolic Risk With JAK Inhibitors in Immune-Mediated Inflammatory Skin Diseases

Alopecia areata: What's new in the diagnosis and treatment with JAK inhibitors?

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