Long‐term corticosteroid use, adrenal insufficiency and the need for steroid‐sparing treatment in adult severe asthma

Gurnell, Mark; Heaney, Liam G.; Price, David; Menzies‐Gow, Andrew

doi:10.1111/joim.13273

Cited by 22 publications

(24 citation statements)

References 87 publications

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“…This may limit the risk of steroid-related side effects such as adrenal suppression and delayed growth in children. 7 , 58 , 59 Development of new small-molecule drugs with broader immunomodulatory effects and suitability for delivery by inhalation may be more effective than blocking the action of a single cytokine while still conferring corticosteroid-sparing advantages, and may potentially expand treatment options for patients with asthma.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma

Nilsson¹,

Rhedin²,

Hendrickx³

et al. 2022

DDDT

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Purpose Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation. Methods The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 μg/kg and AZD4604 at 30 µg/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]). Results Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model. Conclusion AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.

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Section: Discussionmentioning

confidence: 99%

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma

Nilsson¹,

Rhedin²,

Hendrickx³

et al. 2022

DDDT

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show abstract

“…Recommendation : Given the long duration of steroid treatment that may be required for some patients, consultation with an endocrinologist may be considered when pursuing treatment, given the risk of adrenal insufficiency. 74 This is important to ensure adrenal function is normal in treated patients, especially in context of a respiratory infection or other physiological stress. Examinations in older children may include a morning (8:00 AM) cortisol test and adrenocorticotropic hormone (ACTH) stimulation tests to ensure patients have recovered normal adrenal function after steroid exposure.…”

Section: Post‐dosage Monitoring and Management Of Corticosteroidsmentioning

confidence: 99%

“…Recommendation: Given the long duration of steroid treatment that may be required for some patients, consultation with an endocrinologist may be considered when pursuing treatment, given the risk of adrenal insufficiency. 74 Recommendation: For patients receiving prolonged corticosteroids, physicians should consider using injectable stress dosing hydrocortisone if evidence of acute illness presents in the post-dosage period. Physicians may also consider consultation with an endocrinologist in the context of acute illness of a hospitalized child receiving post-dose corticosteroids.…”

Section: Role Of Prophylactic Prednisolonementioning

confidence: 99%

Section: Post‐dosage Monitoring and Management Of Corticosteroidsmentioning

confidence: 99%

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Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy

et al. 2021

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Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disease caused by biallelic mutations in the survival motor neuron 1 (SMN1) gene. SMA is characterized by motor neuron degeneration, resulting in progressive muscle atrophy and weakness. Before the emergence of disease-modifying therapies, children with the most severe form of SMA would never achieve the ability to sit independently.Only 8% survived beyond 20 months of age without permanent ventilator support.One such therapy, onasemnogene abeparvovec, an adeno-associated virus-based gene replacement therapy, delivers functional human SMN through a one-time intravenous infusion. In addition to substantially improving survival, onasemnogene abeparvovec was found to increase motor milestone attainment and reduce the need for respiratory or nutritional support in many patients. This expert opinion provides recommendations and practical considerations on the patient-centered decisions to use onasemnogene abeparvovec. Recommendations include the need for patientcentered multidisciplinary care and patient selection to identify those with underlying medical conditions or active infections to reduce risks. We also describe the importance of retesting patients with elevated anti-adeno-associated virus serotype 9 antibodies. Recommendations for prednisolone tapering and monitoring for potential adverse events, including hepatotoxicity and thrombotic microangiopathy, are described. The need for caregiver education on managing day-to-day care at time of treatment and patient-and family-centered discussions on realistic expectations are also recommended. We detail the importance of following standard-of-care guidance and long-term monitoring of all children with SMA who have received one or more

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“…OCS-sparing treatment strategies are increasingly important in improving patient outcomes, 11,12,21 due to the well-known toxicity and morbidity burden associated with long-term OCS use, 6,8,12,22 in addition to the greater health care costs and health care resource utilization connected with their use. 9,10,22 GINA 2020 recommended that, whereas add-on maintenance OCS of 7.5 or more mg/d prednisone equivalent may be needed for some patients with severe asthma, because of serious side effects, maintenance OCS should be avoided if other options are available for the management of severe asthma.…”

Section: Discussionmentioning

confidence: 99%

Dupilumab Efficacy in Steroid-Dependent Severe Asthma by Baseline Oral Corticosteroid Dose

Domingo

Máspero

Castro

et al. 2022

The Journal of Allergy and Clinical Immunology: In Practice

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Long‐term corticosteroid use, adrenal insufficiency and the need for steroid‐sparing treatment in adult severe asthma

Abstract: Long-term corticosteroid use, adrenal insufficiency and the need for steroidsparing treatment in adult severe asthma (Review).

Cited by 22 publications

References 87 publications

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma

Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy

Dupilumab Efficacy in Steroid-Dependent Severe Asthma by Baseline Oral Corticosteroid Dose

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