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• Response to: Inhaled corticosteroids are safe and crucial for treatment of asthma
  Merel van der Meulen, Olaf M Dekkers and Onno C Meijer
  Published on: 30 October 2022
• Inhaled corticosteroids are safe and crucial for treatment of asthma
  Deborah R Liptzin, Bruce G. Bender and Stanley J Szefler
  Published on: 17 October 2022

• Published on: 30 October 2022

  Response to: Inhaled corticosteroids are safe and crucial for treatment of asthma

  • Merel van der Meulen, PhD student Leiden University Medical Center
  • Other Contributors:
    • Olaf M Dekkers, Professor of Internal Medicine
    • Onno C Meijer, Professor of Molecular neuroendocrinology of corticosteroids

  We thank dr. Liptzin for her nuanced response to our publication Association between use of systemic and inhaled glucocorticoids and changes in brain volume and white matter microstructure: a cross-sectional study using data from the UK Biobank.
  We agree with the author that inhaled glucocorticoids are still a crucial part of current asthma treatment and that for the large majority of patients, they are safe too. Nevertheless, various studies have shown that even inhaled glucocorticoids can have side effects, including neuropsychiatric symptoms, due to a (relatively small) systemic uptake of glucocorticoids [1-4]. Generally, physicians are aware that limiting glucocorticoid exposure as much as a patient’s condition allows is desirable, and as illustrated by dr. Liptzin, important efforts have already been made in that direction. Sometimes, however, a patient requires higher doses of inhaled or systemic glucocorticoids, for lack of a better alternative. Importantly, not all prescribers may be aware of the substantial differences in potency of inhaled glucocorticoids that are on the market [5].
  In our study, we show that systemic glucocorticoid use is associated with a decreased white matter integrity, and to a smaller extent a similar pattern was seen in patients using inhaled glucocorticoids. It is likely that the clinical significance of these effects is small, at least for most patients. Yet, we cannot rule out the possibility that these observations contribu...

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  We thank dr. Liptzin for her nuanced response to our publication Association between use of systemic and inhaled glucocorticoids and changes in brain volume and white matter microstructure: a cross-sectional study using data from the UK Biobank.
  We agree with the author that inhaled glucocorticoids are still a crucial part of current asthma treatment and that for the large majority of patients, they are safe too. Nevertheless, various studies have shown that even inhaled glucocorticoids can have side effects, including neuropsychiatric symptoms, due to a (relatively small) systemic uptake of glucocorticoids [1-4]. Generally, physicians are aware that limiting glucocorticoid exposure as much as a patient’s condition allows is desirable, and as illustrated by dr. Liptzin, important efforts have already been made in that direction. Sometimes, however, a patient requires higher doses of inhaled or systemic glucocorticoids, for lack of a better alternative. Importantly, not all prescribers may be aware of the substantial differences in potency of inhaled glucocorticoids that are on the market [5].
  In our study, we show that systemic glucocorticoid use is associated with a decreased white matter integrity, and to a smaller extent a similar pattern was seen in patients using inhaled glucocorticoids. It is likely that the clinical significance of these effects is small, at least for most patients. Yet, we cannot rule out the possibility that these observations contribute to neuropsychiatric symptoms in some patients using inhaled glucocorticoids. As for the reversibility of these associations, no conclusions can be drawn based on the present cross-sectional study. From studies in patients with Cushing disease, who have been exposed to very high levels of cortisol for a long period of time, we know that not all effects of glucocorticoid exposure on the brain are reversible upon normalization of cortisol levels [6-9]. However, patterns in Cushing disease cannot be directly compared to the daily practice of synthetic glucocorticoid use.
  The danger of media attention for scientific research is that nuance can be lost, even though the discussion section of our paper tried to bring forward many nuances. It would be highly regrettable, and by no means in line with the intention of the paper, if patients or their parents refused essential glucocorticoid therapy out of fear of brain changes.
  Our publication is part of a long process of unraveling the interaction between glucocorticoids and the brain. As such, it contributes to our basic understanding of our stress system, and also emphasizes – yet again – the need to dose glucocorticoids as low as possible until alternative treatment options are available. The future may even show the need of individualized approaches, given the differences in glucocorticoid sensitivity that exist between subjects [10]. Of course, many questions remain to be elucidated. Whether white and grey matter changes can also be observed in younger patients using inhaled glucocorticoids, as questioned by dr. Liptzin, is one of those questions that deserves attention in future research.

  References
  1. Savas M, Muka T, Wester VL, van den Akker ELT, Visser JA, Braunstahl GJ, et al. Associations Between Systemic and Local Corticosteroid Use With Metabolic Syndrome and Body Mass Index. J Clin Endocrinol Metab. 2017;102(10):3765-74.
  2. Savas M, Vinkers CH, Rosmalen JGM, Hartman CA, Wester VL, van den Akker ELT, et al. Systemic and Local Corticosteroid Use Is Associated with Reduced Executive Cognition, and Mood and Anxiety Disorders. Neuroendocrinology. 2020;110(3-4):282-91.
  3. Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM. Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2015;100(6):2171-80.
  4. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch Intern Med. 1999;159(9):941-55.
  5. Daley-Yates PT. Inhaled corticosteroids: potency, dose equivalence and therapeutic index. Br J Clin Pharmacol. 2015;80(3):372-80.
  6. Bauduin S, van der Pal Z, Pereira AM, Meijer OC, Giltay EJ, van der Wee NJA, et al. Cortical thickness abnormalities in long-term remitted Cushing's disease. Transl Psychiatry. 2020;10(1):293.
  7. Andela CD, van der Werff SJ, Pannekoek JN, van den Berg SM, Meijer OC, van Buchem MA, et al. Smaller grey matter volumes in the anterior cingulate cortex and greater cerebellar volumes in patients with long-term remission of Cushing's disease: a case-control study. Eur J Endocrinol. 2013;169(6):811-9.
  8. Andela CD, van Haalen FM, Ragnarsson O, Papakokkinou E, Johannsson G, Santos A, et al. MECHANISMS IN ENDOCRINOLOGY: Cushing's syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies. Eur J Endocrinol. 2015;173(1):R1-14.
  9. van der Werff SJ, Andela CD, Nienke Pannekoek J, Meijer OC, van Buchem MA, Rombouts SA, et al. Widespread reductions of white matter integrity in patients with long-term remission of Cushing's disease. Neuroimage Clin. 2014;4:659-67.
  10. Quax RA, Manenschijn L, Koper JW, Hazes JM, Lamberts SW, van Rossum EF, et al. Glucocorticoid sensitivity in health and disease. Nat Rev Endocrinol. 2013;9(11):670-86.

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  Conflict of Interest:
  Onno C. Meijer receives research funding from Corcept Therapeutics, Menlo Park, USA.

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• Published on: 17 October 2022

  Inhaled corticosteroids are safe and crucial for treatment of asthma

  • Deborah R Liptzin, MD pediatric pulmonologist University of Colorado School of Medicine
  • Other Contributors:
    • Bruce G. Bender, Psychologist and Professor, University of Colorado School of Medicine
    • Stanley J Szefler, Pediatric allergist and Professor, University of Colorado School of Medicine

  We read with interest and concern the published report by van der Meulen et al:(1) Association between use of systemic and inhaled glucocorticoids and changes in brain volume and white matter microstructure: a cross-sectional study using data from the UK biobank.
  Inhaled corticosteroids have revolutionized asthma care for children. In the 1980's, several of us remember the pediatric inpatient service at National Jewish Health with its steroid dependent children with asthma, many with multiple adverse effects related to systemic steroid therapy including short stature, osteoporosis and adrenal suppression. Theophylline was the other maintenance medication with its narrow therapeutic window, requirement for therapeutic monitoring and significant risk for adverse effects.(2) Based on this past history of adverse effects related to systemic steroid therapy, parents are often reluctant to start or continue their children on any form of steroid therapy, including inhaled forms.(3) While inhaled corticosteroids may be associated with some small impact on height in early childhood, they are considered very safe, especially at low dose.(4) Using the lowest dose of inhaled corticosteroid to maintain asthma control along with a spacer device, will further reduce risk of adverse effects.(5)
  The van der Meulen publication, at least by publication title, unfortunately lumps both forms of steroids together and thus, raise concern over effects of all corticosteroids...

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  We read with interest and concern the published report by van der Meulen et al:(1) Association between use of systemic and inhaled glucocorticoids and changes in brain volume and white matter microstructure: a cross-sectional study using data from the UK biobank.
  Inhaled corticosteroids have revolutionized asthma care for children. In the 1980's, several of us remember the pediatric inpatient service at National Jewish Health with its steroid dependent children with asthma, many with multiple adverse effects related to systemic steroid therapy including short stature, osteoporosis and adrenal suppression. Theophylline was the other maintenance medication with its narrow therapeutic window, requirement for therapeutic monitoring and significant risk for adverse effects.(2) Based on this past history of adverse effects related to systemic steroid therapy, parents are often reluctant to start or continue their children on any form of steroid therapy, including inhaled forms.(3) While inhaled corticosteroids may be associated with some small impact on height in early childhood, they are considered very safe, especially at low dose.(4) Using the lowest dose of inhaled corticosteroid to maintain asthma control along with a spacer device, will further reduce risk of adverse effects.(5)
  The van der Meulen publication, at least by publication title, unfortunately lumps both forms of steroids together and thus, raise concern over effects of all corticosteroids on white volume and white matter. Upon reading the publication carefully, the major effect on these measures, if clinically significant, would be largely related to systemic steroids. The publication should have been clearer in differentiating the effect based on historical information for the two forms of steroid therapy. Noteworthy is that a number of those on systemic steroids had other diseases, such as autoimmune disease that could have its own effect on these measures.
  Unfortunately, the finding of white matter volume changes in patients treated with glucocorticoids opens the door to arguing that glucocorticoids, inhaled or oral, cause permanent changes in the brain structures and should be avoided. This position is inconsistent with a history of studies showing that in many cases glucocorticoids side effects are temporary. “Steroid dementia” and “steroid psychosis” often appear within the first few days or weeks of treatment,(6) too soon to have produced structural brain changes. Further, side effects are frequently dose dependent (7, 8) and often reverse after discontinuation of treatment.(8, 9) These studies suggest that for many--if not all—patients, glucocorticoids do not produce permanent changes in brain structure. Until more is known, and additional research with more tightly controlled information about type and dose of glucocorticoids is conducted, decisions about glucocorticoids should not be based on this single report.
  There are many strategies that can be applied to further reduce exposure to steroid therapy in the treatment of asthma. The 2020 GINA guidelines endorsed SMART or single maintenance and reliever therapy using combination medication of inhaled steroid and formoterol, anywhere from as needed to scheduled daily with as needed.(10) Studies have shown that using the "SMART" approach can lead to decreased exacerbations including reduced need for systemic corticosteroids as well as reduce exposure to the total dose of inhaled steroid therapy.(11) Other approaches to reducing steroid therapy exposure include quick relief medications such as albuterol and ipratropium, but these do not treat airways inflammation and do not prevent exacerbations. Leukotriene antagonists such as montelukast can be a very effective therapy in about 50% of asthmatics, but in the remaining 50% it is ineffective, and in 10% of children, it can cause nightmare, behavior changes, and even psychosis.(12) Tiotropium is an effective adjunctive therapy in many asthmatics, but has not been recommended as monotherapy.(13) Novel biologic medications for asthma such as omalizumab, mepolizumab, and dupilomab are highly effective therapeutics, and can help to minimize courses of systemic steroid therapy for acute exacerbations.(14)
  Our concern is that this publication could prompt parents to decide not to use inhaled corticosteroid therapy or refuse courses of systemic steroid therapy when necessary. With the limited use of systemic steroids in modern day treatment of asthma, we believe the younger patients of today are receiving much lower steroid exposure then the older participants evaluated in this study. It is indeed possible that these older patients currently receiving inhaled steroid therapy alone may have received higher courses of systemic steroid therapy in the past, leading to the current modest effects reported in this study. Therefore, evaluation of the younger patient population in a similar study would likely reveal much less associated features on brain volume and white matter. We encourage the investigators to conduct further studies of their observation in patients receiving modern day asthma therapy.

  References:

  1. van der Meulen M, Amaya JM, Dekkers OM, Meijer OC. Association between use of systemic and inhaled glucocorticoids and changes in brain volume and white matter microstructure: a cross-sectional study using data from the UK Biobank. BMJ Open. 2022;12(8):e062446.
  2. Weinberger M, Hendeles L. Theophylline for chronic asthma: rationale for treatment, product selection, and dosage schedule. Pediatr Pharmacol (New York). 1983;3(3-4):273-85.
  3. Bender BG, Bender SE. Patient-identified barriers to asthma treatment adherence: responses to interviews, focus groups, and questionnaires. Immunol Allergy Clin North Am. 2005;25(1):107-30.
  4. Szefler S, Weiss S, Tonascia J, Adkinson NF, Bender B, Cherniack R, et al. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000;343(15):1054-63.
  5. Volerman A, Balachandran U, Siros M, Akel M, Press VG. Mask Use with Spacers/Valved Holding Chambers and Metered Dose Inhalers among Children with Asthma. Ann Am Thorac Soc. 2021;18(1):17-22.
  6. Deyo RA. Drug therapy for back pain. Which drugs help which patients? Spine (Phila Pa 1976). 1996;21(24):2840-9; discussion 9-50.
  7. Brown ES, Suppes T. Mood symptoms during corticosteroid therapy: a review. Harv Rev Psychiatry. 1998;5(5):239-46.
  8. Lewis DA, Smith RE. Steroid-induced psychiatric syndromes. A report of 14 cases and a review of the literature. J Affect Disord. 1983;5(4):319-32.
  9. Ancelin ML, Carrière I, Helmer C, Rouaud O, Pasquier F, Berr C, et al. Steroid and nonsteroidal anti-inflammatory drugs, cognitive decline, and dementia. Neurobiol Aging. 2012;33(9):2082-90.
  10. Global Initiative for Asthma. Global Strategy for Asthma Management and
  Prevention. 2022 [Available from: https://ginasthma.org/reports.
  11. Reddel HK, Bateman ED, Schatz M, Krishnan JA, Cloutier MM. A Practical Guide to Implementing SMART in Asthma Management. J Allergy Clin Immunol Pract. 2022;10(1S):S31-S8.
  12. Glockler-Lauf SD, Finkelstein Y, Zhu J, Feldman LY, To T. Montelukast and Neuropsychiatric Events in Children with Asthma: A Nested Case-Control Study. J Pediatr. 2019;209:176-82.e4.
  13. Lazarus SC, Krishnan JA, King TS, Lang JE, Blake KV, Covar R, et al. Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level. N Engl J Med. 2019;380(21):2009-19.
  14. Menzies-Gow A, Szefler SJ, Busse WW. The Relationship of Asthma Biologics to Remission for Asthma. J Allergy Clin Immunol Pract. 2021;9(3):1090-8.

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  Conflict of Interest:
  None declared.

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