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Dose-related patterns of glucocorticoid-induced side effects
Abstract
Objective To identify patterns of self-reported health problems relating to dose and duration of glucocorticoid intake in unselected patients with rheumatoid arthritis from routine practice. Methods Data from 1066 patients were analysed. The clinical status and drug treatment were reported by the physician, health problems during the past 6 months by the patient using a comprehensive list of symptoms. Patients with ongoing glucocorticoid treatment for more than 6 months and current doses of less than 5, 5-7.5 and over 7.5 mg/day prednisone equivalent were compared with a group without any glucocorticoid treatment for at least 12 months. Results The frequency of self-reported health problems was lowest in the group without glucocorticoid exposition and increased with dosage. Two distinct dose-related patterns of adverse events were observed. A "linear" rising with increasing dose was found for cushingoid phenotype, ecchymosis, leg oedema, mycosis, parchment-like skin, shortness of breath and sleep disturbance. A "threshold pattern" describing an elevated frequency of events beyond a certain threshold value was observed at dosages of over 7.5 mg/day for glaucoma, depression/listlessness and increase in blood pressure. Dosages of 5 mg/day or more were associated with epistaxis and weight gain. A very low threshold was seen for eye cataract (<5 mg/day). Conclusion The associations found are in agreement with biological mechanisms and clinical observations. As there is a paucity of real-life data on adverse effects of glucocorticoids prescribed to unselected groups of patients, these data may help the clinician to adapt therapy with glucocorticoids accordingly and improve the benefit-risk ratio.
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“A dose-related pattern was found for clinical features such as cushingoid phenotype, skin thinning, ecchymosis, and sleep disturbances.”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [35]
In the citing paper
“Although other adverse effects manifested above a certain threshold of daily glucocorticoid dosage (eg, epistaxis and weight gain with daily prednisone equivalent dose of > 5.0-7.5 mg), whereas depression and high blood pressure were especially prevalent with > 7.5 mg/d (35).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [35]
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“Furthermore, persons with IBD who use corticosteroids, particularly those who use corticosteroids at high doses or over long periods of time, are at risk for numerous side effects and complications, ranging from weight gain and development of acne to more serious consequences, including impaired glucose tolerance, acc…”
BackgroundHashimoto, S., Brinke, A. T., Roldaan, A. C., van Veen, I. H., Möller, G. M., Sont, J. K., Weersink, E. J. M., van der Zee, J. S., Braunstahl, G., Zwinderman, A. H., et al. (2011) · Thorax · doi:10.1136/thx.2010.153411 · Cited by 71
“diabetes, hypertension, cataract and muscle weakness.”
Yan, J.-J., Lee, J.-G., Jang, J. Y., Koo, T. Y., Ahn, C., & Yang, J. (2016) · Kidney International · doi:10.1016/j.kint.2016.09.022 · Cited by 70
Glucocorticoid Therapy and Adrenal Suppression
Nicolaides, N. C., Pavlaki, A. N., Alexandra, M. A. M., & Chrousos, G. P. (2011) · Europe PMC (PubMed Central) · Cited by 71
Maintenance immunosuppression in myasthenia gravis
Feldman, L. M., & Li, Y. (2016) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2016.08.057 · Cited by 69
Zhu, Z., Zhang, T., Guo, W., Ling, Y., Tian, J., & Xu, Y. (2021) · BMC Infectious Diseases · doi:10.1186/s12879-021-05830-4 · Cited by 68
The Use of Glucocorticoids in Lupus Nephritis: New Pathways for an Old Drug
Mejia-Vilet, J. M., & Ayoub, I. M. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.622225 · Cited by 74
“In this review, we discuss the use of GCs from mechanisms, adverse events to management of lupus nephritis, and current strategies to limit toxicity of these drugs.”
BackgroundInfluentialBloom, J., Metz, C. N., Nalawade, S. A., Casabar, J., Cheng, K. F., He, M., Sherry, B. A., Coleman, T. R., Forsthuber, T. G., & Al‐Abed, Y. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.743328 · Cited by 68
“Unfortunately, chronic systemic glucocorticoid use is also associated with a potentially severe adverse effect profile that is a significant source of iatrogenic illness among patients with chronic disease (12, 13).”
BackgroundAdverse events related to low dose corticosteroids in autoimmune hepatitis
van den Brand, F. F., van der Veen, K. S., Lissenberg-Witte, B. I., de Boer, Y. S., van Hoek, B., Drenth, J. P. H., Verdonk, R. C., Vrolijk, J. M., van Nieuwkerk, C. M. J., Bouma, G., et al. (2019) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.15528 · Cited by 68
Expert opinion on the use of biological therapy in non-infectious uveitis
Touhami, S., Diwo, E., Sève, P., Trad, S., Bielefeld, P., Sène, D., Abad, S., Brézin, A. P., Quartier, P., Koné‐Paut, I., et al. (2019) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2019.1595578 · Cited by 67
“3 mg/kg/day in children) for longer than 3 months, or in case of severe side effects [10,11], steroid sparing agents need to be discussed in adults and are systematically introduced in children [5,12].”
BackgroundOrsi, F. A., Lijfering, W. M., Geersing, G., Rosendaal, F. R., Dekkers, O. M., le Cessie, S., & Cannegieter, S. C. (2021) · British Journal of Haematology · doi:10.1111/bjh.17388 · Cited by 70
“Although the association between low-dose glucocorticoids and VTE risk may appear counterintuitive, concerns about the side-effects of low dosages exist(33) and several adverse events, including weight gain, eye cataract, acne and skin bruising, also occur in patients taking low doses of the drug.(36) Given that low-d…”
BackgroundCorticosterone selectively targets endo-cortical surfaces by an osteoblast-dependent mechanism
Henneicke, H., Herrmann, M., Kalak, R., Brennan‐Speranza, T. C., Heinevetter, U., Bertollo, N., Day, R. E., Huscher, D., Buttgereit, F., Dunstan, C. R., et al. (2011) · Bone · doi:10.1016/j.bone.2011.06.013 · Cited by 67
“However, their clinical benefits are often marred by serious adverse effects such as glucose intolerance [1,2], skin atrophy [3,4], sarcopenia [5] and osteoporosis [6].”
BackgroundSelf-citationGlucocorticoid use is associated with an increased risk of hypertension
Costello, R. E., Yimer, B. B., Roads, P., Jani, M., & Dixon, W. G. (2021) · Rheumatology · doi:10.1093/rheumatology/keaa209 · Cited by 64
Analgesics and Sport Performance: Beyond the Pain‐Modulating Effects
Holgado, D., Hopker, J., Sanabria, D., & Zabala, M. (2017) · PM&R · doi:10.1016/j.pmrj.2017.07.068 · Cited by 66
“Long-term administration is capable of producing skin thinning and purpura, lipodystrophy, neuropsychiatric disorders, hypertension [65], memory impairment [66], Cushing syndrome (typical symptoms are weight gain, bruising, hypertension, diabetes, and facial puffiness) [67], and inhibition of the immune response media…”
BackgroundThe Prediction and Monitoring of Toxicity Associated with Long-Term Systemic Glucocorticoid Therapy
Harris, E., Tiganescu, A., Tubeuf, S., & Mackie, S. L. (2015) · Current Rheumatology Reports · doi:10.1007/s11926-015-0513-4 · Cited by 63
Arthritis and the role of endogenous glucocorticoids
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Kesiraju, S., Paritala, P., Ch, U. M. R., & Sahariah, S. (2013) · Transplant Immunology · doi:10.1016/j.trim.2013.10.006 · Cited by 62
Ngo, D., Beaulieu, É., Gu, R., Leaney, A., Santos, L. L., Fan, H., Yang, Y., Kao, W., Xu, J., Escriou, V., et al. (2013) · Arthritis & Rheumatism · doi:10.1002/art.37858 · Cited by 61
Liu, M., Li, X., Li, J., Wu, Z., Wang, F., Liu, L., Tan, X., & Lei, F. (2017) · Journal of Colloid and Interface Science · doi:10.1016/j.jcis.2017.05.041 · Cited by 61
Primpray, V., Chailapakul, O., Tokeshi, M., Rojanarata, T., & Laiwattanapaisal, W. (2019) · Analytica Chimica Acta · doi:10.1016/j.aca.2019.05.072 · Cited by 60
The Role of Glucocorticoids in the Management of COVID-19
Alexaki, V. I., & Henneicke, H. (2020) · Hormone and Metabolic Research · doi:10.1055/a-1300-2550 · Cited by 61
“Adverse effects related to glucocorticoid treatment are common and numerous, and depend on the dose and duration of therapy [7, 42, 43].”
BackgroundImplications of glucocorticoid therapy in idiopathic inflammatory myopathies
Hanaoka, B. Y., Peterson, C. A., Horbinski, C., & Crofford, L. J. (2012) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2012.85 · Cited by 57
Fan, H., Kao, W., Yang, Y. H., Gu, R., Harris, J., Fingerle‐Rowson, G., Bucala, R., Ngo, D., Beaulieu, É., & Morand, E. F. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38689 · Cited by 63
“Unfortunately, the antiinflammatory effects of glucocorticoids are accompanied by dose-dependent metabolic effects, resulting in adverse events such as hypertension, diabetes, weight gain, and osteoporosis (3,4).”
BackgroundPirinen, T., Kolho, K., Simola, P. E., Ashorn, M. H., & Aronen, E. T. (2010) · SLEEP · doi:10.1093/sleep/33.11.1487 · Cited by 56
Current progress and challenges of nanoparticle-based therapeutics in pain management
Andreu, V., & Arruebo, M. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.11.018 · Cited by 54
O’Dwyer, K., Dargent, F., Forbes, M. R., & Koprivnikar, J. (2019) · Journal of Animal Ecology · doi:10.1111/1365-2656.13123 · Cited by 55
Lim, L. S. H., Pullenayegum, E., Lim, L., Gladman, D. D., Feldman, B. M., & Silverman, E. D. (2017) · Arthritis Care & Research · doi:10.1002/acr.23199 · Cited by 55
Rituximab in the Treatment of Refractory Noninfectious Scleritis
Cao, J. H., Oray, M., Cocho, L., & Foster, C. S. (2016) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2015.12.032 · Cited by 53
Cell‐Mediated Assembly of Phototherapeutics
Smith, W. J., Oien, N. P., Hughes, R. M., Marvin, C. M., Rodgers, Z. L., Lee, J., & Lawrence, D. S. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201406216 · Cited by 52
Cytotoxic T cells modulate inflammation and endogenous opioid analgesia in chronic arthritis
Baddack, U., Busch-Dienstfertig, M., González‐Rodríguez, S., Maddila, S. C., Grobe, J., Lipp, M., Stein, C., & Müller, G. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0804-y · Cited by 52
“Standard analgesic treatments such as nonsteroidal anti-inflammatory drugs, opioids, or steroids exhibit detrimental side effects including sedation, respiratory depression, and an enhanced risk for gastrointestinal ulcers, bleeding, myocardial infarction, stroke, and infections [7, 8].”
BackgroundWhat Therapeutic Regimen Will Be Optimal for Initial Clinical Trials of Pig Organ Transplantation?
Bikhet, M. H., Iwase, H., Yamamoto, T., Jagdale, A., Foote, J. B., Ezzelarab, M. B., Anderson, D. J., Locke, J. E., Eckhoff, D. E., Hara, H., et al. (2021) · Transplantation · doi:10.1097/tp.0000000000003622 · Cited by 53
Daugherty, J., Lin, X., Baxter, R., Suruki, R., & Bradford, E. (2017) · Journal of Asthma · doi:10.1080/02770903.2017.1353612 · Cited by 51
“Nevertheless, these results are broadly consistent with several other studies, which have demonstrated an association between SGC use and AEs in a range of diseases including asthma, RA and SLE [11–18], and that the risk of several AEs including cataracts andMI is dose-dependent [26, 27].”
ResultSarcoidosis: Updates on therapeutic drug trials and novel treatment approaches
Obi, O. N., Saketkoo, L. A., Russell, A., & Baughman, R. P. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.991783 · Cited by 60
Metadata
- Authors
- Huscher, D., Thiele, K., Gromnica-Ihle, E., Hein, G., Demary, W., Dreher, R., Zink, A., & Buttgereit, F.
- Affiliations
- German Rheumatism Research Centre (DE)
- Jena University Hospital (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- Huscher, D
- Venue
- Annals of the Rheumatic Diseases
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 68
- Issue
- 7
- Pages
- 1119-1124
- ISSN
- 0003-4967 (ISSN-L)
- OpenAlex
- W2167459187
- Cited by
- 604
- References
- 35
- Citations by year
- 2026: 43 · 2025: 55 · 2024: 67 · 2023: 55 · 2022: 47 · 2021: 41 · 2020: 49 · 2019: 38 · 2018: 27 · 2017: 28 · 2016: 32 · 2015: 21 · 2014: 26 · 2013: 28 · 2012: 19
- FWCI
- 6.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of the Rheumatic Diseases (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- glucocorticoid adverse effects, dose-response relationship, rheumatoid arthritis, prednisone-equivalent dose, glaucoma, cataract, depression, hypertension, weight gain, bruising, lower limb edema, fungal infection, sleep disorders, risk-benefit ratio, threshold dose
- MeSH terms
- Arthritis, Rheumatoid, Data Collection, Dose-Response Relationship, Drug, Female, Glucocorticoids, Humans, Male, Middle Aged, Risk Factors, Time Factors
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