今日の臨床サポート

ステロイドの副作用

著者: 大島久二 東京医療保健大学

著者校正/監修レビュー済:2021/09/29
参考ガイドライン:
  1. 日本骨代謝学会:ステロイド性骨粗鬆症の管理と治療ガイドライン(2014年版)
患者向け説明資料

概要・推奨   

  1. 早期発見と早期からの予防と治療が必要である。
  1. 糖尿病、高血圧症には早期からのモニターが必要である。
  1. 骨粗鬆症の予防は早期から行う。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要とな
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
大島久二 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、ガイドライン表示とステロイドの種類と代謝の文献追加を行った。

まとめ

疾患(疫学・病態)のまとめ  
  1. ステロイドは副腎皮質から分泌されるホルモンが原型であり、投与するすべての患者に程度は異なるが副作用が出る。
  1. 医学的には問題のないものから、予防可能なものと不可能なもの、早期からの対処が望まれるものがある。
  1. ステロイド長期投与患者では、突然の中止は離脱症候群を引き起こす可能性があり、患者教育と内服不可能時の対処が必要である。
  1. 1日の投与量で記載されることが多いが、投与間隔(分3など)が重要である。
  1. 治療開始時に、必要十分量の投与が重要であり、病態に応じて減量速度を考慮し、必要であれば維持量を継続する。
 
  1. ステロイドの種類と代謝(参考文献:[1][2][3][4]
  1. プレドニゾロンは最もよく用いられる合成ステロイドである。ステロイドの種類による違いは膠質コルチコイド作用(塩分貯留作用)の有無と受容体への親和性、半減期であり、抗炎症効果を基に各薬剤使用量を換算して使用している。また、抗結核薬であるリファンピシンは肝臓でのステロイド代謝を促進するため、プレドニゾロンでは2倍の投与量を必要とするが、副作用は効果と同程度と考える。
 
ステロイドの種類とその特徴

 
  1. ステロイドの投与方法(参考文献:[3][5][6][7]
  1. 1日量を分割して投与するほど効果も高いが、副作用も同じ程度高くなる。また、1日おきに朝1回で投与する隔日投与法では、抗炎症効果は連日投与に比べて劣るが副作用も少ない。
 
ステロイド治療の実際の投与法

出典

img1:  著者提供
 
 
問診・診察のポイント  
  1. 副作用がより出やすい疾患があるかを確認する。

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文献 

著者: S Kawai, Y Ichikawa, M Homma
雑誌名: J Clin Endocrinol Metab. 1985 May;60(5):848-54. doi: 10.1210/jcem-60-5-848.
Abstract/Text Since previous reports concerning the altered metabolism of various glucocorticoids in liver or renal diseases were inconsistent, this study was undertaken to reexamine the metabolism of cortisol, prednisolone, and dexamethasone in patients with these diseases. One milligram each of these glucocorticoids was given iv simultaneously to patients with chronic liver disease, patients with chronic renal failure, and normal subjects after 1 mg betamethasone was administered on the previous night to suppress endogenous cortisol secretion. Plasma steroid levels in periodically collected blood samples were assayed by respective RIA after separation by paper chromatography. Prolongation of the t1/2 of cortisol was found in both patients with liver disease and those with renal failure, and prolonged t1/2 and reduced MCR of prednisolone were found in renal failure but not in liver disease. In contrast, while prolonged t1/2 and reduced MCR of dexamethasone were found in liver disease, shortened t1/2 and increased MCR were found in renal failure. These results suggest that different glucocorticoids are metabolized differently in patients with liver disease and those with renal failure, and that these differences may be important when these agents are used for therapeutic purposes or for study of hypothalamic-pituitary-adrenocortical function in patients with liver and renal diseases.

PMID 3980669  J Clin Endocrinol Metab. 1985 May;60(5):848-54. doi: 10・・・
著者: J A P Da Silva, J W G Jacobs, J R Kirwan, M Boers, K G Saag, L B S Inês, E J P de Koning, F Buttgereit, M Cutolo, H Capell, R Rau, J W J Bijlsma
雑誌名: Ann Rheum Dis. 2006 Mar;65(3):285-93. doi: 10.1136/ard.2005.038638. Epub 2005 Aug 17.
Abstract/Text Adverse effects of glucocorticoids have been abundantly reported. Published reports on low dose glucocorticoid treatment show that few of the commonly held beliefs about their incidence, prevalence, and impact are supported by clear scientific evidence. Safety data from recent randomised controlled clinical trials of low dose glucocorticoid treatment in RA suggest that adverse effects associated with this drug are modest, and often not statistically different from those of placebo.

PMID 16107513  Ann Rheum Dis. 2006 Mar;65(3):285-93. doi: 10.1136/ard.・・・
著者: Allyson K McDonough, Jeffrey R Curtis, Kenneth G Saag
雑誌名: Curr Opin Rheumatol. 2008 Mar;20(2):131-7. doi: 10.1097/BOR.0b013e3282f51031.
Abstract/Text PURPOSE OF REVIEW: The introduction of glucocorticoid therapy by Dr Philip Hench in the 1950s revolutionized the treatment of rheumatic and inflammatory disease. These preparations remain an important component of therapy for a variety of diseases. As with any potent medication, however, they are not without side effects. Analysis of physician understanding and practice suggest that appreciation for the frequency and significant morbidity associated with glucocorticoids is poor. The purpose of this review is to provide an update on the most recent literature regarding glucocorticoid use and associated adverse events.
RECENT FINDINGS: Recent studies suggest that adverse events such as weight gain, skin thinning, sleep disturbance and neuropsychiatric disorders may occur in patients taking glucocorticoids. Adverse events may occur even in low-dose therapy and appear to be dose and duration dependent. Glucocorticoid-induced osteoporosis is a potentially preventable complication but physician adherence to preventive guidelines is poor. New data reinforce the understanding that glucocorticoids significantly increase the risk of infection. There are strong data-driven concerns about the increased susceptibility of children and possibly even neonates to glucocorticoid-associated adverse events.
SUMMARY: Glucocorticoid therapy, while important in the treatment of a variety of serious inflammatory diseases, causes significant morbidity among long term users.

PMID 18349741  Curr Opin Rheumatol. 2008 Mar;20(2):131-7. doi: 10.1097・・・
著者: K G Saag, R Koehnke, J R Caldwell, R Brasington, L F Burmeister, B Zimmerman, J A Kohler, D E Furst
雑誌名: Am J Med. 1994 Feb;96(2):115-23.
Abstract/Text PURPOSE: The purpose of this study was to better define the toxicity of low dose (less than or equal to 15 mg/d prednisone or equivalent) long-term (greater than 1 year) corticosteroids in the treatment of rheumatoid arthritis (RA).
PATIENTS AND METHODS: We examined an historical cohort of 112 RA patients on low dose (6.1 +/- 3.1 mg/d, mean +/- SD) long-term (6.2 +/- 4.6 years) prednisone (CS) and compared them to 112 matched RA patients not using prednisone (CO). CS were matched one-to-one with CO for sex (75% women), age (+/- 5 yrs), race (98% white), and duration of disease (+/- 5 yrs). Subjects were determined by review of unselected medical records from three distinct rheumatology practice settings. For CS, charts were abstracted from the date of prednisone start for predefined adverse events (AEs).
RESULTS: Ninety-two (92) AEs were noted in CS versus 31 in CO and included: fracture (CS:21 versus CO:8), serious infections (CS:14 versus CO:4), gastrointestinal (GI) bleed or ulcer (CS:11 versus CO:4), and cataracts (CS:17 versus CO:5). At time of first AE, CS prednisone average dose was 7.0 +/- 2.6 mg with a duration of 4.9 +/- 3.9 years. Stepwise multiple logistic regression analysis was used to create a model which included all clinically relevant variables and all parameters significantly different at the cohort inception. Prednisone average dose of greater than 10 to less than or equal to 15 mg/d correlated most strongly with the development of an AE (Odds Ratio (OR) = 32.3, 95% Confidence Interval (CI) 4.6, 220). Average prednisone 5 to 10 mg (OR = 4.5, 95% CI 2.1, 9.6), RA nodules (OR = 3.9, 95% CI 1.9, 8.0), and bony erosions (OR = 2.4, 95% CI 1.2, 4.7) also entered the final model. Kaplan Meier survival curves for the development of the first AE showed a dose-response relationship between prednisone and AE occurrence, independent of rheumatoid nodules. Subset analyses utilized a nested case control design for the development of three serious AEs: fractures, serious infections, and GI events. These analyses revealed possible relationships between prednisone use and the development of each specific AE (prednisone use OR: fracture 3.9, 95% CI 0.8, 18.1; infection 8.0, 95% CI 1.0, 64.0; and GI event 3.3, 95% CI 0.9, 12.1).
CONCLUSIONS: Although disease severity is an important confounding factor, low dose long-term prednisone use equal to or greater than 5 mg/d is correlated with the development of specific adverse events in a dose-dependent fashion.

PMID 8109596  Am J Med. 1994 Feb;96(2):115-23.
著者: N Duru, M C van der Goes, J W G Jacobs, T Andrews, M Boers, F Buttgereit, N Caeyers, M Cutolo, S Halliday, J A P Da Silva, J R Kirwan, D Ray, J Rovensky, G Severijns, R Westhovens, J W J Bijlsma
雑誌名: Ann Rheum Dis. 2013 Dec;72(12):1905-13. doi: 10.1136/annrheumdis-2013-203249. Epub 2013 Jul 19.
Abstract/Text To develop recommendations for the management of medium to high-dose (ie, >7.5 mg but ≤100 mg prednisone equivalent daily) systemic glucocorticoid (GC) therapy in rheumatic diseases. A multidisciplinary EULAR task force was formed, including rheumatic patients. After discussing the results of a general initial search on risks of GC therapy, each participant contributed 10 propositions on key clinical topics concerning the safe use of medium to high-dose GCs. The final recommendations were selected via a Delphi consensus approach. A systematic literature search of PubMed, EMBASE and Cochrane Library was used to identify evidence concerning each of the propositions. The strength of recommendation was given according to research evidence, clinical expertise and patient preference. The 10 propositions regarded patient education and informing general practitioners, preventive measures for osteoporosis, optimal GC starting dosages, risk-benefit ratio of GC treatment, GC sparing therapy, screening for comorbidity, and monitoring for adverse effects. In general, evidence supporting the recommendations proved to be surprisingly weak. One of the recommendations was rejected, because of conflicting literature data. Nine final recommendations for the management of medium to high-dose systemic GC therapy in rheumatic diseases were selected and evaluated with their strengths of recommendations. Robust evidence was often lacking; a research agenda was created.

PMID 23873876  Ann Rheum Dis. 2013 Dec;72(12):1905-13. doi: 10.1136/an・・・
著者: Jennifer M Grossman, Rebecca Gordon, Veena K Ranganath, Chad Deal, Liron Caplan, Weiling Chen, Jeffrey R Curtis, Daniel E Furst, Maureen McMahon, Nivedita M Patkar, Elizabeth Volkmann, Kenneth G Saag
雑誌名: Arthritis Care Res (Hoboken). 2010 Nov;62(11):1515-26. doi: 10.1002/acr.20295. Epub 2010 Jul 26.
Abstract/Text
PMID 20662044  Arthritis Care Res (Hoboken). 2010 Nov;62(11):1515-26. ・・・
著者: Yasuo Suzuki, Hajime Nawata, Satoshi Soen, Saeko Fujiwara, Hisanori Nakayama, Ikuko Tanaka, Keiichi Ozono, Akira Sagawa, Ryoichi Takayanagi, Hiroyuki Tanaka, Takami Miki, Naomi Masunari, Yoshiya Tanaka
雑誌名: J Bone Miner Metab. 2014 Jul;32(4):337-50. doi: 10.1007/s00774-014-0586-6. Epub 2014 May 13.
Abstract/Text
PMID 24818875  J Bone Miner Metab. 2014 Jul;32(4):337-50. doi: 10.1007・・・
著者: William G Dixon, Michal Abrahamowicz, Marie-Eve Beauchamp, David W Ray, Sasha Bernatsky, Samy Suissa, Marie-Pierre Sylvestre
雑誌名: Ann Rheum Dis. 2012 Jul;71(7):1128-33. doi: 10.1136/annrheumdis-2011-200702. Epub 2012 Jan 12.
Abstract/Text OBJECTIVES: To explore the relationship of serious infection risk with current and prior oral glucocorticoid (GC) therapy in elderly patients with rheumatoid arthritis (RA).
METHODS: A case-control analysis matched 1947 serious infection cases to five controls, selected from 16207 RA patients aged ≥ 65 between 1985-2003 in Quebec, Canada. Adjusted odds ratios for infection associated with different GC patterns were estimated using conventional models and a weighted cumulative dose (WCD) model.
RESULTS: The WCD model predicted risks better than conventional models. Current and recent GC doses had highest impact on current risk. Doses taken up to 2.5 years ago were also associated with increased risk, albeit to a lesser extent. A current user of 5mg prednisolone had a 30%, 46% or 100% increased risk of serious infection when used continuously for the last 3 months, 6 months or 3 years, respectively, compared to a non-user. The risk associated with 5mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month. Discontinuing a two-year course of 10mg prednisolone six months ago halved the risk compared to ongoing use.
CONCLUSIONS: GC therapy is associated with infection risk in older patients with RA. The WCD model provided more accurate risk estimates than conventional models. Current and recent doses have greatest impact on infection risk, but the cumulative impact of doses taken in the last 2-3 years still affects risk. Knowing how risk depends on pattern of GC use will contribute to an improved benefit/harm assessment.

PMID 22241902  Ann Rheum Dis. 2012 Jul;71(7):1128-33. doi: 10.1136/ann・・・
著者: William G Dixon, Samy Suissa, Marie Hudson
雑誌名: Arthritis Res Ther. 2011 Aug 31;13(4):R139. doi: 10.1186/ar3453. Epub 2011 Aug 31.
Abstract/Text INTRODUCTION: Infection is a major cause of morbidity and mortality in patients with rheumatoid arthritis (RA). The objective of this study was to perform a systematic review and meta-analysis of the effect of glucocorticoid (GC) therapy on the risk of infection in patients with RA.
METHODS: A systematic review was conducted by using MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials database to January 2010 to identify studies among populations of patients with RA that reported a comparison of infection incidence between patients treated with GC therapy and patients not exposed to GC therapy.
RESULTS: In total, 21 randomised controlled trials (RCTs) and 42 observational studies were included. In the RCTs, GC therapy was not associated with a risk of infection (relative risk (RR), 0.97 (95% CI, 0.69, 1.36)). Small numbers of events in the RCTs meant that a clinically important increased or decreased risk could not be ruled out. The observational studies generated a RR of 1.67 (1.49, 1.87), although significant heterogeneity was present. The increased risk (and heterogeneity) persisted when analyses were stratified by varying definitions of exposure, outcome, and adjustment for confounders. A positive dose-response effect was seen.
CONCLUSIONS: Whereas observational studies suggested an increased risk of infection with GC therapy, RCTs suggested no increased risk. Inconsistent reporting of safety outcomes in the RCTs, as well as marked heterogeneity, probable residual confounding, and publication bias in the observational studies, limits the opportunity for a definitive conclusion. Clinicians should remain vigilant for infection in patients with RA treated with GC therapy.

PMID 21884589  Arthritis Res Ther. 2011 Aug 31;13(4):R139. doi: 10.118・・・

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