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Long-term Systemic Corticosteroid Exposure: A Systematic Literature Review

Open AccessPublished:October 18, 2017DOI:https://doi.org/10.1016/j.clinthera.2017.09.011

      Abstract

      Purpose

      While corticosteroids are relatively inexpensive and commonly used as treatment for a variety of conditions, long-term use is known to be associated with certain toxicities. Prior systematic reviews have revealed an increased risk for costly adverse events (AEs), including bone fracture, infection, and gastrointestinal bleeding. The objective of this study was to conduct a systematic literature review of recent publications on the burden of long-term corticosteroid exposure, specifically, to summarize the AEs and economic impact of long-term corticosteroid use and to reveal data gaps for additional research.

      Methods

      The Ovid search platform was used to access scientific literature databases. The search strategy targeted the use of corticosteroids and economic outcomes research. Articles were restricted to those published between 2007 and 2016 to cover publications since prior reviews; conference abstracts and articles assessing pediatrics were excluded. Titles and abstracts resulting from inclusion criteria were screened, and reviewers independently extracted relevant information from the relevant full-text articles.

      Findings

      The literature review included 32 articles, with 75% focusing on autoimmune diseases, asthma, or lung diseases. Included articles were 14 database analyses, 6 simulations, 6 clinical trials, 3 systematic literature reviews, 2 patient surveys, and 1 chart review. Commonly-cited AEs associated with long-term corticosteroid exposure included hypertension (prevalence >30%); bone fracture (21%–30%); cataract (1%–3%); nausea, vomiting, and other gastrointestinal conditions (1%–5%); and metabolic issues (eg, weight gain, hyperglycemia, and type 2 diabetes; cases had 4-fold the risk of controls). Association of dose and duration with increased AE risk is not well-quantified. AEs like peptic ulcer and myocardial infarction are particularly costly to payers (1-year cost of $21,825 and $26,472, respectively, in year-2009 USD). The few articles assessing the economic impact of corticosteroid use have found dose-related increases in health care resource utilization and costs, with per-annum incremental costs relative to nonusers ranging from $5700 in low-dose users (<7.5 mg/d) to $29,000 in high-dose users (>15 mg/d). Adherence to treatment guidelines on avoiding AEs (eg, prescribing of oral bisphosphonates, calcium, and vitamin D) remains low.

      Implications

      Although doses of long-term corticosteroids have fallen over the past several decades in response to AEs, dose reduction may not be a sufficient solution. Numerous AEs, some very costly, persist among long-term corticosteroid users, suggesting a need for further research to fill current data gaps, as well as a potential need for alternative treatment options.

      Key words

      Introduction

      Systemic (oral or parenteral) corticosteroids (eg, prednisone, prednisolone, methylprednisolone, dexamethasone) possess potent anti-inflammatory, immunomodulatory, and antineoplastic properties and are integral in the treatment of numerous conditions, including autoimmune diseases, allergic reactions, asthma exacerbations, chronic obstructive pulmonary disease, and select malignancies.
      • Wan E.S.
      • Qiu W.
      • Baccarelli A.
      • et al.
      Systemic steroid exposure is associated with differential methylation in chronic obstructive pulmonary disease.
      However, despite the potentially beneficial clinical effects of these agents, such use is also associated with serious risks, especially at high doses for extended periods.
      • Liu D.
      • Ahmet A.
      • Ward L.
      • et al.
      A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy.
      Well-known adverse events (AEs) associated with systemic corticosteroid use include osteoporosis, cardiovascular disease, impaired immune response and wound healing, alterations in glucose and lipid metabolism, and psychiatric disturbances.
      • Wan E.S.
      • Qiu W.
      • Baccarelli A.
      • et al.
      Systemic steroid exposure is associated with differential methylation in chronic obstructive pulmonary disease.
      • Liu D.
      • Ahmet A.
      • Ward L.
      • et al.
      A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy.
      Such complications may decrease a patient's quality of life and can also be costly to manage.
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      As shown in Figure 1, systemic corticosteroid therapy has been used to treat various ailments for decades. Exogenous corticosteroids were first proposed for use in the 1950s.
      • Hench P.S.
      • Kendall E.C.
      • Slocumb C.H.
      • Pokey H.F.
      Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain other conditions.
      However, beginning in the later part of the decade, the initial enthusiasm surrounding the then-novel therapy was tempered as findings of toxicity and AEs associated with longer-term corticosteroid use arose.
      • Bollet A.J.
      • Black R.
      • Bunim J.J.
      Major undesirable side-effects resulting from prednisone and prednisolone.
      As research on corticosteroid therapy progressed in the 1980s, several studies popularized treatment using lower-dose corticosteroids (<15 mg/d),
      • Saag K.G.
      • Koehnke R.
      • Caldwell J.R.
      • et al.
      Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events.
      including a double-blind study that found that patients' conditions improved, with minimal AEs.
      • Harris E.D.
      • Emkey R.D.
      • Nichols J.E.
      • et al.
      Low dose prednisone therapy in rheumatoid arthritis: A double blind study.
      Use of even lower doses of corticosteroids (<5 mg/d) gained recognition by primary care providers and rheumatologists as both a "bridge" and an alternative to slow-acting antirheumatic drugs, disease-modifying antirheumatic drugs, and NSAIDs.
      • Harris E.D.
      • Emkey R.D.
      • Nichols J.E.
      • et al.
      Low dose prednisone therapy in rheumatoid arthritis: A double blind study.
      Figure Au: In Figure 1, in the legend, (1) is DMARDs ok as spelled out (disease-modifying antirheumatic drugs)?; (2) is SAARDs ok as spelled out (slow-acting antirheumatic drugs)?; (3) please add the note for what was the superscript 3, now an asterisk.1
      Figure 1Evolution of corticosteroid use.
      • Hench P.S.
      • Kendall E.C.
      • Slocumb C.H.
      • Pokey H.F.
      Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain other conditions.
      • Harris E.D.
      • Emkey R.D.
      • Nichols J.E.
      • et al.
      Low dose prednisone therapy in rheumatoid arthritis: A double blind study.
      • Bollet A.J.
      • Black R.
      • Bunim J.J.
      Major undesirable side-effects resulting from prednisone and prednisolone.
      • Saag K.G.
      • Koehnke R.
      • Caldwell J.R.
      • et al.
      Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events.
      DMARDs = disease-modifying antirheumatic drugs; GI = gastrointestinal; RA = rheumatoid arthritis; SAARDs = slow-acting antirheumatic drugs.
      Previous studies have taken a first look at the burden of long-term corticosteroid exposure. Manson et al
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      reported on a systematic literature review on the burden of AEs and the economic implications of oral corticosteroid use. The article covered a period spanning from January 1990 to March 2007 and focused primarily on asthma, estimating that the costs in 2007 associated with selected AEs arising from long-term corticosteroid exposure were £165 per patient taking oral corticosteroids; a comprehensive estimate of the economic burden of long-term corticosteroid exposure more broadly was not provided. Sarnes et al
      • Sarnes E.
      • Crofford L.
      • Watson M.
      • et al.
      Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review.
      built on that earlier work, covering literature published between April 2007 and October 2009 and arriving at similar conclusions regarding AEs and building on those findings with respect to the costs of AEs.
      The objective of the present study was to conduct a systematic literature review on the burden of long-term corticosteroid exposure, specifically: (1) to update prior work conducted by Manson et al
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      covering publications between 1990 and 2007 by compiling articles published during the period from 2007 to 2016 to (a) reflect current medical thinking and (b) identify gaps in research on the use of corticosteroids; and (2) to focus on economic outcomes to better capture the implications of long-term use to payers. Specific end points collected included AEs associated with long-term systemic corticosteroid use, health care resource utilization (eg, visits for the treatment of AEs), health care costs, and patients' quality of life. In addition to articles focusing on oral and parenteral corticosteroids, articles focusing on inhaled corticosteroids were included in the review to bridge this study with the existing literature.

      Materials and Methods

      The Ovid search platform (Wolters Kluwer, Alphen aan den Rijn, the Netherlands) was used to search medical and scientific databases for articles of interest published between January 1, 2007, and September 1, 2016. Ovid includes search capabilities across a range of journal articles and other publications. Databases accessed through Ovid for this systematic review included Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, Health Technology Assessment, and the NHS Economic Evaluation Database.
      The search protocol, developed a priori, can be found in Table I. Titles were searched to identify articles with indicators of systemic corticosteroid use and a focus on costs or health care resource utilization. Articles were further restricted to publication dates between 2007 and 2016 and to populations of adult humans only.
      Table IOvid search strategy.
      MethodStrategy
      DatabasesThe Ovid platform
      Ovid search platform (Wolters Kluwer, Alphen aan den Rijn, the Netherlands): Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily, and Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, Health Technology Assessment, NHS Economic Evaluation Database
      was searched for articles published between January 1, 2007, and September 1, 2016
      Search terms
      The ? and $ symbols denote Ovid wildcards. ? can stand for 0 or 1 character (eg, steroids and steroid would be captured). $ serves as a substitute for any string of 0 or more characters in the search term (eg, cost, costs, and costly would be captured).
      Article titles were searched to identify those with at least 1 key word on systemic corticosteroid use (general terms: steroid?, glucosteroid?, glucocorticosteroid?, corticosteroid?; specific molecules: prednisone, prednisolone, methylprednisolone, betamethasone, dexamethasone) and at least 1 key word on costs or resource utilization (economic$, cost$, utilization)
      Inclusion criteriaPublication dates between 2007 and 2016, adult humans only, focus on economic outcomes or medical resource utilization, nonacute corticosteroid use, corticosteroids (see search terms)
      Exclusion criteriaNon-English language; nonadult populations
      Articles were excluded if they had any of the following key words: pediatr$, infant$, child$, or juvenile$.
      ; nonsystematic reviews without expert opinions, conference abstracts, or abstracts published without an accompanying full-text article; articles with small sample sizes (case study or N < 40); acute corticosteroid use; anabolic or topical steroids
      low asterisk Ovid search platform (Wolters Kluwer, Alphen aan den Rijn, the Netherlands): Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily, and Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, Health Technology Assessment, NHS Economic Evaluation Database
      The ? and $ symbols denote Ovid wildcards. ? can stand for 0 or 1 character (eg, steroids and steroid would be captured). $ serves as a substitute for any string of 0 or more characters in the search term (eg, cost, costs, and costly would be captured).
      Articles were excluded if they had any of the following key words: pediatr$, infant$, child$, or juvenile$.
      Resulting titles and abstracts were assigned to 1 of 2 reviewers. Articles were to be excluded if they focused on nonhumans (eg, mice) or a pediatric population, steroids not of interest (ie, anabolic steroids and topical corticosteroids), or short-term corticosteroid use. The determination of short-term versus long-term corticosteroid use was based on each study's definition; therefore, there was not a uniform definition of short-term corticosteroid exposure applied across all studies. Furthermore, articles were also removed from consideration if the study sample was of small size
      • Gopalakrishnan S.
      • Ganeshkumar P.
      Systematic reviews and meta-analysis: understanding the best evidence in primary healthcare.
      (ie, if the article was a case study or N < 40), they were a selected publication type (eg, nonsystematic reviews without expert opinions, conference abstracts, or abstracts published without an accompanying full-text article), they did not contain outcomes of interest, or the full text was published in a language other than English. Reviewers worked independently, were given detailed instructions on the inclusion and exclusion criteria, and confirmed that the titles and abstracts met those criteria.
      Once the reviewers had confirmed that a given article was appropriately included, relevant information was extracted. Inconsistencies across reviewers were resolved by coauthors. The relevant information extracted included details on title, authors, methods (eg, study period, study population, inclusion/exclusion criteria), results (ie, sample size, demographic characteristics, key clinical and quality of life end points, and health care resource utilization and economic end points), conclusions, and acknowledged limitations. Captured under the clinical end points, the AE information was taken as-reported in the studies.

      Results

      Summary Statistics

      From the initial Ovid search, 155 unique articles were initially identified. Figure 2 summarizes the counts of articles by exclusion criteria and those remaining following the 2 rounds of independent reviews. Of the 155 articles, 53 were excluded because the study population was not of interest, that is, it comprised nonhumans (eg, mice), focused on a pediatric population, or looked at drug therapies other than those of interest (eg, anabolic steroids, topical corticosteroids). Fourteen focused on non–long-term corticosteroid use and were thus removed from further consideration. Four articles were excluded due to inappropriate study designs, typically case studies or studies with a small sample size. Fifty articles were excluded due to being of an inappropriate publication type. These included conference abstracts and nonsystematic reviews lacking expert opinions. Lastly, 2 articles were omitted as the outcomes on which they focused were not clinical and economic outcomes of interest. Following the title/abstract and full-text reviews, data from 32 articles were extracted.
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      • Sarnes E.
      • Crofford L.
      • Watson M.
      • et al.
      Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review.
      • Chen S.Y.
      • Choi C.B.
      • Li Q.
      • et al.
      Glucocorticoid use in patients with systemic lupus erythematosus: association between dose and health care utilization and costs.
      • Beukelman T.
      • Saag K.G.
      • Curtis J.R.
      • et al.
      Cost-effectiveness of multifaceted evidence implementation programs for the prevention of glucocorticoid-induced osteoporosis.
      • van Staa T.P.
      • Geusens P.
      • Zhang B.
      • et al.
      Individual fracture risk and the cost-effectiveness of bisphosphonates in patients using oral glucocorticoids.
      • Aballea S.
      • Cure S.
      • Vogelmeier C.
      • et al.
      A retrospective database study comparing treatment outcomes and cost associated with choice of fixed-dose inhaled corticosteroid long-acting b2-agonists for asthma maintenance treatment in Germany.
      • Akazawa M.
      • Biddle A.
      • Stearns S.
      Economic assessment of early initiation of inhaled corticosteroids in chronic obstructive pulmonary disease using propensity score matching.
      • Ampon R.D.
      • Reddel H.K.
      • Correll P.K.
      • et al.
      Cost is a major barrier to the use of inhaled corticosteroids for obstructive lung disease.
      • Blackhouse G.
      • Gaebel K.
      • Xie F.
      • et al.
      Cost-utility of intravenous immunoglobulin (ivig) compared with corticosteroids for the treatment of chronic inflammatory demyelinating polyneuropathy (cidp) in Canada.
      • Boers M.
      • Buttgereit F.
      A simple model that suggests possible cost savings when modified-release prednisone 5 mg/day is added to current treatment in patients with active rheumatoid arthritis.
      • Chan J.
      • Hiu A.L.
      • Spence M.M.
      Effects on resource utilization of adding salmeterol in combination or separately to inhaled corticosteroids.
      • Chen S.
      • Plauschinat C.A.
      • Wu N.
      • et al.
      Economic impact of using inhaled corticosteroids without prior exacerbation among elderly patients with chronic obstructive pulmonary disorder.
      • Colice G.
      • Wu E.
      • Birnbaum H.
      • et al.
      Use of inhaled corticosteroids and healthcare costs in mild persistent asthma.
      • Dunlop W.
      • Iqbal I.
      • Khan I.
      • et al.
      Cost-effectiveness of modified-release prednisone in the treatment of moderate to severe rheumatoid arthritis with morning stiffness based on directly elicited public preference values.
      • Friedman H.S.
      • Yawn B.P.
      Resource utilization in asthma: combined fluticasone propionate/salmeterol compared with inhaled corticosteroids.
      • Garris C.
      • Shah M.
      • D'Souza A.
      • et al.
      Comparison of corticosteroid nasal sprays in relation to concomitant use and cost of other prescription medications to treat allergic rhinitis symptoms: Retrospective cohort analysis of pharmacy claims data.
      • Geisz M.
      • Ha C.
      • Kappelman M.D.
      • et al.
      Medication utilization and the impact of continued corticosteroid use on patient-reported outcomes in older patients with inflammatory bowel disease.
      • Gheith O.A.
      • Nematalla A.H.
      • Bakr M.A.
      • et al.
      Cost-benefit of steroid avoidance in renal transplant patients: A prospective randomized study.
      • Hernandez R.A.
      • Sullivan F.
      • Donnan P.
      • et al.
      Economic evaluation of early administration of prednisolone and/or acyclovir for the treatment of Bell's palsy.
      • Kemp L.
      • Haughney J.
      • Barnes N.
      • et al.
      Cost-effectiveness analysis of corticosteroid inhaler devices in primary care asthma management: A real world observational study.
      • Martin R.
      • Price D.
      • Roche N.
      • et al.
      Cost-effectiveness of initiating extrafine- or standard size-particle inhaled corticosteroid for asthma in two health-care systems: a retrospective matched cohort study.
      • De Miguel-Diez J.
      • Carrasco-Garriso P.
      • Rejas-Guitierres J.
      • et al.
      Inappropriate overuse of inhaled corticosteroids for COPD patients: impact on health costs and health status.
      • Najafzadeh M.
      • Marra C.A.
      • Sadatsafavi M.
      • et al.
      Cost effectiveness of therapy with combinations of long acting bronchodilators and inhaled steroids for treatment of COPD.
      • Negro R.D.
      • Eandi M.
      • Pradelli L.
      • et al.
      Cost-effectiveness and healthcare budget impact in Italy of inhaled corticosteroids and bronchodilators for severe and very severe COPD patients.
      • O'Neill C.
      • Gamble J.
      • Lindsay J.T.
      • et al.
      The impact of nonadherence to inhaled long-acting b2-adrenoceptor agonist/corticosteroid combination therapy on healthcare costs in difficult to control asthma.
      • Thursz M.
      • Forrest E.
      • Roderick P.
      • et al.
      The clinical effectiveness and cost-effectiveness of steroids or pentoxifylline for alcoholic hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial.
      • Tominaga K.
      • Nakano M.
      • Hoshino M.
      • et al.
      Efficacy, safety and cost analyses in ulcerative colitis patients undergoing granulocyte and monocyte adsorption or receiving prednisolone.
      • Wailoo A.
      • Alava M.H.
      • Scott I.C.
      • et al.
      Cost-effectiveness of treatment strategies using combination disease-modifying anti-rheumatic drugs and glucocorticoids in early rheumatoid arthritis.
      • Wilson E.C.
      • Price D.
      • Musgrave S.D.
      • et al.
      Cost effectiveness of leukotriene receptor antagonists versus long-acting beta-2 agonists as add-on therapy to inhaled corticosteroids for asthma.
      • Kanis J.A.
      • Stevenson M.
      • McCloskey E.V.
      • et al.
      Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.
      • Ligon C.B.
      • Judson M.A.
      Impact of systemic corticosteroids on healthcare utilization in patients with sarcoidosis.
      This count of articles was proportionally similar to those identified by Manson et al,
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      given the difference in the time periods considered.
      Figure 2
      Figure 2Flow diagram of study selection. *Articles were excluded sequentially following these criteria. Counts reflect articles that met the inclusion criteria in both the title/abstract screening and the full-text screening.
      Figure 3 and Table II summarize the characteristics of the 32 articles extracted. The majority of the articles extracted (27) were published between 2007 and 2013, with 5 published between 2014 and 2016. Seventy-five percent of articles focused on 3 disease areas: autoimmune diseases (10 articles [31%]), asthma (8 [25%]), and chronic obstructive pulmonary disease and other lung diseases (6 [19%]). The remaining articles looked at corticosteroid use within the following disease areas: glucocorticoid-induced osteoporosis (2 [6%]), alcoholic hepatitis (1 [3%]), allergic rhinitis (1 [3%]), and kidney disease (1 [3%]). Three articles (10%) also looked at multiple disease areas. Lastly, in terms of study design, 14 were retrospective database analyses, 6 were simulation models, 6 were clinical trials, 3 were systematic literature reviews, 2 were patient surveys, and 1 was a chart review.
      Figure 3
      Figure 3Summary of included articles. *Counts reflect articles that met the inclusion criteria in both the title/abstract screening and the full-text screening. Clinical trials included economic analyses conducted alongside clinical trials. Retrospective database analyses included analyses conducted using claims, pharmacy benefits, observational cohort studies, and clinical-practice databases.
      Table IISummary of included studies evaluating economic burden of long-term corticosteroid use.
      SourceStudy DesignObjectiveDisease Area
      Aballea et al
      • Aballea S.
      • Cure S.
      • Vogelmeier C.
      • et al.
      A retrospective database study comparing treatment outcomes and cost associated with choice of fixed-dose inhaled corticosteroid long-acting b2-agonists for asthma maintenance treatment in Germany.
      Retrospective observational cohort studyTo compare treatment outcomes and health care costs in the year after initiation of maintenance treatment with budesonide/formoterol or FSA in a German health care settingAsthma
      Akazawa et al
      • Akazawa M.
      • Biddle A.
      • Stearns S.
      Economic assessment of early initiation of inhaled corticosteroids in chronic obstructive pulmonary disease using propensity score matching.
      Retrospective cohort studyTo examine potential benefits of ICS treatment initiated earlier than the current guideline-recommended step-wise approach among patients with COPD diagnosed between 1998 and 2004COPD and other lung diseases
      Ampon et al
      • Ampon R.D.
      • Reddel H.K.
      • Correll P.K.
      • et al.
      Cost is a major barrier to the use of inhaled corticosteroids for obstructive lung disease.
      Cross-sectional study of prescribing recordsTo examine the effect of the level of patient copayment on the rate of purchase of ICSs by patients with obstructive lung diseaseCOPD and other lung diseases
      Beukelman et al
      • Beukelman T.
      • Saag K.G.
      • Curtis J.R.
      • et al.
      Cost-effectiveness of multifaceted evidence implementation programs for the prevention of glucocorticoid-induced osteoporosis.
      Computer simulation model (Markov microsimulation)To determine whether an evidence-implementation program (intervention) focused on increasing the appropriate management of GIOP might be cost-effective compared with current practice (no intervention) from the perspective of a third-party health insurerGIOP
      Blackhouse et al
      • Blackhouse G.
      • Gaebel K.
      • Xie F.
      • et al.
      Cost-utility of intravenous immunoglobulin (ivig) compared with corticosteroids for the treatment of chronic inflammatory demyelinating polyneuropathy (cidp) in Canada.
      Markov modelTo evaluate, from a Canadian perspective, the cost-effectiveness of IVIG compared with corticosteroid treatment of CIDPAutoimmune diseases
      Boers and Buttgereit
      • Boers M.
      • Buttgereit F.
      A simple model that suggests possible cost savings when modified-release prednisone 5 mg/day is added to current treatment in patients with active rheumatoid arthritis.
      Retrospective studyTo determine the effects of a 12-wk treatment with MR-pred on the costs of drug treatment of rheumatoid arthritisAutoimmune diseases
      Chan et al
      • Chan J.
      • Hiu A.L.
      • Spence M.M.
      Effects on resource utilization of adding salmeterol in combination or separately to inhaled corticosteroids.
      Retrospective, observational database studyTo assess the key resource utilization outcomes of adding salmeterol, a LABA, to a regimen of fluticasone, an ICS, either as a fixed-dose inhalational combination FSA or as a separate inhalational formulation used concurrently with the ICS beclomethasoneAsthma
      Chen et al
      • Chen S.
      • Plauschinat C.A.
      • Wu N.
      • et al.
      Economic impact of using inhaled corticosteroids without prior exacerbation among elderly patients with chronic obstructive pulmonary disorder.
      Retrospective claims studyTo assess the economic impact of initiating ICS treatment among elderly patients with COPD and without evidence of prior exacerbation on ICSs in the United StatesCOPD and other lung diseases
      Chen et al
      • Chen S.Y.
      • Choi C.B.
      • Li Q.
      • et al.
      Glucocorticoid use in patients with systemic lupus erythematosus: association between dose and health care utilization and costs.
      Retrospective claims database analysisTo investigate the determinants of health care resource utilization and costs with use of GC drugs among adult patients with SLEAutoimmune diseases
      Colice et al
      • Colice G.
      • Wu E.
      • Birnbaum H.
      • et al.
      Use of inhaled corticosteroids and healthcare costs in mild persistent asthma.
      Retrospective claims studyTo determine whether more consistent use of ICS in patients with mild persistent asthma was associated with economic benefits, specifically lower direct health care costsAsthma
      de Miguel-Diez et al
      • De Miguel-Diez J.
      • Carrasco-Garriso P.
      • Rejas-Guitierres J.
      • et al.
      Inappropriate overuse of inhaled corticosteroids for COPD patients: impact on health costs and health status.
      Observational, crossover, descriptive studyTo evaluate the relationship between inappropriate overuse of ICS and self-reported health status and the annual cost of patients with stable COPD recruited in the primary care settingCOPD and other lung diseases
      Dunlop et al
      • Dunlop W.
      • Iqbal I.
      • Khan I.
      • et al.
      Cost-effectiveness of modified-release prednisone in the treatment of moderate to severe rheumatoid arthritis with morning stiffness based on directly elicited public preference values.
      Cost-effectiveness analysis through a health-state–transitional modelTo assess the cost-effectiveness of MR-pred compared with IR-pred for the treatment of morning stiffness due to RAAutoimmune diseases
      Friedman and Yawn
      • Friedman H.S.
      • Yawn B.P.
      Resource utilization in asthma: combined fluticasone propionate/salmeterol compared with inhaled corticosteroids.
      Retrospective analysis of asthma-related insurance claimsTo compare health care resource utilization and asthma-related outcomes in patients with mild asthma on treatment with FPS or an ICS aloneAsthma
      Garris et al
      • Garris C.
      • Shah M.
      • D'Souza A.
      • et al.
      Comparison of corticosteroid nasal sprays in relation to concomitant use and cost of other prescription medications to treat allergic rhinitis symptoms: Retrospective cohort analysis of pharmacy claims data.
      Retrospective cohort analysisTo compare the utilization and costs of concurrent allergic rhinitis drugs among commonly used branded intranasal corticosteroid drugsAllergic rhinitis
      Geisz et al
      • Geisz M.
      • Ha C.
      • Kappelman M.D.
      • et al.
      Medication utilization and the impact of continued corticosteroid use on patient-reported outcomes in older patients with inflammatory bowel disease.
      Retrospective cross-sectional and longitudinal analysesTo describe (1) medication use in older and younger patients with IBD and (2) medication associations with PROs in older patientsAutoimmune diseases
      Gheith et al
      • Gheith O.A.
      • Nematalla A.H.
      • Bakr M.A.
      • et al.
      Cost-benefit of steroid avoidance in renal transplant patients: A prospective randomized study.
      Prospective randomized, controlled, double-arm comparative studyTo assess the cost–benefit ratio of a steroid-free immunosuppression regimen in a prospective RCT in live donor renal transplantationKidney disease
      Hernandez et al
      • Hernandez R.A.
      • Sullivan F.
      • Donnan P.
      • et al.
      Economic evaluation of early administration of prednisolone and/or acyclovir for the treatment of Bell's palsy.
      Decision analytic model alongside an RCTto evaluate the economic impact of early administration of a corticosteroid (prednisolone) and/or an antiviral (acyclovir) compared with placebo for the treatment of Bell palsyAutoimmune diseases
      Kanis et al
      • Kanis J.A.
      • Stevenson M.
      • McCloskey E.V.
      • et al.
      Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.
      Systematic literature review and cost-utility analysisTo examine the evidence for the efficacy of the various agents available for the treatment of osteoporosis, including those for use in the prevention and treatment of GIOP and to model their cost-effectivenessGIOP
      Kemp et al
      • Kemp L.
      • Haughney J.
      • Barnes N.
      • et al.
      Cost-effectiveness analysis of corticosteroid inhaler devices in primary care asthma management: A real world observational study.
      Retrospective database studyTo evaluate and compare real world cost-effectiveness of ICSs administered by MDI, BAI, or DPI in asthmaAsthma
      Ligon and Judson
      • Ligon C.B.
      • Judson M.A.
      Impact of systemic corticosteroids on healthcare utilization in patients with sarcoidosis.
      Retrospective analysisTo determine the impact of SC use in patients with sarcoidosis on unscheduled sarcoidosis-attributed and non–sarcoidosis-attributed health care resource utilizationAutoimmune diseases
      Manson et al
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      Systematic literature review and cost analysisTo identify the range of AEs that have been reported to be related to oral corticosteroid use, to examine the factors that influence their prevalence, and to estimate the economic burden caused by these AEsMultiple disease areas
      Martin et al
      • Martin R.
      • Price D.
      • Roche N.
      • et al.
      Cost-effectiveness of initiating extrafine- or standard size-particle inhaled corticosteroid for asthma in two health-care systems: a retrospective matched cohort study.
      Retrospective matched-cohort analysesTo compare the cost-effectiveness of extra-fine–particle ICS with standard-size–particle ICS in the United Kingdom and the United StatesAsthma
      Najafzadeh et al
      • Najafzadeh M.
      • Marra C.A.
      • Sadatsafavi M.
      • et al.
      Cost effectiveness of therapy with combinations of long acting bronchodilators and inhaled steroids for treatment of COPD.
      Concurrent, prospective, economic analysisTo determine the cost-effectiveness of adding salmeterol or FSA to tiotropium for COPDCOPD and other lung diseases
      Negro et al
      • Negro R.D.
      • Eandi M.
      • Pradelli L.
      • et al.
      Cost-effectiveness and healthcare budget impact in Italy of inhaled corticosteroids and bronchodilators for severe and very severe COPD patients.
      Cost-effectiveness analysisTo evaluate, through a simulation model, the clinical and economic consequences of the implementation of GOLD 2004 guideline on the management of patients with severe and very severe COPD in ItalyCOPD and other lung diseases
      O'Neill et al
      • O'Neill C.
      • Gamble J.
      • Lindsay J.T.
      • et al.
      The impact of nonadherence to inhaled long-acting b2-adrenoceptor agonist/corticosteroid combination therapy on healthcare costs in difficult to control asthma.
      Cohort studyTo examine the costs of health care resource utilization in a nonadherent group of patients with difficult-to-control asthma compared with adherent subjects, and to examine the potential savings if nonadherence to inhaled combination therapy could be addressedAsthma
      Sarnes et al
      • Sarnes E.
      • Crofford L.
      • Watson M.
      • et al.
      Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review.
      Systematic literature reviewTo evaluate the prevalences of and risks for AEs associated with oral and parenteral corticosteroids useMultiple disease areas
      Shah et al
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      Observational, retrospective cohort studyTo examine the AEs related to corticosteroid use and the costs of treating corticosteroid-related AEs in patients with SLEAutoimmune diseases
      Thursz et al
      • Thursz M.
      • Forrest E.
      • Roderick P.
      • et al.
      The clinical effectiveness and cost-effectiveness of steroids or pentoxifylline for alcoholic hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial.
      Randomized, double-blind, 2 × 2 factorial, multicenter designTo evaluate whether prednisolone or pentoxifylline administered for 28 d improved short- and medium-term mortality in patients admitted with severe alcoholic hepatitis, and to assess their relative cost-effectivenessAlcoholic hepatitis
      Tominaga et al
      • Tominaga K.
      • Nakano M.
      • Hoshino M.
      • et al.
      Efficacy, safety and cost analyses in ulcerative colitis patients undergoing granulocyte and monocyte adsorption or receiving prednisolone.
      Retrospective review of patient recordsTo evaluate the efficacy, tolerability, and treatment cost of prednisolone and granulocyte/monocyte adsorptionAutoimmune diseases
      van Staa et al
      • van Staa T.P.
      • Geusens P.
      • Zhang B.
      • et al.
      Individual fracture risk and the cost-effectiveness of bisphosphonates in patients using oral glucocorticoids.
      Patient-based pharmacoeconomic modelTo assess the cost-effectiveness of bisphosphonate treatment in the prevention of GC-induced fracturesMultiple disease areas
      Wailoo et al
      • Wailoo A.
      • Alava M.H.
      • Scott I.C.
      • et al.
      Cost-effectiveness of treatment strategies using combination disease-modifying anti-rheumatic drugs and glucocorticoids in early rheumatoid arthritis.
      Retrospective analysis of a clinical trialTo estimate the cost-effectiveness of combination DMARDs with short-term GCs in early active RAAutoimmune diseases
      Wilson et al
      • Wilson E.C.
      • Price D.
      • Musgrave S.D.
      • et al.
      Cost effectiveness of leukotriene receptor antagonists versus long-acting beta-2 agonists as add-on therapy to inhaled corticosteroids for asthma.
      Economic evaluation conducted alongside a 2-y RCTTo estimate the cost-effectiveness of leukotriene receptor antagonists compared with long-acting β2 adrenergic receptor agonists as add-on therapy in patients whose asthma symptoms are not controlled on low-dose ICSsAsthma
      AE = adverse event; BAI = breath-actuated metered dose inhaler; CIDP = chronic inflammatory demyelinating polyneuropathy; COPD = chronic obstructive pulmonary disease; DMARD = disease-modifying antirheumatic drug; FPS = fluticasone propionate/salmeterol; FSA = fluticasone/salmeterol; GC = glucocorticoid; GIOP = glucocorticoid-induced osteoporosis; GOLD = Global Initiative for Chronic Lung Disease; IBD = inflammatory bowel disease; ICS = inhaled corticosteroid; IR-pred = immediate-release prednisone; IVIG = intravenous immunoglobulin; LABA = long-acting beta2 agonist; MDI = metered dose inhaler; MR-pred = modified-release prednisone; RCT = randomized controlled trial; SC = systemic corticosteroid; SLE = systemic lupus erythematosus.

      Adverse Events

      Table III provides a summary of the most commonly reported AEs. These included cataract, nausea/vomiting/other gastrointestinal conditions, sleep disturbance, fracture or osteoporosis, cardiac conditions (including myocardial infarction), type 2 diabetes mellitus and hyperglycemia, and hypertension.
      Table IIISummary of corticosteroid-related adverse events (AEs).
      Due to large variation across articles considered within systematic literature reviews, several of those articles chose not to attempt to synthesize those results to determine a representative mean increased risk due to long-term corticosteroid exposure.3
      The statistics reported in the table are from Sarnes et al.9 Notably, Shah et al4 reported that corticosteroid users were 1.5-fold more likely to develop chronic AEs, such as sleep disturbance, migraine, cataract, hypertension, and type 2 diabetes mellitus, compared with corticosteroid nonusers. Furthermore, patients with systemic lupus erythematosus receiving corticosteroids were 2-fold more likely to develop acute AEs, such as herpes zoster viral infection, fungal infection, nausea/vomiting, and pneumonia, compared with patients with SLE not receiving corticosteroids.
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      • Sarnes E.
      • Crofford L.
      • Watson M.
      • et al.
      Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review.
      Outcome/AEPrevalence range
      Cataract1%–3%
      Nausea/vomiting/other GI condition1%–5%
      Sleep disturbanceNot reported
      Fracture or osteoporosis21%–30%
      Cardiac condition4%
      Diabetes (type 2) and hyperglycemia≤4-fold that in controls
      Hypertension>30%
      GI = gastrointestinal.
      low asterisk Due to large variation across articles considered within systematic literature reviews, several of those articles chose not to attempt to synthesize those results to determine a representative mean increased risk due to long-term corticosteroid exposure.
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      The statistics reported in the table are from Sarnes et al.
      • Sarnes E.
      • Crofford L.
      • Watson M.
      • et al.
      Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review.
      Notably, Shah et al
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      reported that corticosteroid users were 1.5-fold more likely to develop chronic AEs, such as sleep disturbance, migraine, cataract, hypertension, and type 2 diabetes mellitus, compared with corticosteroid nonusers. Furthermore, patients with systemic lupus erythematosus receiving corticosteroids were 2-fold more likely to develop acute AEs, such as herpes zoster viral infection, fungal infection, nausea/vomiting, and pneumonia, compared with patients with SLE not receiving corticosteroids.
      The existing literature quantified the prevalence of corticosteroid-related AEs, while the event rates were not stratified by corticosteroid dose and duration of exposure, which is an important data gap identified in the present review. In the study by Shah et al,
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      hazard ratios were constructed between patients with any corticosteroid use and patients without such exposure. This comparison did not consider the potential dose–response relationship between level of exposure and rates of AEs. Manson et al
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      discussed the importance of this dose-response relationship, as well as the adverse impact of longer-duration exposure; however, the overall AE rates were not reported with dose and duration stratifications. Finally, Sarnes et al
      • Sarnes E.
      • Crofford L.
      • Watson M.
      • et al.
      Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review.
      attempted to model the benefits of reducing corticosteroid daily dose. When moving from high to low dose exposure (dose assumption was undefined in the model), the potential benefits were the avoidance of 19.4 myocardial infarctions per 10,000 persons and the avoidance of 96 fractures per 10,000 elderly patients.

      Economic Outcomes

      The majority of included studies assessed the cost of corticosteroids in 1 of 3 ways: (1) as a comparator versus other treatments; (2) as a base for an add-on therapy; or (3) comparing different corticosteroid delivery methods against one another (eg, modified- versus immediate-release prednisone). A large number of articles (10 [31%]) evaluated the cost-effectiveness of a wide variety of treatments. Given the wide range of study designs, therapies, and populations, findings were highly sensitive to the specific details of the study (eg, estimates of the burden of treatment-related AEs were found to range from £165 in 2007
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      ($340 in year-2010 USD) among an asthmatic population to $4607 in 2010
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      among a population of patients with systemic lupus erythematosus across studies).
      Very few articles assessed the overall cost impact of long-term corticosteroid exposure, and these articles generally reported that the economic burden associated with the AEs of long-term corticosteroid use was sizable. Specifically, only 3 articles
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      • Chen S.Y.
      • Choi C.B.
      • Li Q.
      • et al.
      Glucocorticoid use in patients with systemic lupus erythematosus: association between dose and health care utilization and costs.
      • Ligon C.B.
      • Judson M.A.
      Impact of systemic corticosteroids on healthcare utilization in patients with sarcoidosis.
      reported economic outcomes in terms of overall patient costs, burden, or health care resource utilization derived from primary research, and all 3 focused on autoimmune diseases (2 based on systemic lupus erythematosus and 1 based on sarcoidosis). Table IV contains key details from these articles. Additional articles
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      • Sarnes E.
      • Crofford L.
      • Watson M.
      • et al.
      Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review.
      reported economic outcomes derived through secondary research. The general consensus among these articles was that, within these disease areas, the AEs associated with long-term corticosteroid use are costly. While these findings have been documented in selected disease areas (eg, systemic lupus erythematosus,
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      • Chen S.Y.
      • Choi C.B.
      • Li Q.
      • et al.
      Glucocorticoid use in patients with systemic lupus erythematosus: association between dose and health care utilization and costs.
      sarcoidosis,
      • Ligon C.B.
      • Judson M.A.
      Impact of systemic corticosteroids on healthcare utilization in patients with sarcoidosis.
      asthma
      • Manson S.C.
      • Brown R.E.
      • Cerulli A.
      • et al.
      The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.
      ), we saw no existing literature on the economic burden of autoimmune disorders more broadly. Quantification of the economic burden of long-term corticosteroid exposure, both in general and in the disease states of interest, and further research to stratify by dose and duration of exposure are important data gaps for future research.
      Table IVSummary of articles containing information on the economic burden of long-term corticosteroid exposure.
      ArticleObjectiveStudy Design and Patient PopulationKey Findings
      Chen et al
      • Chen S.Y.
      • Choi C.B.
      • Li Q.
      • et al.
      Glucocorticoid use in patients with systemic lupus erythematosus: association between dose and health care utilization and costs.
      To investigate the determinants of health care resource utilization and costs with the use of GC drugs among adult patients with SLE
      • Retrospective claims data analysis (Truven MarketScan commercial claims database), focusing on established SLE patients using data from January 2007 to December 2011
      • Patients were included in the study if they had at least 1 claim with the an SLE diagnosis (ICD-9-CM 710.0) and were aged 18 to 64 y
      • High-dose GC users faced mean health care costs of US $45,360 per annum, compared with $27,768, $21,869, $22,940, and $16,162 per annum in medium-dose users, low-dose users, intermittent users, and nonusers, respectively
      Ligon and Judson
      • Ligon C.B.
      • Judson M.A.
      Impact of systemic corticosteroids on healthcare utilization in patients with sarcoidosis.
      To determine the impact of systemic corticosteroids use in sarcoidosis patients on unscheduled (all-cause) health care utilization
      • Retrospective analysis of patients with sarcoidosis referred to the Medical University of South Carolina sarcoidosis clinic
      • Patients were included if they either had a biopsy sample positive for granulomas in at least 1 organ or met at least 1 criterion for "definite" or "probable" sarcoidosis per a diagnostic instrument
      • After demographic adjustment, persons with greater systemic corticosteroid exposure had statistically significantly more sarcoidosis-related visits (3.09 odds), visits not attributable to sarcoidosis relating to infections (1.74 odds), and ~50% increase in cardiovascular disease– or diabetes-related visits
      Shah et al
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      To examine AEs related to corticosteroid use and costs of treating corticosteroid-related AEs in patients with SLE
      • Retrospective claims analysis (IMS LifeLink Health Plans claims database) focusing on patients with a first SLE diagnosis between July 2000 and December 2007
      • Patients ≥18 y of age with at least 2 outpatient claims on different dates or at least 1 inpatient or emergency department claim with a primary or secondary diagnostic code for SLE were selected
      • The mean attributable costs of chronic AEs ranged from ~$2400 to $9800 per annum
      • The incremental 1-y cost difference per corticosteroid user to manage corticosteroid-related AEs compared with corticosteroid nonusers was $784
      AE = adverse event; GC = glucocorticoid; ICD-9-CM = International Classification of Diseases, Ninth Edition–Clinical Modification; SLE = systemic lupus erythematosus.
      More narrowly, Sarnes et al
      • Sarnes E.
      • Crofford L.
      • Watson M.
      • et al.
      Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review.
      provided detailed estimates of the costs of corticosteroid-related AEs. The costs associated with the most costly conditions were reported to be (in year-2009 USD per annum): $21,824 for gastrointestinal complications (eg, peptic ulcer); $17,631 for non-Hodgkin lymphoma; $9914 (per diem) for sepsis; $5411 for metabolic conditions; $1913 for cataract, or $4416 for cataract surgery; $1914 to $12,024 for psychiatric-related AEs; and $1743 to $18,358 for fracture incidents. These demonstrate a considerable economic burden associated with these corticosteroid-related AEs.

      Corticosteroid Treatment Guidelines

      The literature contained several recommendations for managing patients receiving corticosteroid therapy long-term. Disease-specific dosing guidelines provide guidance on maximum daily doses in patients treated with corticosteroids long-term. For example, for rheumatoid arthritis, dosing guidelines suggest that no more than 15 mg/d should be prescribed for long-term use.
      • Bollet A.J.
      • Black R.
      • Bunim J.J.
      Major undesirable side-effects resulting from prednisone and prednisolone.
      Additionally, several articles evaluated the use of preventive measures for glucocorticoid-induced osteoporosis. One study found that, among certain populations, low, yet increasing, adherence to osteoporosis guidelines (eg, prescribing of calcium and vitamin D in long-term corticosteroid users) over the past decade have been observed.
      • Thanou A.
      • Ali T.
      • Haq O.
      • et al.
      Utilization of preventive measures for glucocorticoid-induced osteoporosis among veterans with inflammatory bowel disease.
      Teriparatide, oral bisphosphonates, and physician education for improved management may be cost-effective in specific populations in the prevention of glucocorticoid-induced osteoporosis.
      • Beukelman T.
      • Saag K.G.
      • Curtis J.R.
      • et al.
      Cost-effectiveness of multifaceted evidence implementation programs for the prevention of glucocorticoid-induced osteoporosis.
      • Murphy D.R.
      • Smolen L.J.
      • Klein T.M.
      • Klein R.W.
      The cost effectiveness of teriparatide as a first-line treatment for glucocorticoid-induced and postmenopausal osteoporosis patients in Sweden.
      • van Staa T.P.
      • Geusens P.
      • Zhang B.
      • et al.
      Individual fracture risk and the cost-effectiveness of bisphosphonates in patients using oral glucocorticoids.
      • Kanis J.A.
      • Stevenson M.
      • McCloskey E.V.
      • et al.
      Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.
      It is important to determine methods of improving adherence to prevention guidelines via health system and health policy research.

      Discussion

      This systematic literature review summarizes corticosteroid-related AEs based on the most recent publications, and highlights key data gaps for additional research. Research since the 1980s set the trend of the use of low-dose corticosteroids, with the assumption that such dosing is generally well-tolerated. Yet, evidence from the present review reveals substantial clinical and economic burden. It is unclear whether high-dose corticosteroids are still being used in a significant portion of patients, or whether low-dose corticosteroid use is the reason behind the contemporary burden evidence. This key data gap requires further research.
      The present review summarizes the types and rates of corticosteroid-related AEs given current treatment practices. The dose–response relationship, however, was not well-quantified, indicating another key data gap. The dose–duration relationship with corticosteroid-related AEs is important to delineate, particularly by disease state, so that clinicians and patients can weigh the risks and benefits when making decisions on treatment regimens.
      Increased health care resource utilization has been shown to be associated with long-term high-dose corticosteroid use.
      • Ligon C.B.
      • Judson M.A.
      Impact of systemic corticosteroids on healthcare utilization in patients with sarcoidosis.
      However, this review found that there is very little recent, rigorous, original research available on the economic burden of long-term corticosteroid exposure. There are only a few economic evaluations that have aimed to translate exposure levels into economic terms, such as resource utilization and overall costs. These evaluations, although limited in number, have revealed a clear trend that higher levels of corticosteroid exposure are associated with higher health care resource utilization and cost. This relationship is rather complex to study, as the higher costs likely account for both the treatment of corticosteroid-related AEs as well as other therapies needed because of greater disease severity.
      Also missing from the current literature is the economic burden of corticosteroid use among patients with autoimmune conditions, who rely on corticosteroids as a key therapeutic option. The present review identified only 1 study focused on quantifying the economic burden of long-term corticosteroid use among a population with autoimmune diseases. Specifically, Shah et al
      • Shah M.
      • Chaudhari S.
      • McLaughlin T.
      • et al.
      Cumulative burden of oral corticosteroid adverse effects and the economic implications of corticosteroid use in patients with systemic lupus erythematosus.
      reported that among patients with systemic lupus erythematosus, the incremental cost difference between corticosteroid users with and without AEs associated with corticosteroid use was $4607 per annum. With disease-specific economic burden information, clinicians and researchers can develop different strategies to minimize adverse outcomes and maximize the therapeutic value of available treatments.
      Additionally, the present review found that adherence to guideline-recommended therapies to prevent fracture remains low, likely due to low awareness.
      • Thanou A.
      • Ali T.
      • Haq O.
      • et al.
      Utilization of preventive measures for glucocorticoid-induced osteoporosis among veterans with inflammatory bowel disease.
      Further research on how to accelerate the adoption of such prevention guidelines can greatly reduce the osteoporotic risks induced by corticosteroids.
      Articles reviewed were reported as-is, with no adjustment for potential quality differences. Notably, the majority of the included studies were retrospective studies, in which causality between corticosteroid use and clinical or economic outcomes is suggestive rather than determinative. Furthermore, many of these studies used administrative claims databases, which do not contain all relevant clinical information and are subject to potential coding errors. Another limitation was that many included studies could not adequately control for disease severity. In terms of assessing the economic burden of corticosteroid use, many studies reported only direct health care costs and did not assess other societal costs, such as work loss. Finally, the differences in reported outcomes, patient populations, and corticosteroid dosage and duration of exposure made precise comparisons across the included studies difficult.
      Finally, this review was limited to publications that resulted from the defined search terms in the protocol, and the results were limited to key findings in each article. Consequently, many AEs found in various articles are not described herein (eg, effects on the fetus; effects on mental state; wound healing), and are limited only to those relevant to the resulting studies and may not, for example, be relevant to products other than those searched, such as newer inhaled corticosteroids.
      Despite these limitations, we believe that the present review highlights key gaps in data that future research should investigate. First, the burden of corticosteroid use should be better characterized. It is important to understand whether there are specific aspects of corticosteroid use (eg, dosage, duration of exposure, AEs) driving the burden. Second, the relationship between corticosteroid dose and AEs is not well-quantified. Third, disease-specific measures of burden may help patients and clinicians to assess the cost–benefit tradeoffs of different treatment options.

      Conclusions

      Historically, when corticosteroids have been used for long-term treatment, low-dose treatment regimens have been implemented to minimize AEs. Despite this reduced use, researchers have found a substantial economic impact, demonstrating that negative clinical consequences persist, thus raising questions surrounding the tolerability of present corticosteroid use practice. It is possible that in conditions such as autoimmune diseases with few therapeutic options, the low-dose strategy may be insufficient to reach clinical goals. Additional research is needed to enumerate the relationship between dose and duration of corticosteroid exposure and adverse outcomes, as well as means to improve adherence to corticosteroid-induced osteoporosis–prevention guidelines. Importantly, the latest evidence reaffirms the burdens of corticosteroid use despite corticosteroids being an effective medication class. These findings suggest that in cases in which risks and benefits do not balance, it may be worthwhile to explore additional treatment options and treatment strategies to reduce the reliance on corticosteroids.

      Conflicts of Interest

      This study and its publication was funded by Mallinckrodt Pharmaceuticals, Inc, Bedminster, NJ.
      Drs. Wan and Nelson are employees of Mallinckrodt Pharmaceuticals, which provided research funding to Analysis Group, Inc (employer of Drs. Rice, White, and Scarpati). The authors have indicated that they have no other conflicts of interest with regard to the content of this article.

      Acknowledgments

      All of the authors made substantial contributions to all of the following: conception and design of the study, analysis and interpretation of the data, drafting of the manuscript or revising it critically for important intellectual content. All of the authors approved the final version of the submitted manuscript.

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