Corticosteroid Premedication for Infliximab Remains Unnecessarily Common

ABSTRACT

Objectives: Corticosteroid use can lead to serious adverse events even with short-term use. Data suggest that corticosteroid premedication prior to infliximab (IFX) administration is ineffective at preventing infusion reactions. Therefore, we examined corticosteroid premedication practices in inflammatory bowel disease (IBD), which represent an opportunity for reducing corticosteroid overuse.

Study Design: National cohort study of patients with IBD receiving IFX using 2015-2021 Truven (now Merative) MarketScan data.

Methods: We examined corticosteroid premedication as an outcome of interest using descriptive statistics and identified associated patient-level factors using bivariate analyses. We also explored differences in corticosteroid premedication for first IFX infusions (ie, no opportunity for a prior reaction) and subsequent IFX infusions.

Results: We identified 19,637 patients with IBD who received IFX and met the inclusion criteria. Corticosteroid premedication use declined from 27.4% in 2015 to 20.4% in 2020. During this time, 38.7% of the 4639 patients who received IFX premedication were premedicated for more than 90% of their infusions. Overall, those who received corticosteroid premedication were younger (median age, 30 vs 33 years), more often female (51.6% vs 47.7%), and more likely to have 1 or more comorbidities (21.7% vs 18.8%) than patients who were not premedicated, but the groups had similar rates of diabetes (4.1% vs 4.2%), cataracts (1.4% vs 1.3%), and osteoporosis (1.4% for both). Among patients receiving corticosteroid premedication, 62.5% received it with their first IFX infusion, suggesting routine practice rather than a strategy for those who had a prior infusion reaction.

Conclusions: Corticosteroid premedication for IFX remains unnecessarily common. Corticosteroid premedicating is a common low-value practice that could be targeted to reduce corticosteroid overuse in IBD.

Am J Manag Care. 2025;31(7):In Press

Takeaway Points

• Use of corticosteroid premedication prior to infliximab infusions is declining but remains unnecessarily high despite limited benefit and the risk of serious adverse events from corticosteroids.
• Corticosteroid premedicating is a common low-value practice that could be targeted to reduce overuse and avoidable toxicity in inflammatory bowel disease.
• Deprescribing practices could be especially helpful for patients with comorbid osteoporosis, diabetes, and cataracts, who may be particularly impacted by corticosteroid adverse events.

Inflammatory bowel disease (IBD) affects more than 3 million Americans and 6.8 million individuals worldwide, and it contributes to disability and impaired health-related quality of life.^1,2 Systemic corticosteroids are an effective first-line treatment for clinically active IBD, with 54% and 58% of patients with ulcerative colitis and Crohn disease, respectively, achieving clinical remission within 30 days when treated with corticosteroids.^3,4 However, even short-term systemic corticosteroid use can lead to serious adverse events, including infections, fractures, and cardiac events.⁵ In fact, use of corticosteroids for less than 30 days has been associated with a higher likelihood of developing sepsis, venous thromboembolism, congestive heart failure, gastrointestinal bleeding, and fracture, even in otherwise healthy individuals.^6-8 Further, corticosteroids are not effective in maintaining remission.⁹ Therefore, biologic treatments such as infliximab (IFX) have replaced corticosteroids as the preferred maintenance treatment option, and in some cases as the preferred induction agent, for IBD.

Acute and delayed infusion reactions are a common concern with IFX administration, affecting up to 2.5% of infusions.^10,11 IFX infusion reactions are thought to occur secondary to cytokine release syndrome, IgE-mediated hypersensitivity, massive activation of neutrophils with IgG anaphylaxis, complement activation, or degranulation of mast cells and basophils.¹² These infusion reactions often present as pruritus, flushing, dyspnea, chest pain, myalgias, urticaria, or dizziness. Various premedication strategies have been utilized to prevent IFX infusion reactions, including the use of corticosteroids prior to infusion. However, data suggest that corticosteroid premedication prior to IFX administration is not effective at preventing IFX infusion reactions and should not be routine practice.^13-15 The original data on the ineffectiveness of corticosteroid premedication date to the early 2010s, culminating in systematic review data concluding that premedication should not be part of standard IFX infusion protocols.¹³ Our study objective was to examine national corticosteroid IFX premedication practices as an opportunity for reducing corticosteroid overuse, which is a cause of low-value care in IBD, and preventing harm caused by avoidable corticosteroid exposure.

METHODS

We conducted a retrospective national study on patients of all ages with a diagnosis of IBD having at least 1 IFX or biosimilar infusion on or after the IBD diagnosis date. We utilized the Truven (now Merative) MarketScan Commercial Claims and Encounters and the Medicare Supplemental databases for the years 2015-2021. These large administrative claims databases offer patient-level information on clinical utilization, expenditures, and enrollment across the inpatient and outpatient settings and outpatient prescription drug fills. IBD was defined based on the presence of an International Classification of Diseases, Ninth Revision or International Statistical Classification of Diseases, Tenth Revision diagnostic code of 555.x, 556.x, K50.x, or K51.x on either an inpatient or outpatient claim.^16,17 We applied a 1-year washout period that excluded patients with an IBD diagnosis during 2014 as a means to isolate incident IBD cases during the study period (2015-2021). IFX and biosimilar infusions were defined based on CMS Healthcare Common Procedure Coding System (HCPCS) codes (J1745 [infliximab; Remicade], Q5103 [infliximab-dyyb; Inflectra], Q5104 [infliximab-abda; Renflexis], and Q5121 [infliximab-axxq; Avsola]). Patients with chronic diseases that may require steroids (eg, rheumatoid or psoriatic arthritis) were not specifically excluded. However, we excluded patients who had IFX or biosimilar infusions before their initial IBD diagnosis, with a look back to January 1, 2014, to reduce the effect that a comorbid disease (eg, rheumatoid arthritis)¹⁸ may have on premedication practices during the follow-up period. Further, we excluded patients if their enrollee identifier, birth year, or sex was missing. Patients were also required to have continuous insurance coverage for a minimum of 30 days prior and 120 days following their first infusion. Therefore, the first eligible date of entry for a patient who could be included in the cohort was between January 1, 2015, and September 2, 2021. Patients with coverage beyond 120 days were followed until their coverage ended or the close of the study period.

We identified use of corticosteroid premedication prior to IFX or biosimilar infusion as the outcome of interest. We defined corticosteroid premedication by identifying corticosteroid injections dispensed on the same day as an IFX infusion using HCPCS codes (J1020 [methylprednisolone acetate 20 mg], J1030 [methylprednisolone acetate 40 mg], J1040 [methylprednisolone acetate 80 mg], J1094 [dexamethasone acetate 1 mg], J1100 [dexamethasone sodium phosphate 1 mg], J1700 [hydrocortisone acetate 25 mg], J1710 [hydrocortisone sodium phosphate 50 mg], J1720 [hydrocortisone sodium succinate 100 mg], J2650 [prednisolone acetate 1 mg], J2920 [methylprednisolone sodium succinate 40 mg], and J2930 [methylprednisolone sodium succinate 125 mg]). We did not evaluate other common premedications (eg, acetaminophen, diphenhydramine) because they may be taken at home and thus cannot be definitively associated with the date of infusion. We compared the characteristics of patients receiving corticosteroid premedication with those of patients not receiving corticosteroid premedication using descriptive statistics and Fisher exact, χ², and Wilcoxon rank sum or Mann-Whitney tests for categorical and continuous variables, as appropriate. As the evidence against premedication has grown stronger, we also examined differences in premedication by year. Finally, to address the possibility that some patients may receive corticosteroid premedication in response to previous infusion reactions, we explored differences in corticosteroid premedication for first IFX or biosimilar infusions, where there was no opportunity for a prior infusion reaction.

We collected patient demographics and clinical characteristics during the required insurance coverage period including the Charlson Comorbidity Index score, IBD type (Crohn disease, ulcerative colitis, or IBD unclassified), and presence of rheumatoid arthritis, which could influence corticosteroid use. We also reported any major adverse cardiac events that may be impacted by corticosteroid use as well as other major comorbidities that can be influenced by corticosteroids, such as osteoporosis, glaucoma, and cataracts. All statistical analysis was performed in SAS 9.4 (SAS Institute Inc).

RESULTS

We identified 404,648 patients with a new diagnosis of IBD from 2015 to 2021. Of these, 30,002 (7.4%) received their first IFX or biosimilar infusion on or after their IBD diagnosis date, and 19,637 (4.9%) met the required insurance coverage period with no missing data and were included in the analytic cohort. The cohort had a median (IQR) age of 32 (22-46) years, 51.4% were male (n = 10,091), and 19.5% (n = 3823) had 1 one or more comorbidities (Table 1). Overall, 3507 (17.9%) were 18 years or younger (eAppendix Table [available at ajmc.com]). Patients were followed for a median (IQR) of 593 (315-1055) days and received a median (IQR) of 8 (5-15) IFX or biosimilar infusions.

Among our cohort, 4639 patients (23.6%) received corticosteroid premedication prior to an IFX or biosimilar infusion. The proportion of patients who received corticosteroid premedication declined from 27.4% in 2015 to 20.4% in 2020 (Table 2). Because patients were required to have continuous insurance coverage for a minimum of 120 days following their first infusion, the last eligible date of cohort entry was September 2, 2021, limiting year-to-year comparison for 2021 data. Over this time period (2015-2021), 38.7% of the 4639 patients who received corticosteroid premedication were premedicated for nearly all (> 90%) of their infusions (Figure).

Patients with IBD who received premedication were younger than those who did not receive corticosteroid premedication (median age, 30 vs 33 years, respectively), more likely to be female (51.6% vs 47.7% ), and more likely to have 1 or more comorbidities (21.7% vs 18.8%). Both groups had similar rates of diabetes (4.1% vs 4.2%), cataracts (1.4% vs 1.3%), and osteoporosis (1.4% in each) (Table 1).

Among the 4639 patients who received at least 1 corticosteroid premedication, 2899 (62.5%) received premedication with their first IFX or biosimilar infusion. These patients had a similar age distribution (median, 30 years for each subgroup) and prevalence of 1 or more comorbidities (20.7% vs 23.2%) compared with those who did not receive premedication with their first infusion but were more likely to be male (50.2% vs 45.3%). The groups also had similar rates of comorbid osteoporosis (1.5% vs 1.2%), glaucoma (1.0% vs 1.6%), and diabetes (4.0% vs 4.3%). Rates of premedication with the first infusion varied by region and were lower among patients with rheumatoid arthritis (2.5% vs 4.0%) and higher among patients with mental health disorders (23.2% vs 20.4%) (Table 1).

DISCUSSION

Corticosteroid premedication prior to IFX or biosimilar infusions is common despite serious adverse events associated with corticosteroid use and no proven benefit of the practice.¹³ Therefore, corticosteroid premedicating could be targeted to reduce corticosteroid overuse and associated avoidable toxicity in IBD. We found that the use of premedication declined over the study period but remains unnecessarily high, with 1 in 5 patients receiving IFX premedication. Additionally, despite the known association of corticosteroid use with osteoporosis, diabetes, and cataracts, patients with IBD and one of these comorbid conditions were equally as likely to receive low-value corticosteroid premedication as patients without these comorbidities. Finally, more than half of patients received corticosteroid premedication with their first IFX or biosimilar infusion, suggesting that premedication is often routine practice rather than a response to a prior IFX infusion reaction.

Patients in this study received a median (IQR) of 8 (5-15) IFX or biosimilar infusions. Although the proportion of infusions premedicated with corticosteroids varied, a substantial proportion (38.7%) of the 4639 patients receiving corticosteroid premedication were premedicated for nearly all (> 90%) of their infusions. Corticosteroid toxicity is exposure dependent, so receiving a greater cumulative dose of corticosteroids could lead to a greater risk of corticosteroid-related toxicity. However, findings of multiple recent studies have shown that even short-term corticosteroid use significantly increases the risk of adverse events at a population level. For example, in a self-controlled case series conducted in a commercially insured American cohort, a prescription for 30 or fewer days of oral corticosteroids was associated with an incident risk ratio (IRR) of 5.3 for sepsis, 3.3 for venous thromboembolism, and 1.9 for fracture within 30 days of receipt compared with the 30 days prior.⁶ In a similar study in Taiwan, a single course of 14 or fewer days of oral corticosteroids was associated with an IRR of 1.8 for gastrointestinal bleeding, 2.0 for sepsis, and 2.4 for heart failure compared with unexposed patients.⁸ These rates were observed in the general population for a single course of oral corticosteroids with a median dose equivalent to 10 to 20 mg of prednisone per day^6,8; rates in the highly comorbid IBD population receiving intravenous corticosteroid premedication for a median of 8 IFX infusions could be expected to be much higher.

In the context of these findings, it is important to bring attention to current corticosteroid premedication practices in IBD and consider interventions to reduce their use. Changing clinician behavior, particularly for medication deprescribing, is challenging and requires a comprehensive understanding of clinician knowledge, beliefs, and incentives. Even well-established programs such as the Choosing Wisely campaign have shown mixed results and led to only marginal changes in practice in many instances.^19-21 Choosing Wisely was launched by the American Board of Internal Medicine Foundation to identify low-value clinical practices that provide minimal benefit and to reduce such care using educational materials and communication tools. A more effective way to reduce corticosteroid premedication could involve tailoring existing evidence-based behavioral change models to premedication use in IBD, such as professional education programming, academic detailing, electronic health record (EHR) alerts, and pharmacist-driven interventions.^22,23 EHR interventions have been shown to be effective for reducing overprescribing of histamine₂-receptor antagonists and proton pump inhibitors (PPIs).²⁴ A clinical pharmacist–managed deprescribing program for patients taking long-term PPIs in which pharmacists identified candidates for deprescribing and developed tapering schedules was shown to be effective at reducing or discontinuing PPIs in a majority of patients.²⁵ In addition, it will be interesting to observe how the transition to IFX injectables for maintenance may reduce the opportunity for corticosteroid premedication.

Strengths and Limitations

The strengths of this study include the use of a large commercially insured database that accounts for variation in practice across clinics and regions. Study limitations include the unavailability of data on history of IFX reactions, patient preferences, and shared decision-making on premedication as well as the use of commercial claims data, which are not necessarily generalizable to publicly insured or noninsured patients.

CONCLUSIONS

Corticosteroid premedicating prior to IFX infusion remains a common low-value practice in IBD, with the potential to cause serious, avoidable adverse events. Future studies should focus on evaluating and implementing the several promising interventions that exist for medication deprescribing to reduce unnecessary corticosteroid premedication in IBD, including EHR and pharmacist-driven programs. These findings could also inform similar efforts to minimize corticosteroid premedication practices for patients with other conditions requiring biologic infusions. 

Author Affiliations: Division of Gastroenterology and Hepatology (SC-M, JG, AKW), Division of Rheumatology (BW), Department of Surgery (BK), and Department of Learning Health Sciences (AKW), University of Michigan Medical School, Ann Arbor, MI; VA Center for Clinical Management Research, VA Ann Arbor Healthcare System (SC-M, BW, AKW), Ann Arbor, MI.

Source of Funding: This study was unfunded. Dr Waljee received funding from a Department of Veterans Affairs Health Services Research and Development merit award. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (SC-M, BK, AKW); acquisition of data (BK, AKW); analysis and interpretation of data (SC-M, JG, BW, BK, AKW); drafting of the manuscript (SC-M, JG, BW, BK, AKW); critical revision of the manuscript for important intellectual content (SC-M, JG, BW, BK, AKW); statistical analysis (SC-M, BK); provision of patients or study materials (AKW); and supervision (SC-M, AKW).

Address Correspondence to: Shirley Cohen-Mekelburg, MD, MS, University of Michigan Medicine, 2215 Fuller Rd, Ann Arbor, MI 48105. Email: shcohen@med.umich.edu.

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