Managing Type 2 inflammatory diseases such as chronic rhinosinusitis (CRS) with nasal polyps, asthma, and atopic dermatitis remains challenging. Oral corticosteroids (OCS) are still among the most accessible and widely used treatments worldwide and are typically prescribed as interval pulse courses at a low dose. A short course of oral prednisone, for example, is generally defined as 0.5 mg/kg (maximum 30 mg) per day for 5–14 days. Although there is no universally defined numeric threshold, major guidelines such as the European Position Paper on Rhinosinusitis and Nasal Polyps, and the American Academy of Otolaryngology–Head and Neck Surgery generally consider the need for two or more systemic corticosteroid (SCS) courses per year as markers of poor disease control and excessive steroid exposure. The increasing availability and accessibility of biologic therapies have contributed to a shift away from OCS, but these new medications carry a significant healthcare expenditure. Biologic therapy can be lifelong, and the extended long-term risks of continued therapy remain unknown. There is a recent level of increasing concern regarding potential accumulated risks of morbidity with cumulative exposure from interval dosing of OCS, particularly in patients requiring two or more SCS courses annually or repeated courses within short intervals, but many of the studies being cited regarding this concern are industry-funded and in asthma patients. The aim of this article is to review the recent literature to quantify the risks associated with low-dose, short-term OCS therapy as it pertains to morbidity within CRS with nasal polyposis. In the pre-biologic era, Leung et al. used a probabilistic risk for a healthy 50 year-old patient newly diagnosed with CRS to evaluate medical therapy before considering endoscopic sinus surgery (ESS). From March to July 2019, MEDLINE was systematically searched from inception to determine how each potential complication affected patient health. Using 10,000 Monte Carlo simulations, the minimum effectiveness needed to avoid surgery (MERAFI) was estimated at 16.8% for CRS with nasal polyps (CRSwNP). OCS exceed these thresholds around 48%–63% for CRSwNP, giving a > 99.9% probability that including OCS in therapy reduces the need for surgery. Even under conservative assumptions about recovery, sensitivity analyses confirmed these results. Short-term OCS use carries low risk, with cumulative prednisone doses under 700 mg not linked to increased infections and only rare, transient side effects. The authors concluded that intermittent OCS remains reasonable when dosing is limited to every 2 years for CRSsNP or CRSwNP without asthma, annually for CRSwNP with asthma, or every 6 months for aspirin-exacerbated respiratory disease 1. A large US cohort study by Davis et al. (funded by AstraZeneca) used IBM MarketScan claims data from adults aged ≥ 18 years with CRSwNP between 2003 and 2019. The index date was defined as the first SCS prescription for users or a matched reference date for nonusers, requiring at least 1 year of continuous enrollment before and after the index date. Adverse outcomes and healthcare costs were compared between SCS users and controls, and across subgroups based on 1–3 versus ≥ 4 SCS prescriptions, prior NP surgery, and comorbid asthma, using inverse probability of treatment weighting over a variable-length follow-up found that SCS users with CRSwNP (n = 37,740) had a 10% higher risk of adverse outcomes compared with matched controls (n = 7032; Incident rate ratio IRR = 1.10). Actual incidence per 100 person years were not provided in the paper. There appeared to be a dose–response curve as those with 1–3 prescriptions had an IRR of 1.06 (CI: 1.01–1.11). Interestingly, patients with previous sinus surgery showed no difference in SCS users versus controls for AEs with an IRR of 1.02 (CI: 0.88–1.18). As previously demonstrated, and potentially suggesting other confounding factors, patients with comorbid asthma had a much higher risk of AEs with an IRR of 1.16 2. A self-controlled case series used the nationwide National Health Insurance Research Database in Taiwan to evaluate adults aged 20–64 years who maintained continuous enrollment from 1 January 2013 through 31 December 2015. The study assessed incidence rates of severe adverse events among users of short-term steroid bursts compared with nonusers and calculated incidence rate ratios (IRRs) for these events during 5–30 days and 31–90 days following steroid initiation. Yao et al. reported that OCS bursts of ≤ 14 days in adults with chronic conditions, including CRSwNP, had incidence rates per 1000 person-years of 27.1 for gastrointestinal bleeding, 1.5 for sepsis, and 1.3 for heart failure, mostly occurring within the first 30 days after exposure. Relative risks compared with baseline were elevated but modest: GI bleeding, IRR = 1.80; sepsis, IRR = 1.99; and heart failure, IRR = 2.37 3. Similarly, in a US study combining a retrospective cohort and self-controlled case series design, over 1.5 million adults aged 18 to 64 years enrolled between 2012 and 2014 were included. The study assessed incidence rates of adverse events in corticosteroid users versus non-users and calculated IRRs for events occurring within 30-day and 31–90-day risk periods following treatment initiation. During the 3-year period, 327,452 adults (21.1%) received at least one short-term OCS prescription over 3 years. Median prednisone equivalent dosing was 20 mg/day for seven or more days but less than 30 days in duration. The most common complications were fractures (21 per 1000 users/year), venous thromboembolism (5 per 1000/year), and hospitalizations for sepsis (2 per 1000/year). Absolute risks in the 5–90 days after a clinic visit were low: 0.51% for fractures, 0.14% for VTE, and 0.05% for sepsis, slightly higher than nonusers 4. Of the studies included in this review, one was supported by industry, whereas the other three were funded through non-industry or public sources. This is a relevant consideration when assessing reported adverse event risks associated with intermittent oral corticosteroid use. Current evidence indicates that low-dose, short-term OCS therapy as treatment for Type 2 inflammatory diseases such as CRS carries a small risk of morbidity, most of which is either not clinically significant or resolves after steroid cessation. There are no studies specific to mortality with OCS usage in patients with CRS or examining the effect of cumulative dosage of OCS. More serious adverse events are primarily associated with prolonged and frequently repeated courses of OCS. Adrenal insufficiency does not appear to pose a significant risk. Current industry-sponsored literature is focused on asthmatic patients and appears to overstate the likelihood of morbidity with respect to AEs associated with pulse dosing of low-dose OCS in CRS, and the inferences being made from the asthma population into the CRS population may not be valid. These findings encourage us to better balance the true benefits and risks of OCS, particularly given the cost and the uncertainty surrounding the long-term safety of biologic therapies. The literature comprised heterogeneous levels of evidence, three Level 3 studies, and one Level 4 study. The authors sincerely thank the reviewers for their time and consideration of this manuscript. The authors have nothing to report. Leigh Sowerby, Brian W. Rotenberg—research funding from AstraZeneca, GSK, Sanofi, Eli Lilly, Insmed; Leigh Sowerby—honoraria and advisory board for GSK, AstraZeneca, Sanofi. Papers used in this manuscript are available through electronic databases.
Khalifa et al. (Wed,) studied this question.