The burden of systemic corticosteroids in patients with chronic rhinosinusitis with nasal polyps

Abstract

Background:

Systemic corticosteroids (SCS) are widely used to treat patients with chronic rhinosinusitis with nasal polyps (CRSwNP) that is insufficiently controlled with first-line treatments. However, such treatment must be balanced against the risk of adverse effects with protracted or repeated use. Increasing awareness of these adverse effects and the introduction of biologics are changing established management approaches.

Objective:

The objective was to review the role of SCS in the management of CRSwNP in the evolving treatment landscape.

Methods:

A literature search was conducted for salient articles on SCS in CRSwNP, including guidelines.

Results:

SCS reduce inflammation through broad actions on various immune mediators. Short courses of SCS improve symptoms (especially olfactory function) and reduce polyp size, benefits that do not persist long-term after treatment ends. SCS are widely used before endoscopic sinus surgery to improve the visibility of the surgical field and after surgery to improve outcomes, although evidence for benefit of postsurgical SCS is lacking. Adverse effects associated with SCS can manifest in a wide range of organs and systems. Use of SCS in patients with CRSwNP is associated with an increased risk of avascular necrosis, pneumonia, obesity, anxiety and/or depression, fracture, sleep apnea, hypothalamic-pituitary-adrenal axis suppression, diabetes, and hypertension. The SCS dosage regimen for CRSwNP is not well defined, and there is wide variation in clinical practice. Clinical guidelines refer to “short courses” of SCS but provide minimal guidance and lack consensus. Biologic treatments for CRSwNP have well-documented steroid-sparing effects, but the extent to which biologics might be able to reduce the use of or replace SCS may depend on economics as well as relative benefit-to-risk ratios.

Conclusion:

Short courses of SCS are widely used in patients with CRSwNP, but their use must be balanced against the risk of adverse effects. Use of biologics may reduce the use of SCS in CRSwNP, minimizing these adverse effects.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 chronic inflammatory disease of the upper airways,¹ which is associated with considerable treatment burden, reduced health-related quality of life (HRQoL), and significant socioeconomic costs.^2–7 The main symptoms are nasal congestion, rhinorrhea, and loss of smell.⁸ Management of CRSwNP aims to relieve symptoms and achieve clinical control by interfering with the underlying inflammatory mechanisms. First-line treatments involve saline solution irrigations and intranasal corticosteroids (INCS).⁹ Although these treatments provide relief for some patients, step-up therapy by using short bursts of systemic corticosteroids (SCS) may be necessary for controlling disease exacerbations or to manage severe disease.⁹ A recent U.S. claims analysis of patients with a first medical claim for CRSwNP (N = 21,172) found that 65% of patients used all-cause SCS and 41% used CRSwNP-related SCS over 12 months of follow-up.¹⁰ In patients with CRSwNP and coexisting asthma, SCS use was even more widespread: 75% of patients used all-cause SCS and 47% used CRSwNP-related SCS.¹⁰ Additional management options for uncontrolled disease include sinonasal surgery and, more recently, biologic therapies that target type 2 inflammation.^11–13

Although short courses of SCS have been integral to CRSwNP management for decades, their use is limited by their well-documented systemic adverse-effect profile.^14,15 This review provides an update on the current use of SCS in CRSwNP and how it might evolve with new therapeutic options available in the overall treatment paradigm.

METHODOLOGY

We performed a narrative literature review by searching PubMed for articles and clinical guidelines, and by using the following search terms: SCS, short course, corticosteroids, CRSwNP. Our PubMed search date was unrestricted, allowing for a full comprehensive review.

THE ANTI-INFLAMMATORY PROPERTIES OF CORTICOSTEROIDS

The pharmacologic effects of synthetic corticosteroids mimic the physiologic actions of cortisol, the principal glucocorticosteroid secreted by the adrenal glands.¹⁶ Cortisol regulates carbohydrate, protein, and lipid metabolism, and plays a major role in bone homeostasis, the cardiovascular system, and the nervous system.^16,17 Anti-inflammatory properties of glucocorticoids occur from direct actions on inflammatory cells, including effects on gene expression that can persist even when plasma levels are no longer detectable.^16,18,19 This includes reduction in cytokine synthesis (including interleukin [IL]-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-13, tumor necrosis factor-α, and interferon-γ) by a range of immune and other cells, including macrophages, lymphocytes, fibroblasts, and epithelial cells. The reduction of cytokine synthesis impacts recruitment and survival of key inflammatory cells, e.g., eosinophils. Other effects of corticosteroids include direct induction of eosinophil apoptosis²⁰ and the inhibition of phospholipase A2, which produces numerous inflammatory mediators.¹⁶ Corticosteroids are frequently used to treat chronic inflammatory airway diseases. However, standard pharmacologic dosing that significantly affects physiologic processes may result in undesirable adverse effects.

THE EFFECTIVENESS OF SCS IN ALLEVIATING THE SYMPTOMS OF CRSwNP

In most patients, SCS treatment effectively reduces nasal polyp size and rapidly improves the main sinonasal symptoms of nasal obstruction, decreased sense of smell, and nasal discharge.¹³ Due to the adverse effects of long-term treatment, SCS are usually prescribed as short courses of up to 21 days. Although there are few studies that examined the long-term response to SCS treatment, the available evidence suggests that efficacy with regard to symptom control is quickly lost after cessation of treatment, including for improvement in the sense of smell.^21,22 Repeated courses of SCS are indicative of poor disease control and are often a factor in the decision to opt for surgery.²³

Cochrane systematic reviews published in 2016 evaluated the evidence that supports the use of a short course of SCS (up to 21 days) either alone²² or as adjunct therapy²⁴ in CRSwNP. Based on evidence from eight trials (N = 474), patients who received SCS alone (versus control groups) achieved better quality of life, lower nasal symptom scores, and greater polyp reduction. However, there was no difference between the groups 3–6 months after SCS cessation.²² The review of SCS as adjunct therapy concluded that, although there might be an improvement in symptom severity, polyp size, and computed tomography scores, the quality of the supporting evidence was low or very low, with uncertainties with regard to the effect estimates and benefits beyond the short follow-up period reported (up to 30 days).²⁴

More recent evidence-based reviews concluded that short courses of SCS are efficacious in the short term.^{9, 25} In randomized controlled studies that evaluated SCS therapy of 7–21 days’ duration, improvements were consistently observed in nasal symptoms and nasal polyp scores 2–4 weeks after initiation. The reduction in polyp burden was maintained at 10–12 weeks, but the improvement in symptoms was not. Studies also demonstrated short-term improvements in nasal airflow and the sense of smell.⁹

The use of SCS as an adjunct to sinonasal surgery is widespread and an active area of investigation. Corticosteroids are commonly used before surgery to improve surgical field visibility by reducing inflammation and intraoperative bleeding.¹² Guidelines differ on the best approach: the European Position Paper on Rhinosinusitis and Nasal Polyps⁹ (EPOS) advises the use of topical corticosteroids, whereas the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis¹² (ICAR-RS) describes different regimens of SCS and notes a preponderance of benefit over harm. A 2013 survey of American Rhinologic Society members found that 89% of surgeons used SCS before surgery.²⁶ Notwithstanding their widespread use, there is no consensus on the optimal regimen for preoperative SCS, and evidence that favors any particular regimen is lacking. A randomized trial in 23 patients that compared low-, medium-, and high-dosing regimens was unable to detect a difference in surgical field visibility, intraoperative blood loss, or operative time for endoscopic sinus surgery.²⁷ The ICAR-RS consensus statement¹² remarks that 30–60 mg within 7 days with or without tapering is a commonly prescribed regimen for preoperative oral steroids. The use of postoperative SCS is less well supported. The rationale for steroids after surgery is to reduce edema and improve healing. However, there is increasing evidence that postoperative SCS added to INCS do not impact outcomes or recurrence in the short or long term.^28–30

Many patients with CRSwNP have coexisting type 2 inflammatory diseases, most commonly asthma, allergic rhinitis, and non-steroidal anti-inflammatory drug–exacerbated respiratory disease.^31–33 Upper airway disease also coexists with other lower airway diseases, including chronic obstructive pulmonary disease and bronchiectasis.^34,35 The presence of coexisting type 2 inflammatory diseases increases CRSwNP severity and makes it more difficult to control with conventional therapy.³⁶ Such patients may, therefore, be more likely to receive SCS to control their disease. In supporting this, a single-center U.S. study reported higher rates of corticosteroid dependence among patients with CRSwNP and comorbid asthma versus those with asthma alone (4% versus 1%).³³

ADVERSE EFFECTS ASSOCIATED WITH THE LONG- AND SHORT-TERM USE OF SCS IN CRSwNP

The adverse effects associated with chronic SCS use can manifest in a wide range of different organs and systems, and include increased risk of infections; cardiovascular events, including arrhythmias; gastrointestinal (GI) effects; adrenal suppression; type 2 diabetes; osteoporosis and fracture; ocular effects, including cataracts; and depression (Fig. 1).^15,37,38 An adjusted analysis of the U.S. Medical Expenditure Panel Survey (N = 57,725) found that SCS have a substantial negative impact on patient HRQoL.³⁹

Figure 1.

Adverse effects associated with short- and long-term SCS. Adverse effects associated with short-term SCS can also occur with long-term exposure. ^aAdapted from Refs. 14, 40–43. ^bAdapted from Refs. 15, 19, 37, 67–70. GI = gastrointestinal; SCS = systemic corticosteroids.

Historically, short courses of SCS were not thought to cause long-lasting adverse effects,¹⁶ but recent evidence argues against this. A large retrospective U.S. study found that ∼21% of 1.5 million adults in a commercially insured health plan were given prescriptions for short-term SCS use (defined as a total of <30 days’ duration) over a 3-year period (2012–2014), mostly for upper respiratory tract infections, spinal conditions, and allergies.⁴⁰ Family medicine and general internal medicine physicians were the most common prescribers of short-term SCS, followed by specialists in emergency medicine, otolaryngology, and orthopedics. Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio [IRR] 5.30 compared with SCS non-users [95% confidence interval {95% CI} 3.80–7.41]), venous thromboembolism (3.33 [2.78–3.99]), and fracture (1.87 [1.69–2.07]), which diminished over the subsequent 31–90 days.⁴⁰ The increased risk persisted at prednisone-equivalent doses of <20 mg/day. Another study, which used data from 2.6 million individuals enrolled in the National Health Insurance program of Taiwan (2013–2015) found that oral steroid bursts of ≤14 days significantly increased the risks of GI bleeding (IRR 1.80 [95% CI, 1.75–1.84]), sepsis (1.99 [1.70–2.32]), and heart failure (2.37 [2.13–2.63]) within 5–30 days after initiation relative to non-steroid users.⁴¹ These effects remained 31–90 days after initiating the oral steroid burst, with IRRs of 1.17 (95% CI, 1.14–1.19) for GI bleeding, 1.51 (1.33–1.72) for sepsis, and 1.35 (1.24–1.47) for heart failure.⁴¹ Otolaryngology was also one of the main specialties that prescribed short-term SCS in this study, and acute sinusitis was among the leading indications.⁴¹ Short-course SCS have also been associated with neuropsychological effects, including mood change.^42,43 In a survey of Italian otorhinolaryngologists (N = 437) on management of CRSwNP, the most frequently observed adverse events related to SCS treatment were hypertension (57.6%), hyperglycemia (55.8%), insomnia (50.0%), acid reflux (29.4%), anxiety (23.3%), diabetes (23.0%), mood changes (21.7%), increased appetite (12.7%), and glaucoma (10.8%).⁴⁴ A systematic review of short courses of SCS in children and adolescents found the most common adverse effects to be vomiting, behavioral changes, and sleep disturbance, as well as evidence of increased risk of infection, elevated blood pressure, weight gain, and biochemical hypothalamic-pituitary-adrenal axis suppression.⁴⁵ The risks of hypothalamic-pituitary-adrenal axis suppression and adrenal insufficiency in children include effects on growth and levels of sex hormones in addition to the effects seen in adults.⁴⁶ Taken together, these findings feed into an ongoing debate around the risk-benefit ratio of SCS for high-morbidity, non–life-threatening conditions, e.g., CRSwNP, compared with potentially life-threatening conditions, e.g., asthma.¹⁹

An unanswered question remains about what level of cumulative SCS exposure is associated with an increased risk of adverse outcomes. One study that compared large groups of patients with asthma with and without SCS use showed that a dose–response relationship for cumulative SCS exposure with most adverse outcomes began at cumulative exposures of 1.0 to <2.5 g and for diabetes mellitus at cumulative exposures of only 0.5 to <1.0 g, equivalent to four lifetime SCS courses.⁴⁷

There is direct evidence for similar risks among patients with CRSwNP treated with SCS in real-world practice. In a U.S. claims-based study that covered 2003–2019, patients with one to three SCS prescriptions in the year postindex (n = 28,870; mean 21 days of supply) had a greater risk for any adverse outcome than controls without SCS use (n = 7032) (IRR 1.06 [95% CI, 1.01–1.11]).¹⁴ These patients had a significantly greater incidence of avascular necrosis (IRR 7.77 [95% CI, 1.06–56.70]), pneumonia (1.57 [1.26–1.95]), obesity (1.37 [1.24–1.52]), sleep apnea (1.23 [1.08–1.40]), anxiety and/or depression (1.20 [1.09–1.32]), and fracture (0.15 [1.01–1.31]) than controls without SCS use.¹⁴ In addition, there were comparisons between patient subgroups who had claims for one to three and for four or more SCS prescriptions: the risk for any adverse outcome was greater among patients with claims for four or more SCS prescriptions than among those with one to three prescriptions (IRR 1.16 [95% CI, 1.12–1.21]).¹⁴ The risk for adverse outcomes was highest in patients who did not have surgery for nasal polyps and had four or more SCS prescriptions versus controls without SCS use who did not have nasal polyp surgery (IRR 1.30 [95% CI, 1.18–1.44]).¹⁴ Patients with asthma and four or more SCS prescriptions had a greater risk for SCS-related outcomes versus controls with asthma (IRR 1.36 [95% CI, 1.19–1.55]).¹⁴

CLINICAL GUIDELINES

Clinical guidelines^9,12,13,19 published by both European and U.S. societies recommend short courses of SCS as an option in managing patients with uncontrolled CRSwNP. A position paper from the European Association for Allergy and Clinical Immunology¹⁹ stated that, although there is good evidence that SCS are effective in the short term, the benefits need to be balanced with the long-term potential adverse effects; SCS should therefore not be considered as a first-line treatment for CRSwNP but can be used in short 2–3-week courses as a last resort when combinations of other medications are ineffective. These recommendations are consistent with the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for CRSwNP, which recommends SCS as an option for patients with severe uncontrolled CRSwNP.¹³ The most recent ICAR-RS¹² states that use of SCS is associated with significant short-term improvements in subjective and objective measures in patients with CRSwNP, with a duration of improvement that may last 8–12 weeks when used in conjunction with INCS. The ICAR-RS¹² gave a strong recommendation for SCS in the short-term management of CRSwNP but recommended against longer-term use due to a lack of evidence of benefit and increased risk of harms. Similar advice was included in another recent set of guidelines, which stated that SCS are a second-line option for CRSwNP in patients whose disease is not controlled by using nasal irrigation and/or INCS; however, SCS use should be limited and not used as chronic therapy.¹¹

Although there is general agreement among the various guidelines on the judicious use of SCS for managing CRSwNP, there is currently no consensus that provides specific guidance about the type of SCS, optimal duration of therapy, and minimum effective dose. A recent survey of physicians in Italy confirmed variability with regard to duration and maximum dose of SCS therapy used for CRSwNP, with respondents citing a lack of international guidance.⁴⁴ A comprehensive literature review⁴⁸ that covered 2012–2018 uncovered only seven studies that reported the dosage of oral corticosteroids (OCS) given as part of medical management before, immediately before, or after surgery for CRS (both with and without nasal polyps). The researchers concluded that there is a wide variation in OCS dosing regimens and a lack of evidence from prospective or randomized controlled trials.⁴⁸ EUFOREA/EPOS2020¹³ recommends against prescribing more than two courses of SCS per year due to cumulative adverse effects, but little guidance is available elsewhere. In patients with major comorbidities (e.g., cardiovascular disease or type 2 diabetes), SCS therapy would be considered inappropriate, but this point is not included in many of the guidelines. EUFOREA/EPOS2020¹³ states that SCS use should be considered very carefully and weighed against the induced risks in patients with conditions such as diabetes, glaucoma, or osteoporosis. Taken together, the risk of adverse effects and the lack of consensus across guidelines support a greater need for a precision medicine approach in which treatments such as biologics can be prescribed based on a patient’s underlying pathology.

THE EFFICACY OF BIOLOGICS IN REDUCING CORTICOSTEROID BURDEN

Three biologics that target type 2 inflammatory pathways (dupilumab, which targets the shared receptor for IL-4 and IL-13; mepolizumab, which targets IL-5; and omalizumab, which targets immunoglobulin E) are now available for the treatment of uncontrolled CRSwNP in adults, and more may become available in the future.⁴⁹ In addition, dupilumab is approved in the United States for the treatment of adolescents aged 12–17 years with inadequately controlled CRSwNP.⁵⁰ The three biologics are indicated for uncontrolled CRSwNP in patients receiving INCS, but the place of these agents in the treatment paradigm remains to be fully defined. The efficacy of biologics when combined with standard therapies (INCS) in controlling symptoms and improving HRQoL is well documented from randomized controlled trials^51–53 and there is accumulating evidence of their effectiveness in real-world practice.^54–58

An additional benefit of biologic therapy in CRSwNP may be to reduce the SCS burden, akin to the well-documented “steroid-sparing” effect of biologics in patients with severe asthma.^59–61 The pivotal trials of dupilumab, mepolizumab, and omalizumab in CRSwNP were in patients with severe CRSwNP, and whereas the baseline use of SCS varied between study populations,^51–53 each study provides evidence on the potential steroid-sparing effects of biologics (Fig. 2). Improved disease control was reflected in the reduced need for surgery: compared with placebo, dupilumab was associated with an 83% reduction in the need for surgery and mepolizumab reduced the risk of being included on a waiting list for sinus surgery by 49%.^51,62 Evidence from real-world clinical practice is also emerging on the steroid-sparing effects of biologics. A retrospective study of 165 patients in the United States who initiated biologics for CRS found an estimated yearly reduction in SCS courses of 60%.⁶³ A prospective observational study of 82 patients with CRSwNP in Italy found that the proportion of patients receiving daily OCS significantly decreased from 67.6% at baseline to 16.2% at week 16 after initiating dupilumab (p < 0.001); the median (interquartile range) prednisone-equivalent dose decreased from 6.9 (9.3) mg at baseline (in 50 patients) to 4.0 (3.7) mg (in 12 patients).⁶⁴

Figure 2.

Proportions of patients who required rescue SCS in the phase III trials of dupilumab, mepolizumab, and omalizumab in CRSwNP. SCS = Systemic corticosteroid: CRSwNP = chronic rhinosinusitis with nasal polyps; NR = not reported. *Adapted from Ref. 51. †Ref. 71. ‡Ref. 72. §Ref. 73. ‖Ref. 52.

The extent to which biologics could replace SCS in the CRSwNP treatment paradigm is a question that requires consideration of a range of factors, not only the relative benefit-to-risk ratio of each treatment but also patient preference and economics. Corticosteroids are considerably less expensive than biologics, which is necessarily a key consideration for the payer. However, it is not the only consideration, and increasing awareness of the risks set against the benefits of short-term SCS will help to promote fully informed decision-making by patients, physicians, and policymakers. Costs can also be incurred by the adverse effects of SCS: analysis of 9413 matched pairs of patients with asthma found that health-care resource utilization and health-care costs increased dose-dependently with increasing incremental exposure to SCS.⁶⁵ A recent international survey of ear, nose, and throat surgeons (N = 202) found that 17% would consider prescribing a biologic therapy before surgery,⁶⁶ although this practice may not be consistent with local guidelines or reimbursement regulations. Biologics are indicated for maintenance treatment, with EPOS guidelines recommending evaluation of treatment after 16 weeks.⁹ Because short-term use is not part of the indication and evidence on short-term use is lacking, perioperative use without ongoing maintenance is outside the indication and guideline recommendations. In addition, the question of how to safely wean patients off long-term SCS therapy when introducing a biologic needs to be investigated.

CONCLUSION

Short-term SCS therapy is a widely used option for managing patients with CRSwNP whose disease is uncontrolled by INCS and/or saline solution nasal washes, and may be used adjunctively with sinonasal surgery. Current clinical guidelines for managing CRSwNP lack consensus on the dosage and duration of SCS, and the benefits of short-term use are temporary. With the introduction of biologics, maintenance therapy with SCS is increasingly being questioned in light of systemic adverse effects and suboptimal HRQoL (Fig. 3). Clinical trial data demonstrate that biologic therapy reduces requirement for SCS, but more evidence is needed on the positioning of biologics versus SCS in the overall CRSwNP treatment paradigm.

Figure 3.

SCS in CRSwNP: considerations for current and future practice. SCS = Systemic corticosteroid; CRSwNP = chronic rhinosinusitis with nasal polyps; AE = adverse event.