Oral corticosteroids for patients with eosinophilic disorders: An expert panel view on use, overuse, and strategies to reduce use (2023)

Summary

Severe asthma (SA), chronic rhinosinusitis with nasal polyps (CRSwNP), and eosinophilic granulomatosis with polyangiitis (EGPA) are three disorders caused by IL-5 and eosinophilic inflammation. Because these conditions involve high utilization of healthcare services, as well as lifestyle and psychological distress, well-tolerated treatment is key to achieving optimal control. In all three conditions, as in many other eosinophilic disorders (ED), oral corticosteroids (OCS) are commonly used for both acute and maintenance treatment when disease activity is high. While OCS are generally very effective, their use is limited by a generally recognized high potential for adverse effects (AEs). In addition, the cumulative exposure to OCS may not be recognized in many patients, particularly those treated predominantly in primary care, thereby exposing patients to potentially harmful long-term OCS-related AEs. A panel of European experts from each field was assembled to discuss the use of OCS for these eosinophilic disorders and provide guidance on how to limit their use. Experts completed questionnaires on treatment and referral pathways for patients with SA, CRSwNP, or EGPA; then discussed a number of issues related to the use of OCS in an online meeting. Here the authors present the most important recommendations of the expert advisory board as well as some background information on these diseases in relation to treatment with OCS.

INTRODUCTION

Systemic use of corticosteroids for ED is widespread worldwide.¹An expert panel of advisors was convened to discuss the use, overuse of OCS, and ways to limit its use in patients with EDs such as SA, CRSwNP, and EGPA, all populations where cumulative OCS doses can be high. Discussion included how such use depends on multiple factors, including disease severity and stage, organ involvement, comorbidities, response to therapy, and adherence to therapy. These discussions have implications for other EDs such as hypereosinophilic syndrome. This typically multi-organ and tissue-damaging disease is also mainly treated with OCS, kinase inhibitors and biologicals; and similar issues with long-term use of OCS, discussed below, may apply to this and all EDs where such treatment is common.²Unless expressly stated otherwise, the opinions expressed here are those of the consultants.

Oral corticosteroid dose and side effect profile

As with most diseases, treatment decisions regarding OCS use should be individualized based on the patient's needs and should take into account disease, behavior, comorbidities, and environmental factors. There is no standard definition of what constitutes a low or high OCS dose or an acceptable lifetime cumulative dose, the consultants discussed, so misunderstandings can arise in clinical practice with adverse consequences in terms of morbidity and mortality, even for patients who receive a low OCS dose. Recently, a task force of the European League Against Rheumatism (EULAR) concluded that there is a low risk of harm from chronic use of OCS at doses ≤ 5 mg/day and individual harm assessment is required at > 5-10 mg/day and an increased risk of harm at >10 mg/day.³However, the consultants emphasized how cumulative exposure must be considered, including in other inflammatory conditions, because in a long-term study of 24,117 adults with SA, adverse outcomes began with cumulative OCS exposures of 500 to 1,000 mg, equivalent to four OCS courses over a lifetime long,⁴and, as one of the consultants pointed out, lower than the annual dose for a patient at 5 mg/day.

Although effective, there are myriad AEs associated with OCS exposure (illustration 1) as they regulate inflammation and immune function; lipid, carbohydrate and protein metabolism; brain function; calcium and bone metabolism; and cardiovascular homeostasis.^5,15,16For example, the action of OCS on the anterior pituitary gland and hypothalamus results in decreased release of associated hormones and subsequent potentially iatrogenic adrenal insufficiency.^6,17Another example is psychological effects, with one study finding a high difference in the incidence rates for depression and anxiety between OCS and non-OCS users with asthma, even in patients with low cumulative OCS exposure. Note, however, that this may not be a direct causal effect.¹⁸

Figure 1: Side effects associated with oral corticosteroid use.^5-15

Mortality associated with the use of OCS is also of concern to the consultants. Most of the studies here have been conducted on patients with asthma. For example, in a South Korean study of 16,668 OCS-dependent and paired OCS-independent adults with asthma, there was a hazard ratio (HR) of mortality of 2.17 (95% confidence interval: 2.04-2.31), with the HR with the dose increased.¹⁹A Swedish study of 217,993 patients with asthma aged ≥ 6 years found a HR for mortality of 1.34 (95% confidence interval: 1.24-1.45) for regular OCS users compared to non- or regular OCS users .²⁰

Patients themselves have concerns about using OCS for AEs, with a study of adult patients with asthma reporting that 44% of 268 patients had a 'negative picture' of OCS, with 26% reducing or stopping OCS treatment and 42% and 34%, respectively, of 230 patients who said they would try to find an alternative treatment and would seek advice from another healthcare professional (HCP).²¹

TREATMENT OF EOSINOPHILIC DISEASES WITH ORAL CORTICOSTEROIDS

severe asthma

About 5-10% of the 300 million people with asthma worldwide are diagnosed with SA, which can involve frequent exacerbations and hospitalizations, or have at least one severe exacerbation per year.^22-25

Morbidity and mortality rates are high in SA, and burdens include healthcare costs, corticosteroid-induced comorbidity, psychological factors, and work-related difficulties.^23,26-29SA assessment and management should preferably be performed in a specialized center in an individualized stepwise approach with validation of the diagnosis and consideration of comorbidities. The Global Initiative for Asthma (GINA) has SA treatment goals, including good symptom control and risk reduction with minimal treatment side effects. For patients ≥ 12 years of age, they recommend moderate/high dose inhaled corticosteroids (ICS) as maintenance therapy plus formoterol or, as an alternative agent, long-acting β-2 agonists and consider adding a long-acting muscarinic antagonist and biological treatment if needed. They recommend only short courses of OCS with maintenance OCS “as a last resort” in severely uncontrolled asthma and give high priority to OCS minimization strategies.³⁰

Studies investigating the use of OCS in patients (> 5 years) with SA indicate that mean daily maintenance doses of OCS range from 4.0 to 21.4 mg prednisolone equivalents.¹with daily doses of 5.5-7.5 mg for patients prescribed OCS for ≥2 years.³¹The main reasons health care professionals (HCP) cite for OCS maintenance prescription include relative resistance to ICS and other control drugs, increased number of exacerbations, and increased disease severity.¹The consultants emphasized the need for routine monitoring of inhaler adherence and use, and discussed how worsening symptoms can automatically be attributed to poor asthma control when there are other possible causes. In these latter situations, patients are at high risk of being offered emergency treatment with OCS without objective evidence of deterioration, such as: B. a deterioration in lung function is prescribed.

Despite the availability of biological treatments for SA, the consultants discussed that the use of OCS remains high.^1,32For example, a survey of 4,990 adult patients by the International Severe Asthma Registry (ISAR) found that 63.1% of patients were in Italy, 59.6% in the UK, 23.3% in the US, 24.7% in Australasia and 20.7% in South Korea were affected received OCS maintenance treatment at enrollment; although, advisers say, many of these patients have subsequently progressed to biological therapy in specialized centers.²⁴A study of 1.7 million Hispanic patients (≥12 years) showed that of the 5.5% of the study population with asthma, 7.7% had SA, with almost a third of these patients being OCS-dependent.²⁵In a Portuguese study, 91.3% of 46 physicians with an SA specialty agreed that the use of OCS was necessary to control SA and almost two-thirds did not agree that there was maintenance OCS overuse .³³

Both long-term and short-term use of OCS is associated with increased healthcare costs for people with asthma compared to non-use, as is long-term use compared to short-term use.¹For example, in one study, patients receiving OCS maintenance therapy had a 43% higher cost than patients not receiving it, due in part to the cost of drugs used to treat OCS-related AEs.³⁴In fact, another study showed that such costs are higher in SA patients with high OCS exposure than in mild/moderate asthmatic patients with low OCS exposure.³⁵

Chronic rhinosinusitis with nasal polyps

In CRSwNP, which has an estimated global prevalence of 1% to 4%, nasal inflammation may be accompanied by loss/reduction of smell; nasal congestion, discharge and congestion; facial pain/pressure; and polyps, which can lead to partial or total nasal congestion.^36-39CRSwNP is associated with greater symptom burden and medication use, along with absenteeism from work and decreased productivity and quality of life (QoL) compared to people without the disease and people with chronic rhinosinusitis without nasal polyps.^36,38,39CRSwNP and asthma are often comorbid, occurring in approximately 40% of patients with both conditions.^40,41Such comorbidity is associated with higher OCS use, including number of cycles per year and frequency of maintenance therapy.⁴⁰

Surgery may be required for severe CRSwNP; however, postoperative polyp recurrence is high, particularly in patients with eosinophilic polyps and patients with comorbid asthma.^36,42More recently, anti-IL4Rα biologic therapy has been recommended in some patients, including those requiring ≥ 2 OCS cycles/year or requiring OCS therapy > 3 months.³⁶While localized, intranasal steroid treatment is routinely prescribed for CRSwNP, short cycles of OCS can reduce polyp size.^36,43-45However, the consultants noted that in recent years this has not been recommended, even when limited to 1-2 courses/year. Studies of 7-21 days of OCS in CRSwNP, usually in addition to intranasal corticosteroids, show that therapy resulted in a reduction in symptoms, including improved smell and nasal flow, and reduced nasal polyp counts. The latter can remain low for several weeks after the start of therapy; however, symptoms typically recur.^36,44,46,47Evidence is conflicting as to whether OCS is beneficial compared to nasal corticosteroids after CRSwNP surgery, with some studies showing greater effects and lower recurrence rates while others show no benefit.^48-50

According to the consultants, the use of OCS for CRSwNP is generally symptomatic and not preventative. Such therapy is rare in some countries, with OCS being prescribed only before surgery or as rescue medication for severe uncontrolled symptoms.⁵¹However, an Italian study of 437 Otorhinolaryngologists found that 94% prescribed a short course of OCS treatment for renewed CRSwNP exacerbation, with only 41.1% reporting not exceeding two courses/year and 13.4 % no more than four courses/year. While 35.0% considered 4 weeks/year as the cut-off point for high risk of AEs, 16.9% considered the cut-off point to be 8 weeks/year. The total annual dose considered dangerous was 1,000 mg for 23.1% of respondents and 2,000 mg for 11.2% of respondents.⁵²

Eosinophile Granulomatose mit Polyangiitis

The immune-mediated inflammatory disease EGPA, a form of small-vessel, necrotizing vasculitis associated with anti-neutrophil cytoplasmic antibodies, has an estimated annual incidence of 0.5 to 6.8 cases/million.^53-56While disease progression may vary from patient to patient, EGPA typically progresses slowly from early-stage asthma, sinusitis, and rhinitis, followed by tissue infiltration by eosinophils and vasculitis. There may be lung, kidney, and gastrointestinal involvement; damage to the peripheral nervous system; and eosinophilia-driven cardiomyopathy.^53,57

The consultants saw the primary goal of EGPA therapy as inducing remission and preventing tissue/organ damage. Subsequent treatment goals include relapse prevention, minimizing OCS and use of immunosuppressive drugs, and improving quality of life. In the EGPA guidelines, OCS therapy recommendations include starting at 2-3 weeks with 1 mg/kg/day prednisolone, tapering to 0.3, then 0.15 mg/kg/day at 3 and 6 months, respectively, to give a to achieve minimum effective dose or discontinuation.⁵⁵While maintenance doses are ideally <7.5 mg/day prednisolone,⁵⁵One study found that a daily maintenance dose of 12.9 ± 12.5 mg was required to control EGPA symptoms.⁵⁸Such OCS therapy is associated with improved remission and survival rates.^56,59-62In life- or organ-threatening cases, intravenous steroids can be administered.^56,62In patients with more severe EGPA, therapy may include cytotoxic agents such as cyclophosphamide, anti-IL-5 agents, B-cell depletion therapies, or other biologics.^55,56,62,63Asthma symptoms in EGPA, one of the main causes of chronic use of OCS in these patients, are managed as for this condition according to GINA recommendations.^30,56,62

The consultants emphasized that generally high doses of OCS for maintenance therapy may be due to a lack of early referral to the appropriate specialist. Therefore, there is a need for education among HCPs regarding EGPA screening, early diagnosis and treatment, and risks of prolonged OCS use. OCS can be used for EGPA emergency treatment but there should not be a minimum amount that is considered non-harmful as this could 'encourage' the prescription of OCS, albeit at low levels. However, a consultant noted that some patients find it difficult to avoid using OCS due to symptom recurrence and exacerbations. Another consultant stressed that the need for an OCS course should prompt HCPs to review other possible causes of disease recurrence (eg, improper inhaler technique, infection, or poor adherence to therapy).

INITIATIVES TO REDUCE EXPOSURE TO ORAL CORTICOSTEROIDS

Overall, the consultants agreed that the use of OCS for these EDs should be limited to intermittent/rescue therapy only, at the lowest possible dose when flares occur (e.g., 1-2 cycles per year of 0, 5-1.0 mg/kg prednisolone or equivalent). for a maximum of 2 weeks). OCS should be eliminated in maintenance therapy or, if unavoidable due to the need for disease control, prescribed at the lowest dose possible. Measures of success for OCS reduction were either no maintenance OCS or reduced OCS use (by 50-70%; 1-2 cycles/year) and a reduction in symptoms and unfavorable QoL measures.

As can be seen fromFigure 2, the consultants proposed several initiatives to reduce OCS burden.

Figure 2: Possible initiatives to reduce exposure to oral corticosteroids.
general practitioner: general practitioner; HCPs: health professionals; OCS: oral corticosteroids.

Cumulative Dosisrisiko

While there is a lack of evidence as to what an acceptable cumulative OCS dose is, most counselors agreed that the maximum lifetime dose should be 500 to 1,000 mg and ideally no more than three cycles over a lifetime (depending on the Duration of treatment). ) to mitigate severe AE. In particular, in patients requiring long-term treatment, concerns included administration of a dose of >5.0-7.5 mg/day, although even lower doses were of concern; or the use of OCS in patients with comorbidities that may be aggravated by such use of OCS.

The more a patient is exposed to OCS during their lifetime, the consultants discussed, the more complications they can experience later in life. This is important because it has been found that patients may not be asked about a previous use of OCS or may not correctly remember a previous use of OCS. Therefore, calculating the cumulative lifetime exposure can be problematic. While a patient's OCS prescription history can be verified with e-prescribing records, on-demand OCS use can be more difficult to track as the patient may not report it, and a consultant noted that OCS are available over-the-counter and/or patients themselves managed in some countries. Tracking cumulative OCS exposure also becomes more difficult when there is nationwide heterogeneity in electronic medical records and patients change hospital and/or primary care physician (PCP). Additionally, the counselors discussed, not all countries have electronic records, so patient reporting may be the most important way to assess OCS use. This can also be difficult as patients may not always know the details of the medication. For example, a consultant spoke about a patient who was given what her GP called an "allergy shot" that was actually an OCS.

Training health professionals and involving policy makers

The consultants saw a great need to educate all HCPs, particularly in primary care, about treatment options other than OCS for these EDs. However, it was found that OCS are cheap and easy to prescribe, so other options such as biologics could impact a GP's budget. In addition, some countries prohibit PCPs from receiving direct information from manufacturers about biologics. Another issue that the consultants highlighted was how laypeople might prescribe OCS more widely due to a lack of awareness of the cumulative negative impact on health outcomes. OCS can also be prescribed for an acute exacerbation of ED, but the patient is not always followed up to assess the frequency of such OCS prescription or possible AEs. This may be due to limited capacity in basic services. In these cases, the consultants discussed how specialists need to work with and inform a patient's GP to help reduce the dose or discontinue the use of OCS, and finally the consultants recommended SA, CRSwNP, and EGPA in specialized centers treat to avoid indiscriminate treatment OCS management.

Further discussions focused on the need for multidisciplinary team networks for patient care involving PCP and specialists, as well as broader HCP meetings and educational initiatives on the use of OCS. This could include multidisciplinary team workshops and round tables, structured patient interviews by experienced clinicians at symposiums, and collaborative programs with GPs where patients are treated alongside a specialist.

A strategy suggested by the consultants to raise awareness of reducing the use of OCS in these EDs involved educating policymakers about unmet needs to facilitate changes at the national level. Healthcare system organizers and, where appropriate, insurance companies also need to be aware of the need to use drugs with more favorable safety profiles than OCS, and data are needed to show the impact of using therapies other than OCS.

Referral Checklists

One problem with using OCS, according to the consultants, may be that secondary pathways for eosinophilic disease are suboptimal. For example, a UK study found that of 16,409 patients (≥16 years) identified as having potential SA in primary care, 72% had not been referred to a specialist in the past year.⁶⁴Referral checklists could be helpful in ensuring that patients who require specialist care are referred appropriately and early in the disease process. A consultant suggested developing protocols to ensure patients are referred to specialists before being prescribed maintenance OCS.

Monitoring parameters or triggers for referrals could include not only disease-related factors, but also OCS-related prompts, including repeat prescriptions of OCS and/or injectable steroids, potential steroid-associated AEs, and high-dose OCS use, according to the consultants. An alert system could be linked to a patient's electronic medical records to notify GPs if patients receive more than two cycles of OCS per year, for example, as is practiced in the UK to indicate overuse of short-acting β2-agonists. However, it has been discussed that the feasibility of such an initiative is not clear due to the differences between healthcare systems in their ability to have a patient-level alert system and in some cases the heterogeneity of the software packages used in a country.

patient education

Involving patients in OCS reduction initiatives is critical because withdrawal symptoms such as adrenal suppression can make patients dependent on OCS.³³Suggestions from the consultants included patient education via videos in a clinic/PCP waiting room, as well as patient conventions and online meetings. Patients should also be counseled on ways to minimize risk of AEs (eg, avoiding weight gain, exercise to support bone protection, and cardiovascular AEs).

The consultants suggested that patients could complete an AE symptom checklist under the supervision of their GP, as many patients recognize OCS-related AE but may not be aware of alternative treatments. For example, the Glucocorticoid Toxicity Index (GTI) can track changes in multiple areas, including glucose tolerance, bone mass index, skin toxicity, bone density, infection, and neuropsychiatric symptoms.⁶⁵Patients reporting symptoms and OCS use via health apps are possible; However, a consultant reported that such apps did not engage their patients and many only used them for a few days. Such health apps, it was discussed, are also burdened with the complexity of data protection and the corresponding analysis by commercial companies.

Oral corticosteroid restriction More specific in severe asthma, chronic rhinosinusitis with nasal polyps, or eosinophilic granulomatosis with polyangiitis

Regarding SA, the consultants noted how with the advent of biologics, it is possible to maintain disease control without the use of OCS or just use the smallest dose that maintains disease remission in combination with QoL. They proposed a systematic approach to OCS dose limitation that assesses and improves medication adherence, provides training on ICS device technology, provides an asthma self-management plan, optimizes asthma treatment, and manages comorbidities. Such a strategy is associated with exacerbation reductions, better symptom control, increases in lung function, improved QoL, and significant reductions in OCS dose.⁶⁶After OCS usage was reduced/eliminated, the consultants discussed how ICS usage should also be tailored to individual needs.

While OCS are recommended in the CRSwNP guidelines,^36,45The consultants noted that there is little information on dosing regimens and duration of treatment, and that there are few studies on the minimum dose for maintenance therapy. Although some consultants reported that they would consider alternative treatment options when patients with CRSwNP receive >2 cycles of OCS per year, others indicated that one cycle was sufficient to warrant treatment switching or escalation to biologics, and it was stresses that HCPs need to be more aggressive about limiting OCS usage. However, one consultant cautioned against outright "steroid phobia" because OCS are relatively inexpensive and effective in cases involving airways. Another suggestion was that PCPs managing CRSwNP should attend specialist-led training events to educate them on the use of OCS.

In cases of EGPA with clear vasculitis manifestations, the consultants discussed how the use of OCS together with biologics such as anti-IL-5 or immunosuppressants might be required for maintenance therapy. A dose of ≤ 5 mg/day prednisolone was considered potentially acceptable (although it was noted that this is still a large cumulative dose) or the minimum dose required for a patient to have < 3 exacerbations/year and im with a view to tapering off whenever possible. Increased awareness of comorbidities that could represent treatable disease features is required, and when other vital organs are affected, careful reduction of the OCS dose to a minimal dose is required. Age is also a factor of concern for consultants, as younger patients may be at greater risk of being on maintenance therapy for a longer period of time. One consultant stressed that "rheumatologists will not accept long-term OCS treatment for anything but EGPA." Therefore, alternatives to the use of OCS should be explored for all patients and there is a need for early, steroid-sparing treatment routes. However, it should be noted that complete OCS removal is not possible in some patients as it can lead to exacerbations.

DIPLOMA

Although there are alternatives to OCS treatment, the consultants discussed that many patients are prescribed intermittent and/or maintenance OCS therapy despite the known AE profile in SA, CRSwNP and EGPA. They emphasized how education and initiatives are needed to raise awareness of OCS-UE and underlined the need to focus on optimal efficacy with minimal toxicity. These will help reduce the use of OCS to only when needed and then to the lowest dose possible if necessary to maintain an effect and limit adverse events.