Steroids vs immunotherapy for allergic rhinitis – out with the old, in with the new

Abstract

Treatment for seasonal allergic rhinitis induced by airborne allergens can be divided into two major groups: symptom-dampening drugs, such as antihistamines and corticosteroids, and disease-modifying drugs in the form of immunotherapy. It has been speculated that depot-injection corticosteroids given once or twice a year are a safe and patient-friendly alternative to the time-consuming immunotherapy. Our data indicate otherwise.

Keywords::

• allergy
• rhinitis
• SCIT
• SLIT
• specific immunotherapy
• sublingual tablet immunotherapy

It has been estimated that 20% of the population in western societies has allergic rhinitis triggered by airborne allergens [1]. The severity of rhinitis varies greatly between individuals, ranging from mild symptoms easily alleviated with oral antihistamines to severe rhinitis with systemic impairment, which is more difficult to manage. Treatment of rhinitis is a cumulative stepwise approach, beginning with antihistamines or topical steroids and progressing to specific immunotherapy; only in rare cases should short-term treatment (<7 days) with oral corticosteroids be considered [2]. Specific immunotherapy is the only disease-modifying treatment available and therefore also the only potentially curative treatment. All other treatment modalities, including antihistamines and topical corticosteroids, are purely symptom dampening.

Specific immunotherapy is available in three forms: subcutaneous immunotherapy (SCIT; the traditional treatment available for most airborne allergens); sublingual allergen tablets (SLIT tablets; currently available to treat only grass pollen-induced allergic rhinitis) and sublingual allergen droplets (SLIT-droplets), a treatment likely to be gradually replaced by SLIT tablets, and which, accordingly, will not be discussed further here. SCIT treatment consists of increasing doses of allergens, initially administered weekly, and subsequently, with increasing time spans and allergen doses until a high maintenance dose is administered every 8 weeks for 3–5 years. By contrast, SLIT tablets give a fixed allergen dose administered daily as a sublingual tablet for 3–5 years, that is, a treatment period similar to that of SCIT. The efficacy and safety of SCIT [3] and SLIT [4] have been thoroughly investigated, and both treatments provide a 50–70% decrease in symptoms and a 30–60% reduction in rescue medication score (antihistamines and steroids). Recent data on the treatment of grass pollen-induced allergic rhinitis indicate that SCIT and SLIT-tablet treatments are similar in terms of efficacy [5]; however, safety is an issue. SCIT treatment has involved the loss of human life, and lessons have been learned. Nevertheless, the risk of experiencing a severe adverse event is minimal when SCIT is performed by a trained specialist [6]. In comparison, SLIT-tablet treatment with grass pollen looks very promising; the treatment seems safe and tolerable for most individuals and administration does not require the same level of expert training [7]. Consequently, SLIT tablets are seemingly the better option for mono-treatment of grass pollen-induced allergic rhinitis [5].

The exact immunological mechanisms modulated in individuals undergoing immunotherapy against airborne allergens are not yet fully described [8]. Traditionally, several humoral and cellular assays are used to assess treatment initiation, long-term disease modification during continuous maintenance therapy and cessation of treatment [9]. Whereas these assays vary greatly in speed and complexity, the general principle most thoroughly described is the induction of mainly IgG-class blocking antibodies capable of inhibiting the allergen–IgE complex formation and subsequent effector cell activation and symptom development [10,11]. Research has tended to focus on this topic despite the fact that the induction of blocking antibodies is most likely an oversimplification as many cell types, antibodies and cytokines are involved in immune activation. The existence of a T-cell subset capable of regulating immune activation, Treg cells, has been known for several years, and it has been demonstrated that immunotherapy can induce the differentiation of naïve T cells into Tregs, thus inhibiting allergic inflammation [12]. The induced Tregs can be distinguished from the naturally occurring Tregs because the induced form does not express the transcription factor Foxp3. The mechanisms by which these Treg cells inhibit or regulate allergic inflammation is largely unknown, but it probably has something to do with the production of IL-10 in the microenvironment as IL-10 can inhibit the Th2 response upon allergen exposure in vitro. Furthermore, several mucosa-specific cells have been shown to play a role in the development of allergic disease, among these cutaneous dendritic cells, which seem to be powerful and versatile players in allergic inflammation [13]. Genetic factors probably also play a role, and with the complete mapping of the human genome and the consequent increased availability of gene sequencing techniques, it seems surprising that more effort has not been put into this field.

As treatment of allergic rhinitis is most often done by general practitioners (GPs) – especially in rural areas where specialist referral is not possible – most rhinitis patients have no alternative to antihistamines and steroids to treat their disease. This presents a dilemma for many GPs when they run out of guideline-compliant non-specialist treatment options (antihistamines and topical steroids), and consequently a large group may turn to high-dose depot-injection corticosteroids [14], skipping immunotherapy due to lack of specialist training. Some GPs have argued that treating individuals with 1–2 depot-steroid injections annually is safe and effective [15]. Unsurprisingly, allergologists do not agree [16]. The disagreement has resulted in a stalemate, partly for ethical reasons related to potential randomization into high-dose corticosteroid therapy and partly because of difficulties acquiring funding for proper randomized, double-blinded, placebo-controlled trials. As a result, the papers published on side effects of depot-steroid injections used to treat allergic rhinitis are mainly based on case studies. More clarification is needed.

The permanent, unique civil registration number that all citizens in Denmark receive is used by pharmacies and hospitals to record drug usage [17] and diagnosis [18]. The registries contain complete data on all citizens from 1995 and onward; accordingly, the registries can be used to ascertain associations between drugs and diagnoses. Based on the data from the registries, we identified a group of individuals diagnosed with grass and/or birch pollen-induced allergic rhinitis who were receiving immunotherapy or depot-injection corticosteroids to treat their rhinitis (N = 39,173) [14]. We found that individuals treated with depot steroids received an average of 1.6 annual depot-steroid injections (95% CI: 1.5–1.6), and the severity of rhinitis between the groups that received SCIT and steroids was comparable; steroids were favored over SCIT at a rate of 14:1 (p < 0.001) [14]. These findings indicate that there was a large group of individuals receiving only depot steroids, in violation with guidelines, and there was an urgent need for clarification of possible side effects of these steroids. Subsequently, in another study including data during 1995–2011 (N = 47,382), we examined the prevalence of well-known side effects of steroids in a group receiving annual depot injections to treat rhinitis compared with immunotherapy. We also examined the prevalence of infections, tendon rupture, diabetes and osteoporosis. A 40% increase in diabetes (p = 0.003) and a 60% increase in osteoporosis (p = 0.002) were found in the group receiving regular steroid injections compared with the group receiving immunotherapy [19].

Although we had expected to find some association and a low prevalence, an increase in risk between 40 and 60% surprised us, especially when considering that the groups investigated comprised relatively young individuals, 18–45 years of age at the time of inclusion into the study. Moreover, we followed individuals over 15 years only, meaning that the oldest individuals at the time of inclusion (45 years) were followed only until the age of 60 years. Within 15 years, individuals with allergic rhinitis would have been treated with depot steroids or immunotherapy and possibly diagnosed with diabetes or osteoporosis at the maximum age of 60 years. We can only speculate that both prevalence and risk may increase greatly for 70- or 80-year-old individuals, thus severely affecting their quality of life in retirement.

Lastly, in assessing whether the administration of immunotherapy would reduce the need for depot-injection corticosteroids, we demonstrated that applying immunotherapy to allergic individuals previously treated with depot steroids did indeed minimize the need for steroid treatment after successful immunotherapy [14]. Before immunotherapy, 47% of individuals received 0.5–1.0 depot-steroid injections annually, and 53% received more than one annual injection. After successful immunotherapy, 72% of individuals did not receive further injections of depot steroids (p < 0.001) [14].

Although our work indicates that depot-steroid injections used to treat allergic rhinitis are associated with severe side effects, such as osteoporosis and diabetes, we acknowledge that this does not necessarily prove causality, merely association. However, as causality between steroids and unwanted side effects has been demonstrated for steroids used to treat cancer, respiratory illness and rheumatic diseases [20], it is our opinion that safer and more thoroughly documented options, such as topical steroids, antihistamines or immunotherapy, should be used instead of depot-injection corticosteroids when treating allergic rhinitis.

Acknowledgements

The authors wish to thank C Torp-Pedersen for statistical guidance.

Financial & competing interests disclosure

The authors have received an unrestricted grant for their research from ALK, Hoersholm, Denmark. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.