Introduction

Chronic rhinosinusitis (CRS) is an inflammatory disease of the mucous membranes of the nose and sinuses [1,2,3,4,5]. CRS affects approximately 5–12% of the general population worldwide, and the cost to health care systems and national economies is substantial [1,2,3,4, 6]. CRS is divided into a phenotype with (CRSwNP) and one without the development of nasal polyps (CRSsNP) [5,6,7,8]. CRSwNP is also called polyposis nasi et sinuum and is associated with endoscopic and/or radiological evidence of polypous-hyperplastic tissue in the nasal cavity and/or paranasal sinuses. CRSwNP is an immunologically triggered chronic inflammatory disease of mucosa and subepithelial tissue, for which specific endotype-oriented immunologic therapies have been developed only in the last decade [9,10,11,12], whereas immunotherapies [13,14,15,16,17] for exogenous-allergic nasal mucosal diseases have been therapeutic standard for a long time.

In various position papers, we have given general recommendations for the diagnosis and therapy of CRSwNP and formulated criteria according to which the currently approved biologics dupilumab, omalizumab, and mepolizumab should be used in the German health care system [11, 18, 19].

We summarize these results in the following publication and provide concrete and reliable recommendations on treatment documentation, adapted to the specific conditions in the German health care system.

Polyposis nasi as an immunological disease of the airway mucosa

Regarding the immunology of CRSwNP, we refer to several reviews [12, 20,21,22,23,24]. Cyto- and chemokines have specific functions in this regard. IL‑4 is a mediator and modulator of the immune and inflammatory response and is mainly produced by Th2 cells. In addition, IL‑4 is able to promote the differentiation of CD4+ T cells into Th2 cells and also to inhibit IFN‑γ production and Th1 response [25, 26]. In nasal polyps, upregulation of IL‑4 occurs, whereas no differences were found between nasal polyps and healthy nasal tissue for IFN‑γ [23, 27, 28]. IL‑5 is the major eosinophil-activating cytokine, promotes the survival of mature eosinophils in tissue [29, 30], and is upregulated in nasal polyps [31]. Eosinophil cationic protein (ECP) and eotaxin (CCL11) are also found to be elevated in polyp tissue and promote attraction and activation of eosinophils [22, 23, 32]. IL‑6, as a proinflammatory cytokine, inhibits neutrophil recruitment [33,34,35], while IL-25 and IL-33 maintain Th2-dominated inflammation [36,37,38].

IL-33 is a local endogenous danger signal for various immune cells and a chemoattractant for Th2 cells. It promotes the production of Th2 cytokines such as IL‑4, IL‑5, and IL-13 and is produced by epithelial cells, while its receptor is expressed by eosinophils and Th2 lymphocytes, among other cells [39,40,41]. IL-33 plays a significant role in the maintenance of Th2-mediated eosinophilic inflammation [42].

The cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) also have effects on type 2 innate lymphoid cells (ILC2) [43]. ILCs are lymphocyte-like cells that do not express antigen-specific T‑cell receptors. ILC2 cells are considered as non-antigen-specific Th2-like cells because both cell types produce Th2 cytokines such as IL‑4, IL‑5, and IL-13 [44]. ILC2s are abundant in nasal polyps and are associated with increased numbers of eosinophils in the blood and tissues of patients with CRSwNP and severe clinical symptoms [45, 46].

Comorbidities and therapies of CRSwNP

CRSwNP is often accompanied by comorbidities such as bronchial asthma, allergies, N‑ERD (NSAID-exacerbated respiratory disease), also known as Samter’s triad or Widal’s triad [7, 47,48,49]. Asthma affects 30–70% of CRSwNP patients at the same time [48, 50,51,52]. The severity of asthma disease is associated with the presence of CRSwNP [53, 54]. In mild asthma, only 10–30% have CRSwNP, whereas in severe asthma, 70–90% of patients have CRSwNP [53, 54]. Type 2 inflammation (T2 inflammation) is the most common immunological endotype for both diseases [52, 55,56,57]. This is characterized by eosinophilic inflammation associated with the detection of Th2-type cytokines such as IL‑4, IL‑5, and/or IL-13 and circulating and/or local IgE [52, 58, 59].

The basis of treatment for both CRSwNP and asthma is anti-inflammatory therapy with local glucocorticosteroids (GCS) [6, 60, 61]. If this is not sufficient, short-term applications of oral/systemic GCS (usually for a maximum of 2–3 weeks) are the therapeutic standard for CRSwNP [62, 63]. Adaptive deactivation treatment with acetylsalicylic acid (aspirin) can also be given, but may be associated with side effects (e.g., gastrointestinal complaints) [62,63,64,65]. Surgical intervention of CRSwNP is considered the treatment of choice if standard therapy fails [66,67,68]. As of November 2019, three biologic therapies have been approved to date that can effectively target T2 inflammation and interfere with the inflammatory process at different sites. Dupilumab, which binds to the common alpha subunit of interleukin receptors 4 and 13, inhibiting IL-4/IL-13 signaling and thus TH‑2 inflammation [69, 70]. This was followed by omalizumab (inhibition of IgE-mediated immune responses) and mepolizumab (inhibition of interleukin [IL]-5 immune responses).

Therapeutic options for CRSwNP

Therapy with biologics in adults

For CRSwNP patients who continued to suffer from recurrent polyps under drug treatment and/or surgical intervention to date, not achieving sufficient symptom control, and thus suffered from refractory, uncontrolled CRSwNP, no therapeutic alternatives existed until the approval of biologics. Biologics are also recommended as standard therapy for another group of CRSwNP patients in whom an improvement in control of their CRSwNP can be achieved with long-term therapy with systemic GCS), but only with toleration of associated adverse effects [11].

In recent years, various immunomodulating antibodies have been introduced for therapy in indications such as bronchial asthma, urticaria, or atopic dermatitis. These interfere either with IgE-mediated immune responses (omalizumab), or with IL-5- (mepolizumab, benralizumab) or IL-4-/IL-13- (dupilumab) mediated immune responses [71,72,73]. Dupilumab, mepolizumab, and omalizumab are approved for the treatment of CRSwNP.

Cost-effectiveness requirement for biologics prescriptions in the German statutory health insurance (SHI) system: sufficient, appropriate, necessary

We had already pointed out the need for economic prescribing, taking into account the socioeconomic importance of the high direct, indirect, and intangible costs of CRSwNP in our position papers [11]. In this context, the cost-effectiveness of interventions is derived from the benefits of the measures in relation to the expenditures used for them, especially the costs. Essential topics of the cost–benefit assessment are the costs of disease as well as the cost-effectiveness of therapeutic measures and the existence of therapeutic alternatives.

Infobox The definition of the efficiency requirement in SGB V § 12 reads

“The performance must be sufficient, appropriate and economical; they must not exceed what is necessary. Performances that are not necessary cannot be provided by insured persons, cannot be provided by service providers, and cannot be granted by health insurance funds”.

Cost-effectiveness is assumed to be given if the contract physician (service provider) provides the (necessary, sufficient and expedient) services at the lowest possible cost (in the sense of expenditure by the health insurance funds). The terms “expedient”, “sufficient” and “necessary” are to be interpreted as follows (KBV Training No. 9):

  • A medical measure is considered appropriate if it is objectively suitable for the intended purpose, i.e. successful treatment.

  • Services are sufficient if they are adapted to the individual case, correspond to the generally recognized state of medical knowledge and take medical progress into account. The performance must be sufficient to achieve the desired healing effect. The service provider or service initiator is obliged to consider the quantity of his actions.

  • Necessary is treatment that does not go beyond the scope of what is indispensable in the individual case to maintain or restore health. Necessary is everything that the physician cannot waive in treating a patient according to the state of medical knowledge, otherwise the treatment is insufficient.

If the criteria expedient and sufficient aim at ensuring that not less happens than has to happen to achieve the healing success, the criterion necessary aims at ensuring that not more happens than corresponds to this aim.

Transferred to the therapy of CRSwNP with biologics, this means that initially a standard therapy with INCS, among others, must always be applied in order to achieve a sufficient and appropriate healing success. If this cannot be achieved, an additional therapy with biologics may also be sufficient, appropriate and necessary and indispensable for the restoration of health.

Analogous to our preceding position papers [11, 18, 19], we provide the following practical recommendations for the use of biologics in CRSwNP based on scientific evidence and the current state of medical knowledge.

Practical recommendations for the use of dupilumab in CRSwNP (according to [74])

Dupilumab was the first biologic approved in Germany for the indication CRSwNP and is indicated on the label as add-on therapy with intranasal corticosteroids for the treatment of adults with severe CRSwNP that cannot be adequately controlled with systemic corticosteroids and/or surgical intervention.

According to the expert information, treatment should be started by a physician experienced in the diagnosis and treatment of diseases for which dupilumab is used. Dupilumab is offered in a prefilled syringe or a prefilled pen for single use. Prefilled syringe and prefilled pen contain 300 mg dupilumab in 2 ml solution (150 mg/ml).

The recommended dosage for dupilumab for the treatment of CRSwNP in adult patients is 300 mg every 2 weeks.

Dupilumab is intended for long-term treatment. In patients who do not respond to treatment of CRSwNP after 24 weeks, termination of treatment with dupilumab should be considered. If necessary, this may include a trial of therapy with another biologic. Some patients with an initial partial response may benefit from continued treatment beyond 24 weeks. If a dose is missed, it should be made up as soon as possible. Thereafter, dosing at the regular scheduled time should be resumed. No dose adjustment is recommended in elderly patients (≥ 65 years of age), nor in patients with mild or moderate renal impairment. Very limited data are available for patients with severe renal impairment and for patients with hepatic impairment.

No body weight-based dose adjustment is recommended for adults with CRSwNP. Safety and efficacy in children under 18 years of age with CRSwNP have not been established, as no data are available for this purpose.

Dupilumab should be injected subcutaneously into the upper arm or thigh or into the abdominal wall, except within 5 cm of the umbilicus.

It is recommended to choose a different injection site for each injection. Dupilumab must not be injected into sensitive, injured or scarred skin sites or into skin sites with hematomas.

If deemed appropriate by the treating physician, dupilumab may be injected by the patient or by a caregiver. In this case, patients and/or caregivers must be instructed on how to prepare and administer dupilumab prior to use in accordance with the instructions for use provided in the package insert. The manufacturing company provides appropriate training material.

Dupilumab should be stored in a refrigerator at 2–8 °C and should not be frozen. Both prefilled syringe and prefilled pen should be stored in the original packaging to protect the contents from light. If necessary, prefilled syringes or prefilled pens may be stored at room temperature up to 25 °C for a maximum of 14 days. Do not store above 25 °C.

Practical recommendations for the use of omalizumab in CRSwNP (according to [75])

Omalizumab is the second biologic approved in Germany for the indication CRSwNP and is indicated on the label as an add-on therapy to intranasal corticosteroids for the treatment of adults with severe CRSwNP in whom therapy with intranasal corticosteroids cannot achieve sufficient disease control. In contrast to the indication “allergic asthma”, no reference to IgE-mediated genesis of CRSwNP is listed as a prerequisite in the Summary of Product Characteristics (SmPC). However, the dosage of omalizumab is based on the baseline serum IgE level.

According to the SmPC, treatment should be initiated by a physician experienced in the diagnosis and treatment of CRSwNP. In the SmPC of omalizumab, the conversion of the dosage to the number of prefilled syringes, the number of injections and the total amount injected per administration as well as the dose determination are tabulated (Table 1).

Table 1 Conversion of omalizumab dosing in chronic rhinosinusitis with nasal polyps (CRSwNP) to number of syringes, number of injections, and total injection volumes per administration
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The efficacy of ongoing therapy should be evaluated every 6–12 months based on the degree of symptom control. Dose setting after interruptions in treatment of less than one year should be based on serum IgE levels determined at the time of the initial dose setting, otherwise IgE levels will be erroneously measured. Total serum IgE levels should be redetermined for dose setting if treatment has been interrupted for one year or longer.

Under ongoing omalizumab therapy, if significant changes in body weight occur, the dose should be adjusted (Table 2) using the initially determined total IgE value. Limited data are available on the use of omalizumab in patients over 65 years of age; it is assumed that dose adjustment is not required.

Table 2 Dosage of omalizumab (milligrams per dose) for subcutaneous injection every 2 or 4 weeks
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Omalizumab must be stored in a refrigerator at 2–8 °C and should be administered subcutaneously. Doses greater than 150 mg should be divided between two or more injection sites. There is limited experience with self-administration of omalizumab. Initial administration by or under the supervision of a healthcare professional is recommended for the first 3 applications. Patients without a known history of anaphylaxis may self-administer omalizumab beginning with the fourth application or have a caregiver inject omalizumab (approved for self-injection since 2018) if deemed appropriate by the physician. The patient or caregiver should be trained in the administration and possible early signs of adverse reactions and allergic reactions. The manufacturing company will provide appropriate training materials. To improve the traceability of biological medicinal products, the name of the medicinal product and the batch number of omalizumab should be clearly documented according to the expert information and indicated in case of adverse reactions. Here, we recommend that the manufacturer provide ready-made labels with the batch numbers to simplify documentation.

Practical recommendations for the use of mepolizumab in CRSwNP (according to [76])

Mepolizumab, as the third biologic approved for CRSwNP, is indicated as add-on therapy with INCS for the treatment of adults with severe CRSwNP that cannot be adequately controlled with systemic corticosteroids and/or surgical intervention. The biologic is available as 100 mg solution for injection in a prefilled pen, 100 mg solution for injection in a prefilled syringe, or 100 mg powder for solution for injection. Prefilled syringe and prefilled pen for single use each contain 100 mg mepolizumab in 1 ml solution (100 mg/ml).

Mepolizumab should be stored in a refrigerator at 2–8 °C and should not be frozen. Both prefilled syringe and prefilled pen should be stored in the original packaging to protect the contents from light. If necessary, the prefilled pen and prefilled syringe may be removed from the refrigerator and stored in the original unopened package for up to 7 days at room temperature (up to 30 °C) away from light.

Mepolizumab should be prescribed by physicians experienced in the diagnosis and treatment of severe CRSwNP. The recommended dose of mepolizumab is 100 mg administered subcutaneously once every 4 weeks and is intended for long-term treatment. In patients who do not respond to treatment for CRSwNP after 24 weeks, alternative treatments may be considered. Some patients with an initial partial response may benefit from continued treatment beyond 24 weeks.

The dosage of mepolizumab is independent of weight or other factors. No dose adjustment is required in elderly patients and patients with renal or hepatic impairment.

The prefilled pen or prefilled syringe may only be injected subcutaneously. Administration may be performed by the patient or by a person caring for the patient if the healthcare professional has decided that this is appropriate and the patient or the person caring for the patient has been trained in injection techniques (see information in the SmPC). If self-administered by the patient, the recommended injection sites are the abdominal wall or thigh. A person caring for the patient may also inject mepolizumab into the upper arm. Detailed instructions for subcutaneous administration of mepolizumab in a prefilled pen or syringe are provided in the instructions for use in the package insert.

The powder must be reconstituted before use and should be used immediately. The reconstituted solution containing mepolizumab 100 mg/ml is intended for subcutaneous injection only and should be administered only by healthcare professionals. It may be injected into the upper arm, thigh, or abdominal wall. For doses requiring more than one injection, it is recommended that each injection be administered at least 5 cm apart. Each vial of mepolizumab should be used for a single patient and any remainder in the vial should be discarded.

There is limited experience (less than 300 pregnancy outcomes) with the use of mepolizumab in pregnant women. There are no data on whether mepolizumab passes into breast milk in humans or whether it has an effect on fertility in humans.

Documentation forms for indication and therapy control

In order to facilitate indication, documentation forms have been developed for all three biologics approved to date, which can serve as a basis for documentation. (Figs. 1, 2 and 3).

Fig. 1
figure 1

Documentation sheet for the use of dupilumab in CRSwNP

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Fig. 2
figure 2

Documentation sheet for the use of omalizumab in CRSwNP

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Fig. 3
figure 3

Documentation sheet for the use of mepolizumab in CRSwNP

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Discussion

Currently, there are three approved monoclonal antibodies in Germany and Europe for the treatment of CRSwNP with dupilumab, mepolizumab, and omalizumab [11, 18, 19].

The aim of this publication is to summarize the current recommendations for the indication and documentation of therapy with biologics in CRSwNP in the German health care system.

CRSwNP is a chronic inflammatory disease of the mucous membranes of the nose and paranasal sinuses based on different immune processes, which has been phenotypically classified so far. Depending on the nature of the underlying immunology, different endotypes are characterized, exhibiting differential signaling pathways from the process of inflammation initiation, maintenance and chronification to tissue destruction [12, 21]. Accordingly, biologics are endotype-based treatment approaches, as they intervene in the pathological immune processes in a regulatory manner. So far, in CRSwNP, they target T2-based, IgE- and/or eosinophil-dominated inflammation [55]. These include dupilumab (anti-IL-4/13), mepolizumab (anti-IL-5), benralizumab (anti-IL-5Rα), and omalizumab (anti-IgE) [12, 21, 77, 78].

Biologics are cost-intensive drugs, which is why compliance with the economic efficiency requirement in SGB V § 12 is of particular importance for their use in the German statutory health insurance (SHI) system. SHI-accredited physicians must provide the necessary, sufficient, and appropriate performance at the lowest possible cost to the health insurance funds. This will always be the case if therapeutic alternatives have already been used unsuccessfully or are not applicable due to unacceptable side effects. In the case of surgery, a high surgical risk or lack of anesthetic capability can also be a reason, as well as the rejection of surgery by the patient. The German Patients’ Rights Act (Gesetz zur Verbesserung der Rechte von Patientinnen und Patienten), which came into force in February 2013, is particularly significant here. It establishes regulations for the standardization of the treatment contract and the associated obligations of those providing treatment, such as in particular the concrete formulation of the obligations to provide information and clarification, regulations on the documentation of treatment and the patient’s right to inspect medical records, as well as the introduction of rules on the burden of proof. According to Section 630e “Obligations to inform”, the following applies: (1) The healthcare provider is obligated to inform the patient about all circumstances that are essential for consent. This includes, in particular, the type, scope, implementation, expected consequences and risks of the measure, as well as its necessity, urgency, suitability and prospects of success with regard to the diagnosis or therapy. The information must also refer to alternatives to the measure if several methods that are medically equally indicated and customary can lead to significantly different burdens, risks or chances of recovery.

This is likely to be clearly fulfilled in the weighing of the therapy alternatives “surgery” or “biologics administration”, which is why we recommend referring to biologics in the patient information prior to surgical interventions in CRSwNP.

The selection of the appropriate biologic among the currently approved dupilumab, omalizumab, and mepolizumab for CRSwNP is based on the freedom of therapy of the treating physician. Here, criteria such as the pathophysiological mechanisms involved, practical aspects (dosage, dosing interval, etc.), concomitant diseases (approval for severe asthma and atopic eczema for dupilumab, for severe allergic [IgE-mediated] asthma and chronic spontaneous urticaria for omalizumab, for severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis [EGPA] and hypereosinophilic syndrome [HES] for mepolizumab), but also different side effect profiles should be considered.

In Germany, only INCS with the active ingredients budesonide and mometasone furoate are approved for the treatment of CRSwNP [79, 80]. The recommended initial dose for mometasone furoate is 1 × 2 sprays of 50 µg per side of the nose (i.e., 100 µg per side of the nose once daily). After 5–6 weeks without symptom improvement, the dose may be increased to 2 × 2 sprays per nostril (i.e., 100 µg per side of the nose twice daily). The permanent dosage for mometasone furoate should be adjusted to the lowest amount at which good symptom control can be achieved. For budesonide, an initial dose of 2 × 2 spray bursts of 50 µg per side of the nose is recommended (i.e., 100 µg per side of the nose twice daily). Once good symptom control has been achieved, the dosage can be reduced on a trial basis to 2 × 1 sprays per side of the nose (i.e., 50 µg per side of the nose twice daily) [79, 80]. We consider a consistent uninterrupted use of at least 3 months necessary to assess whether an additive therapy with a biologic is necessary under this standard therapy.

In addition to current therapeutic options, biologics may help to realize the principle of “personalized medicine” also for polyposis nasi in the future.