Biologicals: How can they treat severe chronic upper airways diseases (SCUAD)?
Severe chronic upper airways diseases (SCUAD) can be a substantial impairment for the patients’ quality of life. In search of effective therapies, scientists have focused on biologicals, monoclonal antibodies, as a possible therapeutic option, which were very successful in treating severe asthma and chronic spontaneous urticaria. But will biologicals also be able to help SCUAD-patients? MeinAllergiePortal spoke with Prof. Joaquim Mullol, Director, Rhinology Unit & Smell Clinic, ENT Department, Hospital Clínic – IDIBAPS, Barcelona, Catalonia, Spain about his research activities on biologicals and monoclonal antibodies and how they can help patients with severe chronic upper airways diseases (SCUAD).
Prof. Mullol, what is the definition of “chronic upper airways diseases“ (SCUAD) and which diseases belong into this category?
Severe chronic upper airways diseases (SCUAD) is the term used for diseases affecting the nose and the paranasal sinuses which are severe, chronic and do not respond to treatment. It does not matter whether those chronic upper airways diseases are allergic or non-allergic.
One important characteristic is: SCUAD-patients do not respond to regular treatment recommended by international guidelines like ARIA (Allergic Rhinitis and its Impact on Asthma) or EPOS (European position paper on rhinosinusitis and nasal polyps). This means, that the symptoms of those patients are not well controlled and remain severe even after treatment.
Chronic upper airways diseases are inflammatory diseases such as severe chronic rhinosinusitis, severe allergic rhinitis, nasal polyposis and Samter’s triad (AERS or Aspirin Exacerbated Respiratory Disease). Severe chronic rhinosinusitis is most common amongst SCUAD patients. Samter’s triad is a distinct phenotype of chronic rhinosinusitis and one of the most severe phenotypes of chronic rhinosinusitis with nasal polyposis.
How many patients are affected by severe chronic upper airways diseases (SCUAD)?
Depending on the study, one estimates that between 10 and 40 percent of the patients that come to a doctor or hospital are potentially SCUAD-patients. But: One has to keep in mind thatonly a fraction of all patients with upper airways diseases will seek medical help. Patients with only mild symptoms of rhinosinusitis or allergic rhinitis will not go to see a doctor. Those patients will usually ask a pharmacist for help or simply treat themselves.
Are there risk factors for becoming a SCUAD-patient?
There are several risk factors for becoming a SCUAD-patient. For example, for chronic rhinosinusitis, age is a risk factor and for Samter’s triad, female gender is a risk factor.
But one of the most important risk factors for developing severe chronic upper airways diseases is having lower airway diseases in association.
Another risk factor is the patient’s non-compliance, which means that, for example, the patient is taking the medication either in a lower dose than prescribed or irregularly. One reason for non-compliance is corticophobia. Some patients (and some doctors) are simply afraid of possible side effects of topical corticosteroids.
Also smoking could be a risk factor for chronic rhinosinusitis and SCUAD.
Is there a genetic risk for developing severe chronic upper airways diseases?
We know, for example, that there is a genetic risk for developing allergic rhinitis. But so far we do not know if there is also a risk for rhinosinusitis severity or SCUAD.
How can biologicals help patients with severe chronic upper airways diseases (SCUAD)?
Biologicals are being investigated as part of the precision medicine concept, which is very close to the concept of personalized medicine. According to this concept biologicals are focusing on the treatment of specific phenotypes/endotypes. In respect to severe chronic upper airways diseases “phenotype” refers to any visible/clinical characteristic of the disease, while “endotype” refers to the underlying mechanisms of action of the disease. Biologicals are targeting specific molecules that are involved in those mechanisms of action of a disease.
What is the difference between biologicals and traditional therapies?
Corticosteroids, the classical treatment for sinusal inflammatory diseases, have a number of effects. Corticosteroids are acting on inflammatory cells, reducing cytokines and other inflammatory markers or respiratory mucus.
With biologicals, humanized monoclonal antibodies, we may target a specific molecule like IgE, IL-5 or IL-13 or a common receptor of the IL-4/IL-13 pathway.
Does that mean that only certain endotypes of severe chronic upper airways diseases can be treated with biologicals?
At the moment we do not exactly know which kind of patients with severe chronic upper airways diseases can benefit from biologicals, because the association between the concept of SCUAD and biologicals has not been very well established.
For example, biologicals are currently mainly used for the treatment of severe chronic rhinosinusitis, an area where the use of biologicals has been growing for the last five years and more and more biologicals are been developed.
But: Most of the studies using biologicals for the treatment of severe chronic rhinosinusitis are addressing patients who do not respond very well to corticosteroid treatment. In spite of medical treatment and sometimes even in spite of surgery, these patients remain chronic, severe, and uncontrolled. Whether those patients also fit into the definition of SCUAD has still to be researched.
Which of the many biologicals in the market can be used for treating SCUAD-patients?
First of all: The concept of biomarkers is very important for the use of biologicals. Only if we find a relevant biomarker for an endotype, we can reach our goal to use them to select a specific endotype of patients with severe chronic upper airways diseases for treatment with a specific biological.
The studies on biologicals executed so far have not used a biomarker approach when selecting patients as inclusion criteria in the clinical trials. The main objective of these studies was to find out if the respective monoclonal antibody was able to control the symptoms, severity, or quality of life of the treated patients. But: We are currently using the very same studies to find out more about the relevant biomarkers to be used in the future.
What could a possible biomarker for severe chronic upper airways diseases look like?
A possible biomarker could be, for example, an increase of IgE, IL-5, or IL-13. This is why we want to use the studies on biologicals to find out which specific indicators can be used as biomarkers. Once the biomarkers are defined, we can pick the exact monoclonal antibody for the treatment of a patient representing the respective endotype.
This means you will use the existing biologicals-studies on patients with severe chronic upper airways diseases for finding a link between the response rates and a possible biomarker?
Exactly. For example, Omalizumab is targeting IgE, the typical indicator of an allergic disease. One would expect, that patients with a high IgE-level would respond better to Omalizumab than patients with a rather low IgE-level. Unfortunately the correlation is not so clear in this case because many urticaria patients respond very well to Omalizumab, even though urticaria is not an allergic disease associated with increased IgE. Obviously IgE is not the only factor which is relevant for the effectiveness of Omalizumab. It seems like targeting IgE may provoke a cascade of events which can affect many other biomarkers.
Another biological, Dupilumab is targeting the receptor which controls the pathways of IL-4 and IL-13 but we are not using Dupilumab for treating patients who have an increase of these receptors. Our studies with Dupilumab have shown that one the markers mainly affected is IgE, which is released as a consequence of the stimulation of the IL-13 pathway. We are still at the beginning of understanding how these mechanisms are working.
To sum it up: We still do not understand the link between biomarkers and the patients’ response to treatment with biologicals. We definitely need to do more studies, which means, we need to classify the patients we include in the studies, not only according to phenotypic information, but also according to their endotypes.
What else is important in respect to treating SCUAD with biologicals?
Biologicals are very effective – 80 to 90 percent of the patients treated are responding to the therapy.
A general advantage of biologicals is that the prevalence of side effects is much lower than for traditional systemic therapies, while the positive effects are quite similar. Compared to systemic corticosteroids, which are the traditional medication for severe chronic upper airways diseases like severe chronic rhinosinusitis, severe allergic rhinitis, nasal polyposis and Samter’s triad, this is a substantial advantage.
So far, biologicals have one great disadvantage, their price! Corticosteroids are moderately inexpensive and biologicals are extremely expensive. But I am sure that, in the future, this will gradually change and biologicals might be produced much easier and at lower costs. Biologicals could then be used even for a broader group of patients and not only for those with severe uncontrolled symptoms. Maybe, in the future, biologicals could even be used to avoid the development of diseases in patients at risk.
So which biologicals are currently being researched?
In respect to upper airway diseases, we are talking about Omalizumab which is targeting IgE, Mepolizumab and Benralizumab which are targeting IL-5 and Dupilumab which blocks IL-4 and IL-13 pathways. There are three or four more biologicals like, for example, Lebrikizumab and Tralokinumab for IL-13 which are being developed at the moment, but those studies have not started yet.
How can patients to benefit from biologicals, do they have to participate in studies?
Some biologicals, like e.g. Omalizumab are already available in some countries for the treatment of severe asthma. Mepolizumab is available in Germany and soon will be in Spain but only for the treatment of severe asthma, which is mainly associated with upper airway inflammatory diseases – 70 to 80 percent of the patients are affected of chronic rhinosinusitis.
Interestingly we can see positive effects in the nose, when we treat asthma patients with biologicals but we have no biologicals available - so far - for the indication of severe chronic upper airways diseases like, for example, severe chronic rhinosinusitis.
What will be the next step in SCUAD-research?
Finding biomarkers will definitively be our next, very important goal for research. Our objectives in precision medicine in respect to severe chronic upper airways diseases are to study the endotypes and the mechanisms of action and to find the target molecule we have to treat to get a positive response. The final goal is a more precise treatment of patients!