The Effect of Anti-IL17 on Airway Hyperresponsiveness and Resistance

Background:

Antibodies towards interleukin 17 (IL-17) are approved for treating various rheumatological and dermatological diseases like psoriatic arthritis, ankylosing spondylitis and plaque psoriasis. In recent years, IL-17 has been suggested as a potential driver of severe non-Type 2 asthma because of its' association with glucocorticoid resistance and symptoms of severe asthma. Since conventional treatment is often less effective in patients suffering from non-Type 2 asthma, sometimes adequate disease control cannot be achieved, thus limiting these patients' opportunity for physical exercise, and thereby increasing the risk of obesity and heart disease. Furthermore, obesity has been shown to increase asthma symptoms and frequency of exacerbations.

IL-17 has shown to be upregulated by female sex hormones which may explain the sex specific traits of severe non-Type 2 asthma. In obese mice, IL-17 has shown to be directly responsible for the induction of airway hyperresponsiveness (AHR), thus making it a potential target for treatment. It is especially of interest that none of the previously performed human studies have investigated the effect of blocking IL-17 on AHR. A previous study investigating the effect of blocking IL-17 on lung function, measured as change in FEV1 (forced expiratory volume in 1 second) in moderate to severe patients with asthma, did not find any significant effect. However, this study included both men and women as well as lean and obese participants which could explain the lack of clinical difference. Another previous study also showed no effect of anti-IL17 in general. However, this study showed that those with the greatest reversibility to bronchodilators had the best improvement in symptoms. Although negative, these studies brought us further by showing that anti-IL-17 treatment was safe and tolerable for patients with moderate to severe asthma. Oscillometry has been known for several decades but is only on its' way into clinical practice. Oscillometry is more sensitive than spirometry in detecting small airway disease and AHR. Thus, using oscillometry in studies investigating airway resistance in asthmatic individuals in addition to spirometry, is warranted.

Objectives The overall objective of this study is to determine whether AHR and airway resistance is reduced when initiating treatment with anti-IL17 antibodies for other indications than pulmonary disease. Changes in AHR to methacholine challenge will be reported as response-dose-ratio before and after initiation of anti-IL17. Airway resistance will be assessed using both conventional spirometry for measuring changes in FEV1 and Airwave oscillometry.

Hypothesis

Primary hypothesis: In rheumatologic and dermatological patients commencing anti-IL-17 for other reasons than pulmonary disease, we expect a reduction in airway responsiveness to methacholine challenge after 2-4 months of treatment when compared to prior to initiation of anti-IL-17 treatment.

Secondary hypotheses: Anti-IL17 treatment will show no effect on FEV1, measured using conventional spirometry but will improve measures of airwave oscillometry.

Inclusion criteria

• Patients planning to start treatment with anti-IL-17 antibodies

Exclusion criteria

• Current pregnancy
• FEV1 < 1.5L or less than 60% of predicted value expected.
• Previous anaphylactic shock or severe allergic reaction to medicine
• Uncontrolled hypertension
• Myocardial infarction or stroke within the last 3 months
• Known aortic aneurysm
• Recent eye surgery or risk of elevated intracranial pressure
• Treatment with systemic corticosteroids within 6 weeks