Type 2 inflammation – making the connection between atopic, allergic, and inflammatory diseases

Johannesburg – 11 November 2020 – Allergic diseases are increasingly becoming a global epidemic.1 Systemic type 2 inflammation is emerging as a unifying feature of both classically defined allergic diseases such as asthma, atopic dermatitis (AD), and allergic rhinitis, as well as a diverse range of diseases with less clear aetiologies, including chronic rhinosinusitis with nasal polyps (CRSwNP), eosinophilic oesophagitis (EoE) and aspirin-exacerbated respiratory disease (AERD).1,2

When type 2 immune responses are dysregulated, they can become important drivers of disease. Type 2 immunity induces a complex inflammatory response characterised by eosinophils, mast cells, basophils, type 2 innate lymphoid cells, interleukin (IL)-4- and/or IL-13-conditioned macrophages and T helper 2 (TH2) cells, which underlie the pathogenesis of many allergic disorders.3

Reducing inflammation by systemically administering broad-acting immunosuppressants can effectively alleviate symptoms of severe atopic, allergic and inflammatory diseases;1 however, numerous different atopic conditions often co-exist in affected patients which suggests that efforts to target the key proximal type 2 cytokines IL‑4, IL‑5 and IL‑13 represent a promising integrated strategy to achieve therapeutic benefit across multiple diseases.1

 

What is the burden and impact of type 2 inflammatory diseases?

Asthma is one of the most common chronic conditions in the world and yet despite available therapies, asthma control in clinical practice is suboptimal with patients experiencing exacerbations characterised by symptoms of chest tightness, coughing, wheezing, shortness of breath and sputum production.4,5 Asthma is a heterogeneous disease that varies in aetiology; asthma onset in early childhood has largely been associated with atopy, and this association remains until adulthood.5,6 Uncontrolled asthma increases the risk of debilitation, reduces productivity, and impairs quality of life; 30–50% of individuals who have asthma experience depression, and mental health symptoms are common in caregivers of children with asthma.4,7 Patients with severe asthma also experience higher levels of anxiety and depression.5

EoE is an atopic condition of the oesophagus that shares many clinical and pathophysiologic characteristics with asthma.8 Eosinophils infiltrate the oesophagus contributing to tissue damage and chronic inflammation, potentially giving rise to gradual progressive remodelling.8 Established risk factors for EoE include atopy and other allergic conditions such as allergic rhinitis, asthma and AD, as well as genetic and environmental risk factors.8 Treatment strategies available for EoE include trigger avoidance through dietary modification, pharmacologic therapy (topical corticosteroids delivered to the oesophagus) and mechanical dilation of the oesophagus.8 Neither dietary elimination nor medical therapy has been shown to modify the natural history of EoE.8

CRS is a prevalent inflammatory disease of the mucosa of the nasal cavity and paranasal sinuses with symptoms that include nasal blockage, rhinorrhoea, facial pain and loss of sense of smell lasting for longer than 12 weeks.2,6 Although the pathogenesis of CRS is poorly understood, genetic susceptibility, infection, anatomic abnormalities, and local immunologic imbalance that gives rise to chronic airway mucosal inflammation and remodelling are factors recognised as contributing to the development of the disease.9

AD, also known as atopic eczema, is a common inflammatory skin disorder characterised by visible skin lesions and intense itching and inflammation, affecting 15–20% of children in developed countries and 1–5% of adults.10,11 Frequent use of emollients and the intermittent use of topical corticosteroids to control acute flares may be effective; new topical immunosuppressive treatments inhibit calcineurin in the skin and overcome some of the drawbacks of topical corticosteroid therapy.10,12 Commonly used options for systemic treatment of AD include cyclosporine and systemic corticosteroids.11 The considerable impact of AD on quality of life, especially in severe cases, is greater than seen in other common skin conditions such as psoriasis.12 Less than optimal disease control results in patients experiencing intractable itch, bleeding from the skin, loss of sleep, lack of concentration, and impaired school-work productivity.10,12 AD also has a greater negative effect on the mental health of patients compared with other chronic conditions, such as diabetes and hypertension, and this can extend to a patient’s family.10

 

What is the impact of excessive type 2 inflammation on comorbid atopic disease? 

CRS coexists with asthma in 34–50% of patients.6,9 Population-based studies have confirmed the association between the two conditions to be a bidirectional relationship, with CRS patients having higher incident asthma and asthmatic patients having higher incident CRS.6 Both severity and duration of CRS are associated with increasing levels of comorbid asthma, suggesting poor control of CRS heralds more lower respiratory tract disease.2 Reports of the prevalence of allergic rhinitis in CRS vary wildly, ranging from as low as 10% to as high as 84%.2

There is a higher incidence of nasal polyposis in patients with severe asthma.5,6,9 Nasal polyposis is characterised by a pronounced type 2 inflammation with elevated levels of IL-4/-5/-13 and eosinophilia, giving rise to hyperresponsiveness of the airway.6 Coexistence of asthma and CRSwNP and their similar characteristics of inflammation support the assumption that they may be, at least in part, the same disease process.8

AERD remains a disease with high morbidity, and evidence shows that the actual rate of aspirin sensitivity is higher than the patient-reported rate and that prevalence of AERD doubles in severe asthmatics.2,13 AERD encompasses the triad of asthma, aspirin or nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, and nasal polyposis.13 A worsening of respiratory symptoms follows ingestion of COX-1 inhibitors, which lead to increased production of leukotrienes and intensification of airway inflammation.2,13 Patients with AERD are more likely to suffer from allergies in general.2 Steroids and leukotriene pathway modifiers are the mainstays of AERD management.13

AD has been associated with multiple comorbid disorders that influence one another, with a higher incidence of asthma, hay fever, food allergy, anxiety and depression, and autoimmune disease. These associations are significant in mild and/or moderate disease, with even stronger effects in severe AD.14

 

References
  1. Gandhi NA, Bennett BL, Graham NMH, et al. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016 Jan;15(1):35-50. https://doi.org/10.1038/nrd4624.
  2. Philpott CM, Erskine S, Hopkins C, et al. Prevalence of asthma, aspirin sensitivity and allergy in chronic rhinosinusitis: data from the UK National Chronic Rhinosinusitis Epidemiology Study. Respir Res. 2018 Jun 27;19(1):129. https://doi.org/10.1186/s12931-018-0823-y.
  3. Wynn TA. Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol. 2015 May;15(5):271-82. https://doi.org/10.1038/nri3831.
  4. Price D, Fletcher M, Van der Molen T. Asthma control and management in 8 000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med. 2014 Jun 12;24:14009. https://doi.org/10.1038/npjpcrm.2014.9.
  5. Shaw DE, Sousa AR, Fowler SJ, et al. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J. 2015 Nov;46(5):1308-21. https://doi.org/10.1183/13993003.00779-2015.
  6. Staniorski CJ, Price CPE, Weibman AR, et al. Asthma onset pattern and patient outcomes in a chronic rhinosinusitis population. Int Forum Allergy Rhinol. 2018 Apr;8(4):495-503. https://doi.org/10.1002/alr.22064.
  7. Rand CS, Wright RJ, Cabana MD, et al. Mediators of asthma outcomes. J Allergy Clin Immunol. 2012 Mar;129(3 Suppl):S136-41. https://doi.org/10.1016/j.jaci.2011.12.987.
  8. Carr S, Chan ES, Watson W. Eosinophilic esophagitis. Allergy Asthma Clin Immunol. 2018 Sep 12;14(Suppl 2):58. https://doi.org/10.1186/s13223-018-0287-0.
  9. Staikuniene J, Vaitkus S, Japertiene LM, et al. Association of chronic rhinosinusitis with nasal polyps and asthma: clinical and radiological features, allergy and inflammation markers. Medicina (Kaunas). 2008;44(4):257-65.
  10. Zuberbier T, Orlow SJ, Paller AS, et al. Patient perspectives on the management of atopic dermatitis. J Allergy Clin Immunol. 2006 Jul;118(1):226-32. https://doi.org/10.1016/j.jaci.2006.02.031.
  11. Schram M, Roekevisch E, Leeflang M. A randomized trial of methotrexate versus azathioprine for severe atopic eczema. J Allergy Clin Immunol. 2011 Aug;128(2):353-9. https://doi.org/10.1016/j.jaci.2011.03.024.
  12. Ashcroft DM, Dimmock P, Garside R, et al. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials. BMJ. 2005 Mar 5;330(7490):516. https://doi.org/10.1136/bmj.38376.439653.D3.
  13. Steinke JW, Wilson JM. Aspirin-exacerbated respiratory disease: pathophysiological insights and clinical advances. J Asthma Allergy. 2016 Mar 10;9:37-43. https://doi.org/10.2147/JAA.S88739.
  14. Silverberg JI, Gelfand JM, Margolis DJ, et al. Association of atopic dermatitis with allergic, autoimmune, and cardiovascular comorbidities in US adults. Ann Allergy Asthma Immunol. 2018 Nov;121(5):604-612.e3. https://doi.org/10.1016/j.anai.2018.07.042.
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