Type 2 Inflammatory Diseases in Atopic Dermatitis: A Short Review : Indian Journal of Paediatric Dermatology

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Review Article

Type 2 Inflammatory Diseases in Atopic Dermatitis: A Short Review

Choudhary, Ankita; Agarwal, Pooja1; Kulkarni, Sandeep2; Madke, Bhushan3,

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Indian Journal of Paediatric Dermatology 23(4):p 275-281, Oct–Dec 2022. | DOI: 10.4103/ijpd.ijpd_58_22
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Abstract

Introduction

Inflammation is a complex biological response initiated by the immune system and triggered by inflammogens. Due to the underlying inflammation, there is coordinate activation of diverse signaling pathways, which in turn regulate the inflammatory cell mediators.

Type 2 inflammation is an immune response pattern, which involves a subset of CD4+ T cells known as Th2 cells. These Th2 cells secrete certain cytokines such as interleukin (IL)-4, IL-5, and IL-13, which in turn lead to stimulation of type 2 immunity. The type 2 immunity is characterized by high titers of IgE antibody and eosinophilia along with stimulation of mast cells and basophils.[1]

The type 2 inflammatory diseases are characterized by the dysregulation of the Th2 pathway, which is triggered due to parasitic or helminthic infestations and noninfectious allergens presented by the antigen presenting cells. The epidemiology advocates that individuals with one subset of type 2 inflammatory disease have a prolific risk of developing another.[2]

The type 2 pattern of inflammatory response has been well documented as one of the contributing factors in complex and multifaceted etiology of various diseases such as AD, asthma, parasitic infections, allergic conjunctivitis (AC), chronic rhinosinusitis with nasal polyps (CRSwNP), eosinophilic esophagitis (EoE), chronic idiopathic urticaria, prurigo nodularis, and bullous pemphigoid.[34]

AD is a chronic type 2 inflammatory disorder characterised by cutaneous hyper reactivity to environmental allergens that are innoxious to nonatopic individuals.[5] There is a clinical heterogeneity in terms of age of onset along with severity, distribution and morphology of lesions. According to the current consensus, AD is itself considered a systemic disorder. Atopic asthma is the commonest phenotype of asthma affecting 70%–90% of the children and 50% of the adults.[6]

AD and food allergy have a predilection for infants and young children while asthma and rhinoconjunctivitis predominate in older children and adolescents respectively. This characteristic age dependent progression of atopic diseases is known as ‘Atopic March’. Skin barrier disruption, genetic polymorphism, allergen sensitization, raised IgE levels, micro biome dysbiosis, altered Th2 immune response and environmental triggers are few factors favouring the concept of atopic march and the development of atopic diseases [Figure 1]. The food sensitization besides being a hallmark of AD severity, is also an endotype which can be indicative of a more predictable probable transition to other atopic comorbidities like asthma and allergic rhinitis.[7] However; according to the recent ongoing studies, atopic march need not necessarily follow the classical sequence of events for example a patient with asthma may later develop AD. In addition, the “Atopic March” can get initiated at any age and not only in childhood.

F1
Figure 1:
Flow chart depicting the various pathogenic factors in the causation of Atopy

The canonical type 2 inflammatory cytokines involved in driving the chronic itch and inflammation in AD lead to activation of cutaneous sensory neurons. This in turn primes the immune and epithelial cells to release various proinflammatory as well as pruritogenic mediators.[8] The signaling provided by IL-9 and IL-5 leads to recruitment of mast cells along with eosinophils to the inflammation site, on the other hand IL-13 is involved in airway remodeling and hyper responsiveness, goblet cell hyperplasia and mucus over secretion, explaining the coexistence of AD and asthma.[9] Genetic studies have also unveiled the common precipitating factors for both EoE and AD which include thymic stromal lymphopoietin (TSLP) gene polymorphism and filaggrin functional mutation.[10]

Methodology

A search of PUBMED database was made with the keywords “type 2 inflammatory diseases AND atopic dermatitis” with the time duration limited to last 5 years. 288 results were found corresponding to the same and all the titles and abstracts were screened for their relevance and any duplication. Out of these, 25 studies pertaining to the pathogenesis, clinical features and management of type 2 inflammatory diseases in atopic dermatitis (AD) were included for the present review. Remaining 263 articles were excluded. There were 10 reviews, 5 meta-analysis, 5 original research articles, 3 randomised control trials and 1 case report and commentary (for an original article) each.

Pathogenesis

The evolution of skin lesions in AD is orchestrated by the secretion of proinflammatory cytokines in the local tissue. There is a preponderance of Th2 cytokines in acute AD lesions however during subsequent progression to the chronic phase both T helper (Th1) and Th22 subset of cytokines plays a pivotal role, with variable levels of Th 17 cytokines in both acute and chronic AD. In AD, the skin is infiltrated markedly by the innate lymphoid cells (ILCs) type 2 subset, which are responsible for driving the Th2 responses. Th2 mediated inflammation in turn suppresses the expression of antimicrobial peptides leading to frequent super infections in AD.

Impaired barrier function resulting in increased permeability and decreased epidermal hydration, is one of the elementary etiopathogenetic factor in atopic individuals which allow easy access to environmental antigens and allergens to underlying layers.[11]

Responding to deranged barrier function, mechanical injuries and increased susceptibility to microbial invasion, epidermal keratinocytes release cytokines like TSLP, IL-25 and IL-33.[12] These cytokines also being labelled as “Alarmins” play a regulatory role in stimulation and transformation of ILCs and Naïve T cells into Th2 cells.[13]

TSLP produced by skin and lung derived epithelial cells, serves as a potent growth and survival factor for Th2 effector cells and has been implicated in the causation of atopic march. Henceforth it is an attractive therapeutic option for the treatment of allergic inflammatory diseases. Increased TSLP expression has been associated with AD, Netherton syndrome and other allergic conditions. Dysregulated immune response may also result in disproportionate activation of Th2 cell subset. Primary cytokines of Th2 subset includes IL-4, IL-5, IL-9 and IL-13. Increased expression of IL-4 and IL-13 predominantly result in trafficking of eosinophils and basophils to tissues; increased Th2 cell activation and increased IgE production. IL 4 has also been known to be involved in JAK STAT signaling driven activation of Th2 cells and subsequent elaboration of cytokines and chemokines.[14] These cytokines are also known to modulate keratinocyte differentiation with down regulation of expression of fillagrin[15] and other adhesion molecules thereby perpetuating defective barrier function. IL-5 and IL-9 are known to boost increased production of eosinophills and mast cells in bone marrow respectively.

The various markers which are linked to type 2 inflammation and regulated by IL-4 and IL-13 includes serum thymus and activation-regulated chemokine (TARC)/CC chemokine ligand 17 (CCL17), plasma eotaxin-3 (CCL26), serum IgE, serum periostin, fractional exhaled nitric oxide (FeNO) and blood/tissue eosinophil count. These serves as predictors of response to treatment with various monoclonal antibodies. TARC and Eotaxin-3 are two principal chemokines which are chemoattractant of Th2 cells, while periostin being an extracellular matrix protein linked to activated fibroblasts, plays a pivotal role in the tissue remodeling and fibrosis observed in atopic diseases. IL-4 and IL-13 signals via STAT6 causing downstream expression of periostin, TARC and eotaxin-3.

Constellation of abundant production of IgE antibodies along with recruitment of large number of eosinophils and mast cells harbingers onset of clinical manifestations in atopic individuals; also contribute to chronicity of the disease. IgE mediated degranulation of the inflammatory cells result in release of large quantum of vasoactive substances e.g., histamine, bradykinin, substance P, and leukotrienes in systemic circulation as well in areas of local inflammation. Of these, histamine and IL 31 (labelled as pruritus cytokine)[1416] have been attributed as mediators of pruritus which is a prominent symptom in AD. Chronic itch scratch cycle further deteriorates epidermal barrier and intermittently precipitates the episodes of oozy skin lesions.

Clinical Features

AD is a chronic, relapsing inflammatory dermatitis which starts in the initial 5 years of life in approximately 90% of patients.[17] There is a characteristic age-dependent distribution of lesions in AD with a wide range of atopic stigmata. In infants and young children there is involvement of face specially the cheeks, scalp and extensor aspects of extremities usually with sparing of the diaper area while in older children and adults there is predominant flexural involvement. Pruritus is universally seen in almost all patients. Xerosis is commonly encountered in pediatric AD. Acute lesions are characterized by erythematous edematous papules which are extremely pruritic, vesiculations, excoriations, oozing and serous crusting, while in chronic AD there is predominantly thickened plaques with lichenification and prurigo nodularis like lesions. The spectrum of manifestations occurring in AD patients with other type 2 inflammatory diseases is wide. Enlisted below are the salient features of few distinct type 2 inflammatory diseases which occur concomitantly in patients of AD.

Atopic Asthma

Asthma is a reversible, inflammatory disease of airway characterized by airway hyper responsiveness and remodeling. Airways of asthma patients undergoes various structural changes which includes smooth muscle and basement membrane thickening, mucus cell metaplasia, increase airway vascularity and sub epithelial fibrosis.[18] All of these changes have been collectively referred to as airway remodeling.

Atopic asthma is a type I hypersensitivity reaction where allergen exposure leads to characteristic symptoms.[19] Th2 endotype is one of the best-defined widest asthma endotypes, underpinning allergic asthma. This endotype is strongly associated with production of IgE, atopy and eosinophilic inflammation.[20] Over 50% of mild to moderate asthma is mediated by Th2 inflammation.[21] These patients tend to show both local as well as systemic eosinophilia and are more steroid responsive.

Respiratory viral infections and early airways sensitization to aeroallergens exhibit quantitative synergism, and have a propensity to enhance the risk of asthma exacerbations in form of acute wheezing.[22]

Antigen inhalation provokes the sensitized mast cells to degranulate, leading to the release of pro-inflammatory mediators in the nasal and bronchiolar mucosae. Goblet cell hyperplasia, submucosal gland hypertrophy and mucin over secretion lead to constriction of the bronchioles. Airway hyper-responsiveness can cause airway narrowing leading to shortness of breath and breathing difficulties. Other symptoms include coughing (especially at night) and wheezing or gasping for air. An acute attack can lead to almost complete blockage of the airways and in this condition, asthma can prove to be fatal.

The total eosinophil count along with serum levels of IgE are usually raised in allergic asthma. The severity of asthma is assessed by spirometry and peak flow meter testing. The spirometry helps in differentiating asthma from chronic obstructive pulmonary disease. A ratio of forced expiratory volume in 1 s/forced vital capacity <0.70 is suggestive of airway obstruction. Bronchoprovocation testing can be used for measuring airway hyperresponsiveness.

Eosinophilic Esophagitis

It is an “allergen induced motility disorder” of the esophagus. EoE is characterised by a Th2 driven inflammatory immune response and patients usually have an allergic predisposition. The cardinal clinical features of EoE includes impaction of food, dysphagia and dyspepsia which is resistant to proton pump inhibitors (PPI). Histologically the eosinophilia should be isolated to the esophagus and also the eosinophilic infiltration should be significant (>15 eosinophils in atleast one high powered field).[23]

In about 75% of patients of EoE either a personal or family history of allergy in the form of rhinoconjunctivitis, atopic eczema and asthma can be found.[24-26] Peripheral eosinophilia (>300-–50/mm2)[27] and high serum levels of IgE[2829] has been witnessed in approximately 50% of patients. Food specific skin prick test may be positive in 75%–80% of patients.

The clinical presentation of EoE is dependent on the patient’s age and the disease severity [Table 1].[23]

T1
Table 1:
Difference in clinical presentation of eosinophilic esophagitis in children and adults[23]

In order to compensate for the symptoms, patients may develop aberrant eating habits. The chronic progression of the disease may lead to esophageal remodeling, fibrosis and esophageal strictures. An infrequent but well-known complication of EoE in adults as well as pediatric age group include spontaneous esophageal perforation. Esophageal biopsy and histological evaluation of tissue sections obtained at the time of endoscopy aids in the definitive diagnosis of EoE. The common findings on endoscopy include esophageal rings/corrugations, mucosal exudates, linear furrows, edema and mucosal fragility.[30] The various differential diagnoses which should be considered include gastroesophageal reflex disease, primary eosinophilic gastroenteritis, achalasia, pill esophagitis and carcinoma esophagus.

Chronic Rhinosinusitis with Nasal Polyps

CRS is defined as chronic sinonasal inflammation characterized by the presence of two or more of the following symptoms lasting for >12 weeks:[31]

  1. Hyposmia/anosmia
  2. Nasal blockage/obstruction/congestion
  3. Anterior or posterior rhinorrhea
  4. Facial pain/pressure.

Nasal endoscopy or CT scan of the paranasal sinus helps in both objective confirmation of the diagnosis and determining the phenotype: CRS with or without nasal polyp.

CRSwNP is a subcategory of CRS wherein fleshy swellings (nasal polyps) develop in the lining of the nasal and paranasal sinuses.[31] There occurs chronic type-2 inflammation of the sinonasal tissue and is usually linked with allergic rhinitis and asthma.[32]

The main complaints of the patients are usually nasal obstruction, congestion, rhinorrhea, nasal discharge, headache, reduction or loss of smell and coughing. All of these have negative impacts on the quality of life both physical as well as mental including sleep.

Allergic Conjunctivitis

AC is a comprehensive term that incorporates seasonal and perennial AC, atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC).[33]

It can significantly affect the quality of life and very rarely can also be painful and vision-threatening. The commonest feature of AC is pruritus, which can be both mild as well as severely debilitating.[33] Other symptoms include watering, swelling of eyelids, redness, foreign body sensation and mucous discharge.[3435] Conjuctival swelling (chemosis) along with diffuse bulbar and tarsal conjunctival injection can also be seen. It is usually associated with rhinitis and the symptoms are conventionally bilateral.[35] In severe cases photophobia and blurring of vision can occur.[36]

Seasonal AC (SAC) and perennial AC (PAC) are the commonest forms of ocular allergies wherein allergen specific IgE antibodies can be documented[37] SAC usually worsens during spring and summer season and abates in the winter months in contrast to PAC which can cause symptoms throughout the year. The trigger in SAC is airborne pollens while PAC occurs with exposure to perennial allergens.

VKC is a seasonal bilaterally recurring Th2 mediated allergic inflammation of the upper tarsal conjunctival surface. Symptoms have a peak incidence during spring and are seen more commonly in males. The symptoms of VKC include ocular itching, redness, mucoid ropy/stringy discharge, pain, photophobia, blurred vision and foreign body sensation. Itching at times can be very severe and intractable. The tears of VKC patients contain high levels of IgE and mast cell mediators.[3839] Giant papillae (≥1 mm in diameter) on the upper tarsal conjunctiva and trantas dots are the universal findings on ocular examination.[40]

AKC is a chronic, noninfectious inflammatory condition of the ocular surface and is mostly bilateral. It is the most severe ocular allergic disease and is often considered as the ocular counterpart of atopic eczema. Atopic blepharitis is characterized typically by the thickening of the eyelids (tylosis) and along with scaly, wrinkled and eczematized appearance of the periocular skin. The eyelid skin usually exhibits a fine sandpaper-like texture.[33] The canthal skin often undergoes maceration and excoriation of the periorbital region is a common finding. Dennie–Morgan folds, which are infraorbital skin folds caused by persistent rubbing are seen in AKC. Cataracts can occur in patients of AKC. Typically, the atopic cataracts are either anterior or shield-like cataracts, however nuclear, cortical and even posterior subcapsular cataracts can also develop.[33] Chronic ocular surface inflammation is the hallmark feature of AKC. Corneal involvement can occur in form of keratitis and punctuate erosions.

Laboratory investigations are generally not advocated, although skin prick or serum allergy testing can play a role in mitigating the disease process by recognising the culprit allergen.

Management

Allergen management forms an important initial step in management of the type 2 inflammatory diseases in AD. As it cannot be done adequately every time, the need for other therapies arises. As the diseases runs a chronic course, the ultimate goal of treatment is long term control which can be best achieved with a multidisciplinary approach. The core team of first contact physicians includes dermatologists, pediatricians, pulmonologists and ENT specialists. They can help in early detection of other type 2 inflammatory diseases present in patients presenting to them with AD, asthma and nasal polyps respectively.[41]

Systemic corticosteroids have long been the workhorse for treatment of allergic conditions due to the rapid relief provided by them. Their long-term use is however marred with serious adverse consequences and hence the need for alternative effective drugs.

With the increase in knowledge about the role of type 2 inflammatory mediators in the pathogenesis of these diseases and advent in systemic as well as biological drugs, a more targeted approach is now feasible. Although there are many biologics available for the treatment of these type 2 inflammatory conditions, the drug which has emerged as a successful therapeutic option in these diseases is dupilumab [Table 2].[42] It is a humanized monoclonal antibody directed against a subunit of the IL-4 receptor and effectively blocks both IL-4 and IL-13 signaling pathways and hence type-2 inflammation. Treatment with dupilumab (300 mg subcutaneous every 15 days) consistently exhibits significant improvement in the symptoms and quality of life (in AD), lung functions (in asthma), nasal complains like obstruction and anosmia (in CRSwNP) even after the first dose.[43]

T2
Table 2:
Biologics in type 2 inflammatory diseases in atopic dermatitis

Other therapeutic modalities for EoE include dietary modifications, medications like PPIs and corticosteroids and esophageal dilatation. Dietary modifications can be done on the basis of elimination of specific food causing allergies or as an empiric elimination for all the common allergy prone foods. In chronic cases of EoE with signification narrowing of the esophagus, progressive dilatation with the help of bougie or balloon leads to significant improvement in the symptoms. In patients do not get good results from PPIs, topical corticosteroid preparations provide clinical as well as histological improvement. Formulations of budesonide and fluticasone are available in syrup or aerosol forms which coat the esophagus on swallowing.[44]

The initial management of AC includes nonpharmacological options like cold compresses, artificial tears and saline. Alpha-adrenergic agonists (oxymetazoline brimonidine tartrate), topical NSAIDs, topical corticosteroids, oral antihistamines (desloratadine, fexofenadine), mast cell stabilizer (nedocromil sodium, lodoxamide), leukotriene inhibitor (montelukast), oral corticosteroids, immunotherapy and biologics (omalizumab) are various medical treatment options available for AC. Thus, progressive research has definitely widened horizons and given comprehensive insights in understanding pathogenesis of this complex entity which will definitely prove instrumental in introducing therapies targeting this basket of cytokines to ensure better control of disease achieving long term remissions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

Atopic eczema; atopy; inflammation; type 2 inflammation

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