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Atopic dermatitis: More than just skin deep

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Adult AD is considered a systemic disease. In AD (and other atopic diseases) metabolic comorbidities (eg increased body mass index, central obesity, hypertension, hyperlipidaemia, and diabetes), as well as sleep disturbance cause chronic inflammation, which play a key role in the progression to more severe forms of adult AD.3 

Drivers of increases in AD prevalence 

Skin microbiota dysbiosis, altered immune response, environmental and genetic factors, and epidermal barrier disruption are the five main factors involved in the pathogenesis of AD.4 

  1. Microbiota dysbiosis: Bacterial dysbiosis is associated with chronic inflammatory disorders of the skin including AD and psoriasis. In AD, skin inflammation occurs as a result of a misdirected immune reaction against harmless antigens on the one hand, and to a disturbed skin barrier on the other. Increases in Staphylococcus and reductions in colonies of Streptococcus or Propionibacterium species correlate with AD flares.5,6 
  2. Altered immune response: Studies show that aeroallergen exposure leads to worsening of AD symptoms. An overexpression of Th2 cytokines has been observed in acute and subacute lesions of AD.6 
  3. Environmental factors: Urbanisation is increasingly being recognised as one of the causes of the increase in AD in African countries – especially South Africa. Urbanisation is associated with increases in air pollution and stress, which may increase the risk of developing AD and exacerbating symptoms. Furthermore, climate change is affecting the world’s flora and fauna. An estimated 80% of adults suffering from AD are sensitised by specific immunoglobulin E (IgE) antibodies to inhalant or food allergens.2,7  
  4. Genetic factors: Known genetic risk factors include mutations in the filaggrin gene that encodes an epidermal structural protein and risk genes in susceptibility loci related to immune mechanisms of AD. Filaggrin mutations are the best known causes of impaired skin barrier and is considered as predisposing factors for AD.7,8 
  5. Epidermal barrier disruption: The epidermis serves as the first line of defense against invading pathogens and allergens. A defective skin barrier enhances allergen sensitisation, leading to systemic allergic responses such as increased IgE levels and airway hyper-reactivity. Aside from filaggrin mutations, other causes of epidermal barrier defects in AD include environmental factors such as the use of soap and detergents, which exacerbate epidermal barrier breakdown and lead to the elevation of stratum corneum pH. A sustained increase in pH enhances the activity of degradatory proteases and decreases the activity of the lipid synthesis enzymes.8,9 
  6. Essential features of AD and diagnosis 

AD is primarily a clinical diagnosis. Essential features include pruritus and eczematous lesions that can be acute (erythema and vesicular eruptions), subacute (ill-defined weepy crusted plaques), or chronic (well-defined, dry lichenified plaques). Skin lesions often show age-specific morphology and distribution patterns. Important features include early onset, dryness, and increased IgE level (atopy), although about 20% of patients with AD do not have elevated IgE levels.2,10 

The current South African guidelines criteria for diagnosis of AD include:11 

  • Pruritus, and three or more of the following:  
  • A history of flexural dermatitis 
  • Visible flexural dermatitis 
  • History of dry skin in the past year 
  • A personal history of asthma or hay fever (or history of AD in a first-degree relative aged <4 years) or onset <2 years.  

Diagnosis starts with a detailed clinical history, which should include:10  

  • Age of onset  
  • Personal and family history of atopy  
  • Pattern and severity of symptoms (see table 1 and figure 2) 
  • Frequency of itch with a focus on affected body areas 
  • Response to previous or current treatments 
  • Possible irritants or allergic triggers 
  • Dietary history 
  • Growth and development 
  • The psychosocial impact of AD on the patients as well as their caregivers. 

Treatment update: Conventional vs biological therapies 

Reducing signs and symptoms of AD, inducing disease remission, and improving the quality of life (QoL) of both the patient and his/her caregivers, are the overarching goals of treatment.10 

A number of treatment options are available and their use depends on the severity and frequency of symptoms (see table 1 and figure 2). Therapies range from general daily management with emollients to topical anti-inflammatory medication.10  

The majority of patients living with AD can be treated in primary care. However, patients with moderate-to-severe AD, as well as severe, refractory AD, frequent flares, a history of concomitant allergic manifestations including immediate-type food allergy, or a poor response to treatment, should be referred to a dermatologist, paediatrician, or allergist.10 

The cornerstone of pharmacotherapy is topical and systemic corticosteroids (CS) – regardless of disease severity. In moderate and severe cases, several systemic treatments are used, including cyclosporine, which is the only one approved for the treatment of adult AD, followed by methotrexate, azathioprine, and mycophenolate mofetil.10 

In 2021 a South African panel of experts published a consensus statement focused on the contemporary management of AD. The consensus document also included recommendations about the use of dupilumab, the first biological agent approved for the treatment of moderate-to-severe AD in South Africa.12    

Dupilumab, which was launched in South Africa in 2021, is a human monoclonal antibody against interleukin (IL)-4 receptor alpha and inhibits signalling of IL-4 and IL-13, and type 2 cytokines, which may be important drivers in AD.13,14 

In South Africa, dupilumab is approved for use in adult patients (>18 years old) with moderate-to-severe AD, not adequately controlled by traditional topical or systemic therapies, or when those therapies are not advisable. The registered dose is an initial loading dose of 600mg subcutaneously (SC) followed by 300mg SC every second week.14 

In terms of pharmacotherapy, this is what the expert panel recommends:12 

  1. Consider systemic CS only in short courses as rescue therapy. 
  2. Cyclosporin should not be used for long-term control of AD. Short-term use of cyclosporin may be considered for rapid control in patients who experience acute flares or have unstable disease. 
  3. Off-label use of methotrexate is an effective option for the treatment of moderate-to-severe AD. 
  4. Discontinuation of systemic therapy should be considered if there is no visible improvement in skin involvement or QoL or in the event of severe adverse events. 
  5. Dupilumab is an effective long-term treatment option for patients with moderate-to-severe AD who are eligible for systemic therapy. 

Efficacy and safety of dupilumab 

The approval of dupilumab for the treatment of moderate-to-severe AD was based on four pivotal randomised, placebo-controlled phase-3 clinical studies.13,15,16  

In SOLO 1 and SOLO 2, Simpson et al (2016)enrolled adults with moderate-to-severe AD whose disease was inadequately controlled by topical treatment.13 

Patients (n=671) were randomised (1:1:1) to SC dupilumab (300mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo for 16 weeks. The primary endpoint was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment (IGA) and a reduction of 2 points or more in that score from baseline at week 16.13 

In SOLO 1, the primary endpoint was achieved by 38% of patients who received dupilumab every other week and by 37% who received dupilumab weekly, compared to 10% who received placebo.13  

The results were similar in SOLO 2, with the primary endpoint achieved by 36% of patients who received dupilumab every other week and in 36% who received dupilumab weekly, compared to 8% who received placebo.13  

Furthermore, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index (EASI) was reported in significantly more patients in SOLO 1 and SOLO 2 who received each regimen of dupilumab than in patients who received placebo.13  

Dupilumab was also associated with improvement in other clinical endpoints, including reduction in pruritus and symptoms of anxiety or depression, as well as improvement in QoL.13  

In the Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial, Blauvelt et al (2017) randomised patients (3:1:3) to SC dupilumab 300mg once weekly, dupilumab 300mg every two weeks, or placebo. All three groups (n=740) were given concomitant topical CS with or without topical calcineurin inhibitors where inadvisable for topical CS.15  

Topical CS could be tapered, stopped, or restarted on the basis of disease activity. Primary endpoints were the percentage of patients who achieved IGA 0 to 1 and 2-point or higher improvement from baseline, and EASI-75% improvement from baseline at week 16.15  

At week 16, 39% of patients who received dupilumab plus topical CS once weekly, and 39% who received dupilumab every two weeks plus topical CS, achieved the primary endpoints of IGA 0 to 1, vs 12% who received placebo plus topical CS. Furthermore, 64% of patients in the weekly group, and 69% in the every two weeks group achieved EASI-75 compared to 23% in the placebo group. Week 52 results were similar.15  

In the Dupilumab with concomitant topical corticosteroid treatment in adults with atopic dermatitis with an inadequate response or intolerance to ciclosporin A or when this treatment is medically inadvisable: a placebo-controlled, randomised phase III clinical trial (LIBERTY AD CAFÉ), patients (n=390) were randomised (1:1:1) to SC dupilumab 300mg weekly or every two weeks or placebo.16  

All patients received concomitant medium-potency topical CS from week 2 to week 16. The dosage could be tapered if lesions cleared or stopped for adverse reactions to topical CS.16 

Some 59.1% and 62.6% of patients in the dupilumab weekly and topical CS and the every two weeks groups achieved EASI-75 improvement from baseline, compared to 29.6% in the placebo group.16  

Other clinical outcomes and AD symptoms were significantly improved in both the dupilumab and topical CS groups, including pruritus, pain, sleep disturbance, symptoms of anxiety and depression, and QoL.16 

 Table 1: Eczema Area and Severity Index 

The EASI score rates the four involved regions (head and neck, trunk, upper extremities, and lower extremities) on a 0% to 100% scale for each region.17 

Figure 1: Area of involvement 

The area of involvement must be visually estimated in each of the four body regions separately and assigned an area score: 1 (1%–9%), 2 (10%–29%), 3 (30%–49%), 4 (50%–69%), 5 (70%–89%), and 6 (90%–100%). The feet and buttocks are included as part of the lower extremities, whereas the axilla and groin are counted as part of the trunk.17 

References 

  1. Nguyen GH, Andersen LK, Davis MDP. Climate change and atopic dermatitis: is there a link? Int J Dermatol, 2019.  
  2. Al-Afif KAM, Buraik MA, Buddenkotte J, et al. Understanding the Burden of Atopic Dermatitis in Africa and the Middle East. Dermatol Ther (Heidelberg), 2019. 
  3. Campanati A, Bianchelli T, Gesuita R, et al. Comorbidities and treatment patterns in adult patients with atopic dermatitis: results from a nationwide multicenter study. Arch Dermatol Res, 2022. 
  4. Mesjasz A, Zawadzka M, Chałubiński M, Trzeciak M. Is Atopic Dermatitis Only a Skin Disease? Int J Mol Sci, 2023.  
  5. Pascal M, Perez-Gordo M, Caballero T, et al. Microbiome and Allergic Diseases. Front Immunol, 2018. 
  6. Roesner LM, Werfel T, Heratizadeh A. The adaptive immune system in atopic dermatitis and implications on therapy. Expert Rev Clin Immunol, 2016. 
  7. Luschkova D, Zeiser K, Ludwig A, Traidl-Hoffmann C. Atopic eczema is an environmental disease. Allergol Select, 2021. 
  8. Kim BE, Leung DY. Epidermal barrier in atopic dermatitis. Allergy Asthma Immunol Res, 2012.  
  9. Cork MJ, Danby SG, Vasilopoulos Y, et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol, 2009. 
  10. Kannenberg SM, Karabus S, Visser WI, et al. Paediatric atopic eczema (atopic dermatitis) in South Africa: A practical algorithm for the management of mild-to-moderate disease in daily clinical practice. S Afr Fam Pract, 2004.  
  11. Sinclair W, Aboobaker J, Green R, et al.Guidelines on the management of atopic dermatitis in South Africa, 2015. Available from https://www.mm3admin.co.za/documents/docmanager/8e7be0a4-2b8d-453f-875e-cd1e5132b829/00079177.pdf 
  12. Kannenberg SM, Karabus DJ, Levin M, et al. Consensus statement of the management of severe, difficult-to-treat atopic dermatitis in adults and adolescents in South Africa and the role of biologics. Current Allergy & Clinical Immunology, 2021. 
  13. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. NEJM, 2016. 
  14. Tod BM, Visser WI. Emerging targeted therapies for atopic dermatitis in the South African context. Current Allergy & Clinical Immunology, 2022.  
  15. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet, 2017. 
  16. De Bruin-Weller M, Thaçi D, Smith CH, et al. Dupilumab with concomitant topical corticosteroid treatment in adults with atopic dermatitis with an inadequate response or intolerance to ciclosporin A or when this treatment is medically inadvisable: a placebo-controlled, randomized phase III clinical trial (LIBERTY AD CAFÉ). BJD, 2017. 
  17. Hanifin JM, Baghoomian W, Grinich E, et al. The Eczema Area and Severity Index-A Practical Guide. Dermatitis, 2022. 

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