Endogenous forms of eczema

Eczema is a common and burdensome condition that affects one-in-five children and one-in-10 adults in Ireland. In this article, some of the endogenous forms of eczema will be discussed, including atopic dermatitis, seborrhoeic dermatitis, discoid eczema, and venous eczema.

ATOPIC DERMATITIS

Atopic dermatitis (AD), or atopic eczema, is a chronic, relapsing and remitting inflammatory dermatosis, associated with itching, xerosis, erythematous lesions, and lichenification. The condition tends to fluctuate in severity between periods of flares and remissions.

Epidemiology

With regards to the epidemiology of AD, there is substantial variation with age and sex, and there is unequal distribution across different geographical regions. AD is the principal cause of the global burden from dermatological disease. It affects approximately 20 per cent of the paediatric population and up to 10 per cent of adults coming from high-income countries. The burden of this condition has been stable between 1990 and 2017, with the prevalence rate seen to be the highest during early childhood years and a second rise from middle age.

Clinical features

In infants, AD tends to present between three-to-six months of age with a red scaly rash on the cheeks, wrists, and extensor aspects of legs, arms, and neck. Older children and adults tend to have a red scaly eruption on the flexural surfaces, primarily the antecubital and popliteal fossae. Xerosis and itching are very common features, with the scratching worsening the eczema, leading to lichenification. Presence of oedema and increased skin temperature to touch are signs of underlying erythema and inflammation.

During remission, skin lesions may be absent, and the skin that is clinically unaffected tends to appear dry. The predominant colour changes include post-inflammatory hyperpigmentation and hypopigmentation, which is quite common.

Pathogenesis

The pathogenesis of AD is very complex, involving intrinsic and environmental factors, which contribute to disruption of the epidermal barrier. Immune responses and skin commensal microbiota are also affected.

Factors that determine the epidermal barrier function include:
1. Filaggrin deficiency: Major factor contributing to dysfunction of the epidermal barrier. Filaggrin plays a critical role in producing the natural moisturising factor (NMF). NMF maintains skin hydration and water retention in environments of low humidity.
2. Imbalance between stratum corneum proteases and antiprotease activity.
3. Abnormalities in tight junction function.
4. Altered cutaneous microbiome – increased amounts of Staphylococcus aureus and reduced diversity of the microbial community leading to an exacerbated Th2 immune response.

In terms of barrier dysfunction, allergens penetrate the skin more easily leading to activation of the damaged keratinocytes. This leads to the release of cytokines including interleukin (IL)1β, IL-33, and thymic stromal lymphopoietin (TSLP), which in turn leads to activation of Th2 cell-mediated immune responses. TSLP-activated dendritic cells express OX40 ligand and this activates Th2 differentiation of naϊve T-cells, leading to the production of Th2 cytokines, most notably IL-4, IL-5, IL-13, and IL-31. IL-31 plays a critical role in itching.

In view of concordance rates of 80 per cent in monozygotic twins versus 20 per cent in dizygotic twins, genetic factors are also implicated in AD. Studies have been carried out to locate loci associated with skin barrier abnormalities, but it was found that these genetic susceptibility loci account for less than 20 per cent of the inherited component for AD.

Climate has also been implicated in AD pathogenesis. The prevalence of eczema was found to be much lower in areas with high humidity, mean temperatures, and ultraviolet (UV) indices, along with less indoor heating and precipitation.

Studies also show that AD is more prevalent in urban areas compared to rural ones. AD has been significantly and positively associated with consistent exposure to benzene, nitrogen oxides, and carbon monoxide.

AD might be exacerbated when the immune response is triggered by food components leading to increased binding of antigens to immature gut microvilli, leading to increased permeability of antigens into the body. Two studies have shown that the most common food allergen in AD patients are egg whites and cow’s milk.

Diagnosis

The diagnosis of AD depends on the history, physical examination, and the distribution of the lesions. Blood tests generally show raised levels of immunoglobulin (Ig) E and eosinophils. The IgE level tends to vary with disease severity, however, some patients may have normal IgE levels despite having severe disease.

Dermoscopy findings include:
1. Hypopigmented zones;
2. Crown of branches vessels with central hypopigmentation;
3. Very small brown roundish dots;
4. Yellow orange clods with a brown rim around them.

The main histological features of AD include spongiosis (reduction and rounding of keratinocytes along with widening of the intercellular spaces leading to sponge-like appearance of the epidermis), acanthosis, and hyperkeratosis, along with chronic inflammatory infiltrate made up of lymphocytes, mast cells, and eosinophils. In the acute stages of AD, spongiosis is the dominant feature along with excessive epidermal oedema, ultimately leading to the formation of vesicles.

To aid diagnosis of AD, several diagnostic criteria have been established including:

• Hanifin and Rajka (H-R) criteria(1980);
• UK Working Party (UKWP) criteria;
• Diagnostic criteria for AD according to the American Academy of Dermatology.

The UKWP criteria represents a shorter version of the H-R criteria and tends to work better for the diagnosis of AD in children than adults.

Assessing disease severity is a crucial step in the management of AD as it gives clinicians a guide to what medication the patient should be commenced on, as well as helping to assess the therapeutic response. Scoring systems to assess severity of AD include:
1. Investigator Global Assessment (IGA);
2. Eczema Area and Severity Index (EASI);
3. Scoring Atopic Dermatitis (SCORAD) scales.

These scoring systems take into account dryness, redness, oozing, swelling, scratch marks, skin thickening, and extent of disease on various body parts. In addition, SCORAD also takes into account subjective assessment of itching and sleep quality.

There are also validated tools for patients so that they can score their disease severity themselves, including:
1. Patient-Oriented Eczema Measure (POEM);
2. Patient Oriented SCORAD (PO-SCORAD);
3. Numerical Rating Scale (NRS)-itch.

Differential diagnosis

1. Allergic contact dermatitis: History of exposure to certain irritants and localisation of the inflammation to a specific skin area suggest allergic
contact dermatitis.

2. Seborrhoeic dermatitis (SD): Can be confused with AD in infants. The presence of erythematous skin patches with greasy scales, with involvement of the scalp and minimal-to-no pruritus, suggests SD.

3. Scabies: The presence of vesiculopustules on the palms and soles along with the demonstration of mites/eggs by skin scraping confirms scabies.

4. Psoriasis: Involvement of diaper area with erythematous patches along with little scale in infants suggest psoriasis.

5. Others: Acrodermatitis enteropathica, cutaneous T-cell lymphoma, tinea corporis and tinea capitis, and molluscum contagiosum.

Biomarkers

• Biomarkers to help distinguish AD from psoriasis: NOS2 and chemokine C-Cmotif ligand (CCL).
• Biomarkers correlating with clinical severity: Cytokines IL-13, IL-22, and IL-33  or chemokines CCL17/ thymus and activation-regulated chemokine (TARC) and CCL26/eosinophil attracting chemokine.
• Barrier related biomarkers such as filaggrin or NMF will correlate inversely with disease severity.
• TSLP: Serum levels being higher in children and adults with AD compared to healthy patients. Tezepelumab is an anti-TSLP monoclonal antibody, which despite showing good safety profiles, has displayed no significant difference when combined with topical corticosteroids (TCS) compared to a combination of placebo and TCS.
• CCL17/TARC has been reported to be the most reliable biomarker, with levels positively correlating with disease severity. Moreover, levels of this biomarker are reduced on adequate treatment of AD. However, it is not specific to AD, being elevated in other conditions including scabies.

Association with other conditions

AD is associated with several other conditions including:

• Rheumatoid arthritis, type 1 diabetes mellitus, and alopecia areata.
• Sleep disturbance – in view of the itch-scratch cycle and secondary effects of inflammatory cytokines on sleep pattern.
• Cardiovascular disease (CVD) – Sleep disturbance itself predisposes to CVD. Adults with eczema have a higher chance of smoking and consuming alcohol from an early age, lower chances of doing exercise, and have a higher prevalence of obesity, hypertension, hyperlipidaemia, and diabetes, leading to a higher risk of CVD. Moreover, AD in the paediatric population has also been found to be associated with obesity and hypertension.
• Infections including cutaneous and extra-cutaneous: Skin barrier dysfunction along with increased colonisation with Staphylococcus aureus and use of immunosuppressing medication all contribute to cutaneous infections. AD has also been associated with systemic infections including pneumonia.

Treatment of AD

General measures

• Short daily baths using fragrance-free soap;
• Using of emollient after bathing;
• Use of petrolatum for anti-inflammatory and barrier effects;
• Avoiding olive oil-based products since these have been linked to pro-inflammatory activity;
• Dilute bleach soaks (1cc/L) of a very low concentration to provide antibacterial effects;
• Avoidance of allergens.

Mild AD

General measures as above

• Using low potency TCS such as dexamethasone 0.1 per cent cream, applied twice a day for three-to-seven days beyond clearance (for <2 weeks).
• Using topical calcineurin inhibitors such as pimecrolimus, tacrolimus, or crisaborole (a topical phosphodiesterase 4 (PDE4) inhibitor) for the face or if there is any concern about TCS.

Moderate-to-severe AD

• Stronger potency TCS are needed for such patients. However, their continued use for months is associated with skin atrophy and skin wrinkling. Therefore, a class III potency topical steroid such as mometasone 0.05 per cent ointment twice daily for up to two weeks (beyond clearance) can be used, with maintenance therapy in the long-term using lower potency TCS or non-steroidal agents.
• Educating patients that AD cannot be cured, but can be controlled.
• Proactive management involves reducing from twice a day application of the TCS to once a day for one-to-two weeks followed by the continued use of a mild potency TCS or tacrolimus ointment three times per week.
• The use of wet wrap technique.
• Use of antihistamines.

Referral to a specialist should be considered in the following circumstances:
1. Severe or recurrent skin infections;
2. Significant psychosocial problems;
3. Uncontrolled facial AD;
4. Poor disease control with first-line agents;
5. Uncertain diagnosis;
6. Patient is being considered for systemic immunosuppressive therapy.

New therapeutic options

1. Dupilumab: A monoclonal antibody that targets IL-4 and IL-13 has produced good therapeutic efficacy.

2. Tralokinumab: A fully human IgG4 antibody that targets IL-13 only, inhibiting its signalling.

3. Fezakinumab: Anti-IL-22 antibody. IL-22 promotes epidermal thickening and skin barrier defects. Fezakinumab was noticed to produce a statistically significant difference in SCORAD scores in a phase II study at week 20 of treatment.

4. Nemolizumab: Humanised antibody against IL-31RA. IL-31 is a cytokine that stimulates nerves leading to itching in AD. In a recent phase III study in Japan, nemolizumab was very effective in inhibiting itching in AD.

5. Upadacitinib, abrocitinib, and baricitinib: Oral JAK (Janus kinase) inhibitors approved for AD, with upadacitinib and abrocitinib showing superior efficacy to dupilumab in several trials.

In summary

It is important to bear in mind that AD has a significant burden on patients in terms of itching, sleep disturbances, psychological distress, anxiety, depression, suicidal ideation, social stigmatisation, and consequently impaired quality-of-life. In addition to this, AD has a significant socioeconomic burden on patients. A multidisciplinary approach is crucial in the management of such patients.

SEBORRHOEIC DERMATITIS

Seborrhoeic dermatitis (SD) is a very common chronic, relapsing condition of papulosquamous morphology, involving areas rich in sebaceous glands, particularly the scalp, face, and body folds.

Epidemiology

SD tends to affect individuals at all ages, with a peak during infancy (two-to-12 months of age) and in early adulthood. SD is more common in immunocompromised patients and patients with human immunodeficiency virus (HIV), with incidence ranging from 30-to-83 per cent. Implicated causative factors include: Male sex; neuropsychiatric factors including Parkinson’s disease (PD); and high environmental humidity and heat.

Clinical features

Dandruff is the commonest form of SD, presenting as scales without visible inflammation over the scalp. Clinically, SD tends to present as greasy yellow scales overlying well-defined erythematous patches, over the central third of the face. Dark-skinned patients tend to present with hypopigmented scaly areas.

In infants, SD typically presents in the third or fourth week of life with fine greasy scales overlying erythematous plaques or as ‘cradle cap’ – greasy, non-inflammatory plaques with overlying yellow scales involving the vertex and frontal areas of the scalp. This is neither itchy nor painful, with sleeping and feeding not being disrupted. SD tends to be more severe in HIV, involving unusual sites such as the extremities, and is generally more difficult to treat.

Differential diagnosis

In infancy it is crucial to differentiate SD from Langerhans cell histiocytosis. In adults, rosacea and lupus erythematosus may resemble SD. Involvement of the nasolabial folds and scaling favours SD, while presence of pustules might indicate rosacea. Sun exposure can worsen both rosacea and cutaneous lupus.

Pathophysiology

The pathogenesis of SD can be classified into five distinctive phases:

1. Lipids are secreted onto the skin surface by the sebaceous glands.
2. Areas of the skin that have lipids are colonised by species of Malassezia.
3. Malassezia secretes lipase, resulting in free fatty acids (FFA)  and lipid peroxides, leading to inflammation.
4. This leads to the formation of cytokines by the immune system including IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, and TNF-α, resulting in proliferation and differentiation of keratinocytes.
5. Disruption of the skin follows, leading to the signs and symptoms of redness, scaling, and itching.

Sebaceous glands are mostly found on the face, back, and chest, which is why SD tends to affect primarily these regions. Sebaceous gland activity is influenced by androgens, hence explaining the high prevalence of SD in males. However, SD is increasingly becoming more common in women, probably in view of the use of cosmetics.

The commonest organisms involved in SD are Malassezia restricta and Malassezia globosa due to their increased expression of lipase genes. The sebaceous lipids are hydrolysed by lipases leading to an increase in FFAs, which are used by Malassezia to produce unsaturated fatty acids including oleic acids, which are very irritating to the skin. The number of yeasts is also thought to be an important factor in the severity of SD, but not all studies agree with this.

Western diet is associated with an increased risk of developing SD compared to individuals on a high intake of fruits and vegetables.

Malassezia is thought to contribute to the secretion of a variety of cytokines including IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, and TNF-α, leading to the skin barrier being disrupted. Keratins 1, 10, and 11, sphingoid lipids, and ceramides – biomarkers that are crucial for skin barrier function – are also disrupted. Upon successful treatment of SD, ceramides, sphingoid lipids, and keratin levels are all restored and inflammatory markers such as IL-1 and Il-8 return to normal.

Genetic factors also play a role. Human leukocyte antigen (HLA) subtypes have been associated with increased risk of developing SD. In 2014, a study found three new alleles to be associated with SD including A 32, DQB1 05, and DRB 101. At least, 11 gene mutations or protein deficiencies have been associated with the condition, with most of these mutations being involved in the immune response of epidural differentiation.

Conditions associated with SD

HIV is often associated with SD due to the immune system being dysregulated with CD4 lymphopenia, allowing for extensive proliferation of Malassezia on the skin. Parkinson’s disease also holds an association due to hyperactivity of the parasympathetic nervous system leading to increased sebum production. Moreover, Parkinson’s patients have elevated levels of melanocyte stimulating hormone, which has also been shown to have a positive correlation with SD.

Diagnosis

Diagnosis of SD is made clinically on most occasions. Nonetheless, a biopsy can be performed should the diagnosis be uncertain. Dermoscopy generally shows fine white yellowish scales along with follicular plugs, dotted vessels in patchy distribution, as well as linear branching vessels. Histology indicates parakeratosis in the horny layer of the epidermis along with mild-to-moderate spongiosis and scale-crusts with pyknotic neutrophils over plugged follicular ostia.

Treatment

With regards to treatment, it is important to clarify with the patient that there is no definitive cure for the condition, so the condition requires treatment over many years.

For mild SD of the scalp in adults, use of antifungal shampoos should be sufficient to manage the condition such as ketoconazole 2 per cent two-to-three times per week. In cases of moderate-to-severe disease, the addition of high potency TCS once daily for up to four weeks should be considered.

Should SD still not improve, then systemic antifungals such as oral itraconazole 200mg once daily for seven days is commonly prescribed. If there is still no improvement, the diagnosis should be reconsidered. Shampoos containing salicylic acid may help to soften thick scales of the scalp. For infants, similar therapeutic interventions are used.

For mild non-scalp SD, topical antifungal treatment, for example ketoconazole 2 per cent, once-to-twice daily is recommended. If there is no improvement, low potency TCS can be added. Should there be no improvement after a further two weeks, TCS may be switched to topical tacrolimus 0.1 per cent, and continued along with the topical antifungal treatment.

Once improvement is noticed, topical antifungal cream is continued once-to-twice weekly to prevent relapse. For moderate-to-severe SD, TCS along with topical antifungal treatment may be given once-to-twice daily for two weeks.

If no improvement is noted, TCS can be switched to tacrolimus 0.1 per cent along with topical antifungal treatment. If the patient does not respond, then systemic antifungals are often prescribed. Topical roflumilast 0.3 per cent and crisaborole 2 per cent, both PDE4 inhibitors, have been shown to be effective in the treatment of SD.

VENOUS ECZEMA

Venous eczema (VE), also referred to as stasis dermatitis, is a chronic inflammatory dermatosis typically involving the lower limbs in patients who have chronic venous insufficiency (CVI). In VE, the function of the deep venous plexus is altered leading to backflow of blood to the superficial venous system, resulting in venous hypertension (VH) and venous ulcers.

Epidemiology

Prevalence of CVI varies from 1-to-40 per cent in females and 1-to-17 per cent in males. In one study, 6.2 per cent of 4,099 patients aged >65 years had VE. The prevalence of VE rises with age.

Risk factors for CVI include:

• Increasing age;
• Family history of venous disease;
• Female gender and pregnancy;
• Obesity;
• Standing occupation;
• Deep vein thrombosis (DVT);
• Sedentary lifestyle;
• Varicose veins and chronic oedema;
• Cellulitis.

Pathogenesis

VH plays a critical role in the pathogenesis of VE. VH results from incompetence of venous valves, obstruction of venous flow, and failure of the calf muscle venous pump. In one study, valvular incompetence was present in 70-to-80 per cent of patients with chronic venous disease.

Studies of immunohistochemistry on biopsies of skin that were affected by VE reveal thickening of basal lamina capillaries, increased presence of macrophages, mast cell, and T-lymphocytes, and increased matrix metalloproteinases – with these findings suggesting that VH plays a critical role in VE. In one study, surgical intervention targeting VH resulted in a complete resolution of VE for all patients who underwent the surgery.

Clinical features

VE typically presents with erythema, scaling, and eczematous patches/plaques on oedematous legs with the medial ankle being most frequently involved. Itching can aggravate wounds leading to increased risk of infection as well as lichenification.

It is important to differentiate between acute VE and chronic VE. In acute VE, there is substantial erythema, worsening oedema, bullae, vesiculation, and crusting. Acute episodes or acute flares on a background of chronic VE are often misdiagnosed as cellulitis.

Hyperpigmentation in the form of brown speckles in view of haemosiderin deposition and scaling are predominant features in chronic forms. Other features of chronic disease include varicose veins, lipodermatosclerosis, atrophie blanche, and ulceration.

A classification system referred to as Clinical-Etiology-Anatomy-Pathophysiology (CEAP) was developed to describe patients with chronic venous disorders based on the clinical features. Patients with VE are classified as C4, meaning changes in the skin and subcutaneous tissue.

Diagnosis

If there is clinical uncertainty, duplex ultrasound can detect direction of blood flow, assess venous reflux, and identify venous obstructions. They are cost-effective, non-invasive, and accurate. CT and MRI can also be used to detect obstructions in proximal veins.

Biopsy shows proliferation of dilated blood vessels in the papillary dermis, hemosiderin-laden macrophages, extravasated erythrocytes, and dermal fibrosis. However, biopsies tend to be avoided in view of the risk of these patients developing a non-healing wound at the biopsy site in view of poor blood supply.

Treatment

General treatment measures are outlined in Box 1. The cornerstone of management is compression therapy, either through bandages or stockings. Compression bandages (including multilayer and Unna boots) are preferred to stockings in patients with acute VE.

The Unna boot is a closed topical dressing made up of a moist zinc oxide-impregnated bandage that provides non-elastic compression. It has drying and anti-inflammatory properties. Compression stockings are typically used in mild or chronic VE. However, patients do not always adhere to their regular use due to discomfort, overheating, itching, and irritation.

Pharmacological measures

TCS can be used to relieve pruritus, erythema, and vesiculation. Prolonged use, however, can lead to skin atrophy and increased risk of ulceration. Topical tacrolimus, a calcineurin inhibitor, has been shown to be effective in the treatment of VE. However, it is associated with burning sensations, which may affect patient concordance.

Oral pentoxifylline is a platelet aggregation inhibitor that reduces blood viscosity leading to improved circulation. In VE, it is given so as to reduce leg pain and to increase the healing rate of venous ulcers. Calcium channel blockers such as amlodipine may lead to peripheral oedema. Switching to alternative medications such as angiotensin-converting enzyme inhibitors may lead to reduced oedema.

Crisaborole ointment 2 per cent is used in AD. A 2024 study showed that crisaborole is associated with significant improvement in patients with VE. Treatment of infections is also vital. Topical mupirocin is the topical antibiotic of choice for impetiginisation of VE when Staphylococcus or Streptococcus is documented. It can be used as an empirical treatment when culture results are pending or unavailable. Topical erythromycin is an alternative when mupirocin is not tolerated. Wet dressings utilising 1 per cent glacial acetic acid solution can decrease the bacterial load over the skin.

DISCOID ECZEMA

Discoid eczema (DE), or nummular dermatitis, is characterised by coin-shaped erythematous, eczematous, and pruritic lesions. Lesions range in size from one-to-10cm in diameter. Common sites include the extremities.

Epidemiology

The condition commonly affects females aged 15-to-25 years and males aged 50-to-65 years, and is more frequent in Asians. Prevalence ranges from 0.1-to-9.1 per cent.

Causes

The exact cause of DE is unknown. Factors implicated in DE include:
1. Dry skin;
2. Stress and presence of AD in children;
3. Venous stasis in the lower limbs;
4. Exposure to certain chemicals including formaldehyde, neomycin, chrome, nickel, mercury in dental amalgam, wool, and breast implantation;
5. Colonisation by Staphylococcus aureus;
6. Chronic alcoholism;
7. Seasonal variation with high incidence of lesions in winter when intake of fluid is low, leading to the stratum corneum being drier than usual, as well as very hot summers;
8. Systemic drugs including gold and isotretinoin.

Pathology

Histological features include spongiosis, lymphocytic infiltrates, occasional eosinophils, neutrophils,
and plasma cells.

Diagnosis

Diagnosis of DE is usually a clinical one. Typical findings would be of coin-shaped, intensely pruritic lesions in a patient with generally diffuse dry skin. Biopsy or laboratory tests are unnecessary. Dermoscopy can reveal irregularly distributed brownish-red globules, shiny yellow clods, and scales. Differential diagnosis may include early stages of Tinea corporis. Potassium hydroxide wet-mount examination of skin scrapings is used to differentiate between the two conditions.

Treatment

Management of DE is based on reducing skin dryness and limiting exposure to skin irritants. General measures may include:

• Moisturisation of the skin using creams with increased lipid content, applied after showering. Creams containing a mixture of ceramides appear to be more effective at diminishing water loss through the skin compared to traditional moisturisers. 
• Using detergents that are primarily based on non-ionic surfactants. These in return, would have the lowest potential for skin irritancy.
• Oral intake of L-histidine has been shown to improve dry skin and promote filaggrin levels in keratinocytes.
• Avoidance of precipitating factors.

Pharmacological therapies

Frontline management includes mid-to-high potency TCS applied once-to-twice daily for two-to-four weeks or until the lesions resolve. Phototherapy may be used for more widespread disease – narrowband UVB light therapy is generally utilised. Usually 10-to-30 sessions given two-to-three times per week are needed before a response can be noticed.

If no response is noted, treatment is discontinued and systemic therapies including corticosteroids, methotrexate, and cyclosporin can be considered. Oral roflumilast 500mcg/day is considered safe and has a low cost. Dupilumab, an IL-4 and IL-13 inhibitor, has also been found to be effective in a small group of patients with DE.

Conclusion

Eczema can be a challenging disorder for both patients and clinicians. Understanding different subtypes and their presentation will allow for appropriate management plans and promote optimal patient outcomes. An individual, patient-centred approach is vital in the treatment of any form of this debilitating skin disorder. n

References on request