Second-line therapy

Severe cases may require hospital admission and systemic treatment:

These second-line therapies require specialist advice:

Systemic corticosteroids

• used in the short term to manage significant flares in eczema, rather than as long-term treatment - note though that a flare of eczema commonly develops once the corticosteroid dose is weaned (1)
  • only short-term use (for a few weeks) to treat severe acute exacerbations of eczema is advised
  • systemic corticosteroids are often prescribed in combination with proton pump inhibitors to protect against gastric irritation, along with calcium and vitamin D supplements to protect against bone density loss
  • systemic corticosteroid use in children may result in stunted growth (2)
  • a suggested course for adults is e.g. prednisolone 30mg daily for one week (4)

Cyclosporin A (ciclosporin)

• is a systemic treatment option that is recommended for patients with eczema that is refractory to conventional topical treatment
• may be used long term (up to 12 months) or for shorter-term courses (e.g. three to six months)
• caution is advised if using ciclosporin in individuals who are taking anti-fungals (e.g. fluconazole), antibiotics (e.g. macrolides, fluoroquinolones, rifampicin), amiodarone, diuretics (e.g. furosemide), calcium channel antagonists (e.g. diltiazem), statins (e.g. atorvastatin, simvastatin), anti-epileptics (e.g. carbamazepine, phenytoin), serotonin reuptake inhibitors (e.g. fluoxetine), warfarin, or anti-HIV drugs (e.g. ritonavir)

Methotrexate

• recommended as a systemic agent for the treatment of refractory eczema
• is teratogenic and must be avoided during pregnancy and breastfeeding

Azathioprine

• recommended as a systemic agent for the treatment of refractory eczema
• metabolism is dependent on thiopurine methyltransferase (TPMT) - genetic polymorphisms in TPMT may result in variable enzyme activity
  • a baseline TPMT level should be checked before azathioprine is initiated
  • should be avoided in those with low or absent TPMT enzyme activity, who are at greater risk of developing azathioprine toxicity
  • co-administration with allopurinol increases the risk of bone marrow suppression and ideally should be avoided.

Mycophenolate

• considered an alternative therapy for refractory eczema

Interferon gamma

• moderately and variably effective, and may be considered as an alternative therapy for refractory eczema in adults and children who have not responded to, or have contraindications to, the use of other systemic therapies or phototherapy

Psoralen-ultraviolet A (PUVA)

• UV radiation has profound effects on skin and systemic immune responses. Both narrow-band UVB and PUVA (psoralen + UVA) therapies are used for atopic eczema
• psoralens work by photosensitising the skin
  • there are possible short-term and long-term side effects to phototherapy:
    • UVB light can cause burning; PUVA increases the incidence of skin cancers (3) - this is a dose-related effect relating to the total amount of PUVA received
    • narrow-band UVB is thought to be safer and therefore can be used in children
    • psoralen tablets can cause nausea; also the photosensitisation requires sunglasses to be wore for a period of time after treatments to help prevent formation of cataracts
    • is a type of ultraviolet radiation treatment that starts with a photosensitising medicine, called a psoralen, and is followed by exposure of the aIected skin to ultraviolet A (UVA)
• for oral PUVA, oral psoralens (e.g. 8- methoxypsoralen, 5-methoxypsoralen) are taken two to three hours before exposure to UVA in a phototherapy cabinet
• often used as a second-line option for treating eczema that has failed to respond to topical corticosteroids and calcineurin inhibitors
• narrowband ultraviolet B (UVB) phototherapy is preferred over broadband UV phototherapy, including PUVA
  • the latter is associated with increased risk of non-melanoma skin cancer, despite its eIectiveness with refractory eczema
• typically, twice-weekly PUVA treatments are given for eczema, and the dose of UVA radiation is gradually increased over the course of treatment.
  long-term continuous treatment is not advised due to increased risk of developing skin cancers
• can be used as a monotherapy or in combination with emollients and topical corticosteroids
• topical calcineurin inhibitors should be avoided on days of PUVA treatment, as these are photosensitising and could increase the risk of burning. Other oral or topical photosensitising treatments (e.g. tetracyclines) should be avoided during PUVA treatment

Small molecule agents

• small molecule agents affect molecules inside immune cells
• various small molecule agents have been developed and show potential to treat moderate to severe eczema in patients not responding to conventional treatments
  • examples of small molecule drugs used in eczema are phosphodiesterase (PDE)-4 (apremilast) inhibitors, Janus kinase (JAK) inhibitors (tofacitinib, baricitinib, PF-04965842 (abrocitinib)), and JAK/spleen tyrosine kinase inhibitors

Biological therapies

• biological therapies use substances made from living organisms or synthetic versions to target the immune system
  • examples of biological agents that have been developed for treatment of moderate to severe eczema include dupilumab, mepolizumab, omalizumab, and baricitinib
• Dupilumab
  • is a humanised monoclonal antibody targeting the alpha subunit of the interleukin-4 receptor (IL-4RX)
    • via blocking this receptor, dupilumab reduces signalling through both interleukin-4 and interleukin-13 pathways
  • NICE suggest that Dupilumab is recommended as an option for treating moderate to severe atopic dermatitis in adults, only if (5):
    • the disease has not responded to at least 1 other systemic therapy, such as ciclosporin, methotrexate, azathioprine and mycophenolate mofetil, or these are contraindicated or not tolerated
      
      
• Mepolizumab
  • is a humanised monoclonal antibody administered by subcutaneous injection that prevents interleukin-5 from binding to its receptor
    
    
• Omalizumab
  • is a humanised monoclonal antibody that specifically binds to free human immunoglobulin E (IgE) in the blood and interstitial fluid, and to membrane-bound forms of IgE on the surface of IgE-expressing B lymphocytes
    
    
• Baricitinib
  • Baricitinib is an oral JAK inhibitor highly selective for JAK1 (Janus kinase 1) and JAK2. In atopic dermatitis molecular signaling, a critical role is played by the Janus kinase (JAK)/signal transducers
  • NICE suggest that Baricitinib is recommended as an option for treating moderate to severe atopic dermatitis in adults, only if (6):
    • the disease has not responded to at least 1 systemic immunosuppressant, such as ciclosporin, methotrexate, azathioprine and mycophenolate mofetil, or these are not suitable (5)
      
• Lebrikizumab
  • a selective anti–IL‐13 monoclonal antibody
  • NICE recommend lebrikizumab as an option for moderate to severe atopic dermatitis that is suitable for systemic treatment, in people ≥12 yrs & ≥40 kg body weight, only if ≥1 systemic immunosuppressant has been insufficient, or dupilumab or tralokinumab would otherwise be offered (7)
    • as per other NICE approved agents for atopic dermatitis, it recommends that treatment should be reviewed at 16 weeks and stopped if there has been an inadequate response
      • an adequate response being defined as:
        • ≥50% reduction in the Eczema Area and Severity Index score (EASI 50) from when treatment started and
        • ≥4‑point reduction in the Dermatology Life Quality Index (DLQI) from when treatment started

With respect to hand eczema NICE suggest that (8):

• alitretinoin is recommended, within its licensed indication, as a treatment option for adults with severe chronic hand eczema that has not responded to potent topical corticosteroids
• only dermatologists, or physicians with experience in both managing severe chronic hand eczema and the use of systemic retinoids, should start and monitor treatment with alitretinoin

A systematic review concluded that (2):

• ".. findings indicate that dupilumab is the most effective biological treatment for eczema. Compared to placebo, dupilumab reduces eczema signs and symptoms in the short term for people with moderate to severe atopic eczema. Short-term safety outcomes from clinical trials did not reveal new safety concerns with dupilumab..."

Reference:

1. NICE (December 2007).Atopic eczema in children Management of atopic eczema in children from birth up to the age of 12 years.
2. Sawangjit R et al. Systemic treatments for eczema: a network meta-analysis. Cochrane Database of Systematic Reviews 2020, Issue 9. Art. No.: CD013206. DOI:10.1002/14651858.CD013206.pub2
3. Prescriber (2001); 12(12).
4. Update (1999); 59 (3): 189-200.
5. NICE (August 2018). Dupilumab for treating moderate to severe atopic dermatitis
6. NICE (March 2021). Baricitinib for treating moderate to severe atopic dermatitis
7. NICE (July 2024). Lebrikizumab for treating moderate to severe atopic dermatitis in people 12 years and over
8. NICE (August 2009). Alitretinoin for the treatment of severe chronic hand eczema