Five Interventions to Promote
Induction of Remission and Maintenance of Remission ('Get Control Then Keep Control')
Skin diseases differ from other internal illnesses because of their visual nature. Because patients can see that the skin is inflamed, the inclination may be to stop topical treatment once the redness has reduced. This contrasts with the treatment of asymptomatic 'invisible' illnesses such as hypertension, where medication adherence is unaffected by symptoms or visible indicators. Eczema is due to a combination of a defective skin barrier and immune dysregulation, leading to cell-mediated cytokine-driven inflammation. A systematic review has determined the effects of cessation of treatment when visible erythema or symptoms have settled by collating evidence on the nature of subclinical inflammation in eczema, the effect of treatment on subclinical inflammation and, importantly, how different treatment strategies affect long-term control. Twenty-six studies were included and the skin biopsy findings in patients with subclinical eczema were reviewed. Across 14 randomized controlled trials, an increased risk of relapse was associated with inadequate control of eczema symptoms during initial therapy (fluticasone: risk ratio, 1.31 [95% confidence interval (CI) 1.02–1.68]; tacrolimus: risk ratio, 1.36 [95% CI 1.12–1.66]). The disparate approaches used to induce remission in these trials, ranging from less than 2 weeks to 16 weeks, highlighted the variations in the optimal duration of initial therapy, which will depend on the thickness and chronicity of eczematous skin changes.
Figure 1 summarizes the clinical implications of the findings of this systematic review, demonstrating the importance of initial treatment beyond the resolution of signs and symptoms in order to treat subclinical inflammation, reducing the risk of relapse and the overall quantity of topical treatment used. Of equal importance to inducing initial remission is the concept of then maintaining remission. Here, the strategy of applying topical anti-inflammatory preparations for two consecutive days (such as weekends) each week to keep the skin clear has been shown to drastically reduce subsequent flares (risk ratios [RRs[ of 0.48 [95% CI 0.35–0.65] with fluticasone vs. vehicle; and 0.74 [95% CI 0.58–0.95] for tacrolimus versus vehicle) without increased risk of adverse effects. This proactive concept of induction of remission followed by maintenance of remission is common to many other diseases, such as treatment of cancer and rheumatoid arthritis. The concept is easily explained to patients by the phrase 'get control then keep control' and 'treating eczema under the skin'.
The concept of 'getting control then keeping control'; inducing remission of eczema with a prolonged burst of potent topical treatment followed by maintenance of remission flares with once weekly topical treatment used on weekends. Reproduced with permission from .
Use More Patient/Carer Education Material, Especially in Adequate Quantities
Translating evidence-based findings into patient benefit relies on good patient and guardian/carer education. Two-way education is particularly pertinent in eczema management because, in most cases, eczema is a long-term chronic condition self-managed by patients in a community setting. Because eczema affects approximately 20% of children, the quality of life of patients and their families is also affected. Recent research on patient education for eczema has focused on children and their guardians; a meta-analysis of eight RCTs investigating the effect of education on eczema management including specially convened evening classes for parents and children, demonstrated that the health education groups had significant reductions of SCORing Atopic Dermatitis (SCORAD) (mean difference (MD) = 8.67 better [95% CI 3.67, 13.67] at 12 months, with SCORAD minimum clinically important difference (MCID) 8.7). Improvements in Infants' Dermatology Quality of Life Index scores (MD = 1.50 [95% CI 0.33, 2.67] at 6 months) compared with the nonhealthy education group also occurred.
Approaches to facilitate patient education have also been investigated. A systematic review of qualitative studies on the effect of written action plans for children with long-term conditions, including two studies on eczema and seven on asthma, highlighted that written instructions boost confidence in disease management, alleviate worry and promote feelings of responsibility amongst guardians and school teachers regarding the child's medical needs.
A recent systematic review of qualitative studies reporting views and experiences of managing eczema highlighted four main challenges, including perceived suboptimal information provision and hesitancy about eczema treatment. Guidance from the National Institute for Health and Care Excellence (NICE) suggests that the primary cause of treatment failure is underuse of topical treatment. Therefore, the second intervention we promote is the use of more educational materials, particularly related to adequate quantities of treatment, a challenge that is being addressed by an ongoing Eczema Care Online (ECO) programme in the UK.
Once Daily Topical Corticosteroids is Enough
Although TCSs are licensed for once to twice daily use, the majority are prescribed and applied twice daily. A NICE systematic review suggested no clinically useful benefit with twice daily compared with once daily use for potent corticosteroids– a position that was reinforced in a further independent panoramic review of all eczema treatments. Implementation of once daily use of TCSs is likely to have a variety of benefits including better adherence, reduced adverse effects and reduced costs.
Know When and Where to use Topical Calcineurin Inhibitors
Topical calcineurin inhibitors (TCIs), including tacrolimus and pimecrolimus, have been licensed for eczema management for almost 20 years and act in an immunomodulatory capacity, inhibiting T-cell proliferation and activation. Though TCSs remain first line, there are specific clinical scenarios in which consideration of TCIs is indicated. As TCIs are not associated with skin atrophy with long-term use, they can be used safely for longer on sensitive sites such as the face. TCIs might also be used for TCS withdrawal syndrome – an uncommon rebound of skin inflammation that results from strong TCSs being used for too long on sensitive sites such as the face or genitalia. Unfortunately, most TCIs have been mainly compared against vehicle rather than optimum active treatments with TCSs (Figure 2).
Network plot summarizing RCTs of eczema management with topical corticosteroids, tacrolimus or pimecrolimus, illustrating overuse of vehicle comparisons for new topical treatments. Reproduced with permission from .
A meta-analysis comparing a range of TCSs of different potencies with TCIs identified similar efficacy between the two treatments and an increased risk of application site adverse effects with TCIs, namely skin burning and pruritus. No differences were identified with regards to skin atrophy, skin infections, severe adverse events or the requirement of treatment discontinuation. The absence of clinically significant skin thinning when TCS are used appropriately supports their continued use as well tolerated and effective first-line treatment. Combination treatment approaches, such as applying TCSs once in the morning and TCIs once nightly, is sometimes also suggested, although there is little robust evidence to support this approach.
Treat Severe Eczema More Aggressively
People with severe eczema are probably undertreated. For the treatment of moderate to severe eczema, several effective systemic therapies are available, including ciclosporin, methotrexate and dupilumab – the latter being a biologic treatment that inhibits interleukin (IL)-4 and IL-13 signalling. Many more new treatments are in the development pipeline, including oral selective Janus Kinase (JAK) inhibitors, such as baricitinib and abrocitinib, and other biologic treatments, including nemolizumab, lebrikizumab and tralokinumab. Although systemic steroids have been commonly used in the management of eczema, a systematic review of 64 studies suggests that they are associated with severe rebound and should not be used in eczema treatment.
A Cochrane network meta-analysis of systemic treatments for eczema published in 2020 included 74 RCTs; 70 were available for quantitative synthesis and 29 systemic immunosuppressive agents were assessed. Analyses identified that dupilumab demonstrated the most robust efficacy data across all biological treatments for eczema (achieving 75% improvement in Eczema Area and Severity Index [EASI75]; a range of follow-up between 4 weeks and 16 weeks, Dupilumab vs. placebo in 8 RCTs (n = 1978), RR 3.04 [95% CI 2.51–3.69], RD 37.6% [95% CI 27.8–49.6]), and that no new serious adverse event concerns were identified; however, this conclusion was based on short-term (2–16 weeks) follow-up data. Most trials (65%) were placebo-controlled and, therefore, it was challenging to rank efficacy and safety against conventional treatments such as methotrexate used at adequate doses. To address the deliberate avoidance of active comparator studies common to most new drugs, a platform trial by the UK Dermatology Clinical Trials Network (UKDCTN) called BEACON (Best systemic treatments for adults with atopic eczema over the long term) is planned to compare oral ciclosporin, subcutaneous methotrexate and dupilumab in the management of eczema in adults. Additional biologics will be added and less effective treatment arms will be dropped using an adaptive design, as evidence accrues. Treatment with systemic agents should be considered more readily for patients with severe eczema, tailoring the therapeutic and safety profiles to the individual patient.
Curr Opin Allergy Clin Immunol. 2021;21(4):386-393. © 2021 Lippincott Williams & Wilkins