Reactive and proactive treatment in atopic dermatitis: Long-term disease control

INTRODUCTION

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease which worldwide affects between 5% and 20% of all children and up to 5% of the adult population, with the highest incidence in affluent countries.^[1,2] The symptoms are an unrelenting itch, chronic eczematous, and oozing skin lesions and an increased number of infections in the skin. There are many different definitions of the disease, but the Hanifin and Rajka criteria from 1980 are very comprehensive. The criteria consist of the major criteria that are (1) pruritus, (2) typical morphology and distribution of the skin lesions, (3) chronic or chronically relapsing disease, and (4) a personal history of atopy, where patients must have three or more of the symptoms. Furthermore, the patient should have 3 or more of the 23 minor criteria for this disease [Table 1].

The relapsing nature of the disease is for many patients, the most severe symptom. They can treat the disease, but often the disease relapses immediately after cessation of therapy, much to the frustration and agony of the patients.

Thus, treatment has two goals: (1) to make the disease and its symptoms subside and (2) to control the disease and minimize the number of flares. Treatment modalities can be topical and/or systemic. In this paper, we will focus on topical therapy and how the concept of proactive treatment can be used to control the disease and prevent flare-ups.

COMORBIDITIES OF AD AND QUALITY OF LIFE

AD adversely affects their physical, psychological, and social well-being, casting its shadow over various aspects of their lives, including education, professional endeavors, and leisure activities. This condition permeates every facet of a patient’s health trajectory, making control of the disease paramount for the patients.

Individuals fighting and suffering from AD face an elevated risk of psychiatric comorbidities, particularly those with severe AD since childhood. This includes an increased risk of developing attention deficit hyperactivity disorder^[3,4] depression, suicidal thoughts, and suicide.^[5] These burdens extend not only to the patients themselves but also to their caregivers. There is growing evidence that disturbed sleep quality, driven by the incessant itch associated with AD, serves as a pivotal causal factor for these psychiatric comorbidities. In addition, inflammation and the itch itself might potentially lead to permanent changes in the brain, contributing to the emergence of psychiatric symptoms.^[6,7] Furthermore, AD can lead to the stigmatization of those afflicted.^[8]

AD significantly alters the life trajectories of those affected. Research from Denmark has revealed that individuals grappling with early and severe AD experience diminished educational attainment. However, it is essential to note that the absolute numbers involved are relatively small, and the potential influence of familial factors remains unclear.^[9] AD escalates the risk of sick leave and the utilization of disability pensions.^[10] In adults, AD imposes a substantial economic burden due to heightened health-care costs when compared to a matched healthy cohort.^[11]

Furthermore, AD patients face an increased risk of comorbidities. This encompasses a heightened risk of other type II inflammatory conditions such as asthma, rhinoconjunctivitis, and eosinophilic esophagitis. In addition, there appears to be a heightened risk of certain cardiovascular diseases, although ongoing debates explore whether this association might be attributable to lifestyle factors among AD patients or the inflammatory nature of the disease itself.^[12,13]

PATHOPHYSIOLOGY OF AD

AD arises from a complex interplay of a compromised skin barrier function, a type II inflammatory response within the skin, and alterations in the skins’ microbiome. The precise mechanisms and intricate pathways driving AD are the subject of intense ongoing research and the basis for understanding the proactive treatment approach for the disease, and we provide a concise and up-to-date overview here.^[14]

For many AD patients, a genetic predisposition contributes to xerosis and a weakened skin barrier function due to mutations in the FLG gene that encodes filaggrin. Filaggrin serves as a crucial structural protein in the keratinocytes’ cytoskeleton within the epidermis. It also plays a central role in the generation of natural moisturizing factor that serve to retain moisture in the skin, regulate skin pH, modulate the activity of protease inhibitors that safeguard corneodesmosome binding between keratinocytes, and offer photoprotection through the production of trans-urocanic acid.^[15] The absence of filaggrin can lead to skin irritation, inflammation, and subsequent downregulation of filaggrin expression.^[16] Other structural proteins such as loricrin, involucrin, and hornerin may be lacking in AD due to inflammation-induced downregulation, further compromising the skin barrier, as may mutations in SPINK5 which encodes the protease inhibitor LEKTI, which also protects the integrity of the corneodesmosomes. Moreover, a decrease in lipid lamellae, particularly the shortage of w-hydroxy fatty acid sphingosine, contributes to barrier impairment.^[14]

The inflammatory response observed in AD-affected skin is a complex interplay involving keratinocytes and immune cells, with a particular emphasis on lymphocytes. This inflammation represents a type II response characterized by a Th2/Th22-dominated pattern, marked by increased proliferation and activation of type 2 innate lymphoid cells (ILC2), immunoglobulin E-producing B cells, and eosinophils.^[17] The significance of Th2 cytokines and type II inflammation is underscored by the therapeutic effectiveness of monoclonal antibodies targeting key players such as interleukin (IL)-4, IL-13, and thymic stromal lymphopoietin (TSLP) that are archetypal Th2 cytokines associated with type II inflammation.^[18,19] While the precise origins of the inflammatory process remain debated, it is increasingly evident that a group of alarmins originating from epidermal keratinocytes, including IL-33, high mobility group box 1 (HMGB1), and TSLP, play pivotal roles.^[20] In addition, the cytokine IL-31 has garnered attention as the “itch-cytokine,” although it also possesses inflammatory properties, as evidenced by clinical trials with anti-IL-31 antibodies, which have demonstrated notable effects on AD-related itch symptoms.^[21]

It is very important to understand that, in AD patients, not only the lesional skin is affected, but also non-lesional skin demonstrates a significantly increased number of inflammatory cells compared to healthy skin and indeed an increased production of inflammatory cytokines, especially the Th₂-cytokines and the skin specific chemokines. This ongoing inflammatory reaction has also been coined as microinflammation.

Thus, even in the so-called healthy or non-lesional skin of AD patients, there is an ongoing inflammatory reaction, and thus AD patients would in many instances require continuous treatment, and this is the basis for the concept of proactive treatment.

TREATMENT OF AD

The target for the treatment of AD is the inflammatory reaction in the skin as described above. However, regardless of the severity of AD or the specific anti-inflammatory treatment chosen, a fundamental aspect of therapy involves the daily application of generous amounts of moisturizer. This practice alleviates xerosis, diminishes transepidermal water loss, and facilitates the restoration of the skin barrier.^[22] By restoration of the skin barrier, emollient therapy also contributes to the reduction of skin inflammation, thereby decreasing the necessity for topical anti-inflammatory treatments. In addition, alongside emollients, it is advisable to incorporate educational programs and strategies for avoiding clinically significant allergens into the treatment regimen.^[23]

Although there is an almost exponential growth in new drugs aiming at specific inflammatory pathways in the skin, including the biologics such as dupilumab, tralokinumab, and lebrikizumab that block the IL4/IL13 pathway, or Janus Kinase Inhibitors which inhibits the intracellular signaling of the inflammatory cytokines, or even the drugs that are tested on the IL-31 pathway and the OX40 pathway, applying either topical corticosteroids (TCS) or topical calcineurin inhibitors (TCIs), is usually well tolerated, simple, often cheap, and with a minimum of adverse effect, and actually often used together with the new and advanced therapies.

WHAT IS REACTIVE AND PROACTIVE TREATMENT

Reactive treatment is the application of a topical drug either TCS or TCI, at the first signs of active disease in the skin. The treatment is upheld for as long as needed to make the symptoms subside. Once the lesions are gone, treatments are tapered down or stopped directly. Both during the period of active treatment and later moisturizers must be applied liberally and daily. Proactive therapy is to continue the use of the active drug (CS or TCI) regularly twice or three times a week, once the symptoms have subsided, either on the entire skin surface or in the regions where the lesions usually appear, combined with the use of moisturizers daily.

The initial study on proactive therapy involved 125 adults and 247 children who were randomized to receive either intermittent fluticasone propionate (twice per week) or a vehicle control.^[40] After a stabilization phase with daily fluticasone propionate use, there was a 16-week maintenance phase with twice-weekly application. Among adults receiving proactive treatment, the likelihood of AD relapse was 7.0 times lower than in the vehicle-treated group. Pediatric patients exhibited an 8.1-fold reduction in AD relapse likelihood compared to the vehicle-treated group. The median time to relapse for the vehicle group was 4.7 weeks, whereas it could not be calculated for the intermittent fluticasone propionate group due to the majority maintaining control at 20 weeks. Importantly, there were no reported cases of skin atrophy in the intermittent fluticasone propionate group, nor other adverse events.^[40]

The first study was a 12-month randomized, vehicle-controlled study involving 257 adults with mild-to-severe AD who were randomized to receive either 0.1% tacrolimus or a vehicle control. All patients underwent an initial treatment phase with twice-daily application of tacrolimus to affected areas for up to 6 weeks. Once the investigator global assessment score reached <2, patients entered a disease control period and were randomized to proactive therapy (twice weekly) with either 0.1% tacrolimus or (IGA) vehicle control. Results demonstrated that proactive treatment with tacrolimus significantly reduced the number of disease exacerbations, and the percentage of days requiring DE treatment, and extended the time to the first disease exacerbation (142 vs. 15 days) compared to the vehicle group. No serious adverse effects were observed during the 12-month study period.^[23]

Numerous subsequent studies have explored proactive therapy with both TCS and TCI, culminating in a meta-analysis of 9 randomized controlled trials. This meta-analysis, conducted in 2011, included four studies with the proactive use of tacrolimus, four with fluticasone propionate, and one with methylprednisolone aceponate. It indicated that each agent, when used proactively, was significantly more effective at preventing flares compared to their respective vehicle agents. In addition, the meta-analysis suggested that TCS might be more efficacious than tacrolimus.^[41] Importantly, the authors addressed potential bias stemming from shorter durations of TCS trials, emphasizing a significant inverse relationship between efficacy and the duration of proactive therapy, which indicated that TCS superiority was not influenced by shorter trial durations.^[41] Nevertheless, it remains unclear whether the benefits of proactive TCS therapy can be sustained for over a year, given the available data. The meta-analysis reported no serious adverse events in the tacrolimus group and no cases of skin atrophy in any of the TCS studies. However, Hanifin et al.’s study identified biochemical signs of adrenal suppression in 4.5% of children.^[40]

A 2018 meta-analysis encompassing 522 pediatric patients with atopic eczema treated with TCS revealed that only 2% of patients using low-potency TCS demonstrated reversible, biochemical HPA axis suppression after daily use for 4 weeks. As the potency of TCS increased, there was a higher proportion of children displaying biochemical signs of HPA axis suppression, though the differences between potency groups were not statistically significant.^[42] A separate study from 2000 investigated HPA axis suppression in 35 children with AD who had used TCS for extended periods. Results were consistent, indicating rare HPA axis suppression in children using low or moderately potent TCS, but a higher occurrence in those utilizing potent TCS either alone or in conjunction with oral, intranasal, or inhaled glucocorticosteroids.^[43] However, a recent registry study from Denmark reported an increased risk of type 2 diabetes associated with TCS exposure.^[44] Difference between proactive and reactive treatment is given in Table 2.

CONCLUSION

The evidence suggests that TCSs may be employed for proactive therapy with low risks of side effects, although not entirely devoid of risks, and the benefits should be weighed carefully against the potential risks. Some studies have assessed the potential economic benefits of proactive therapy with tacrolimus, indicating that it may not lead to extra costs in moderate AD and could even be cost saving for severe AD compared to reactive therapy.^[45,46] Furthermore, proactive therapy has shown improvements in the quality of life for both children and adults, mainly in the context of tacrolimus use.^{[23,45,47,48]} The sense of “gaining control” over the disease and experiencing prolonged periods without eczema have been proposed as contributing factors to this improvement.^[49,50] However, long-term safety data for proactive therapy remains limited, and the challenge lies in addressing the chronic, unpredictable, and recurrent nature of AD, as well as determining the appropriate duration of treatment.