Modern systems therapy – status quo and prospects

The therapeutic landscape for atopic dermatitis is changing. New findings have made it possible to develop modern treatment options that selectively target inflammatory signaling pathways. There are currently two modern therapeutic approaches among the approved system therapeutics that specifically intervene in the inflammatory mechanism: Biologics and Janus kinase inhibitors. A recently published review summarizes important points.

The corresponding author of the review article is Dr. Ilya Mukovozov, dermatologist at the Toronto Dermatology Centre (Canada) [1]. A key message from Dr. Mukovozov and colleagues is that an increasing diversity of anti-inflammatory systemic therapeutics increases the chances for a tailored treatment that is best matched to disease and patient characteristics.

Biologics

Monoclonal antibodies are genetically engineered proteins that target specific components of the immune system (e.g. cytokines or receptors) involved in the inflammatory response. By blocking these cytokine/receptor pathways, biologics modulate the excessive immune system response characteristic of AD, ultimately resulting in a reduction in skin inflammation and itching. Biologics neutralize interleukins or block receptors extracellularly.

Dupilumab: This monoclonal antibody binds to the α-subunit of the interleukin (IL)-4 receptor, thereby inhibiting the IL-4/IL-13 signaling pathways [3]. Dupilumab was the first biologic approved in the AD indication. It is currently approved in many countries (including Switzerland) for AD patients from the age of 6 months [4]. Dupilumab is administered subcutaneously; the dosage in adults is 600 mg, followed by 300 mg as a maintenance dose every 14 days. There is a special dosing regimen for children and adolescents, which is described in the information for healthcare professionals (KFI). The efficacy and safety of dupilumab has been demonstrated in numerous randomized controlled trials, such as SOLO 1, SOLO 2 and LIBERTY AD CHRONOS in adult AD patients and LIBERTY AD ADOL and LIBERTY AD PEDS in children and adolescents with AD [5–9]. Side effects with dupilumab are limited to local reactions at the injection site and conjunctivitis [10].

Tralokinumab: this monoclonal antibody that specifically binds to IL-13 is the second biologic approved in the AD indication. IL-13 is considered a key cytokine in the pathophysiology of AD [11,12]. In Switzerland, tralokinumab is approved for AD patients over the age of 18, in other countries from the age of 12. The initial dosage is 600 mg, followed by 300 mg every two weeks [4]. In the randomized controlled trials ECZTRA 1 and ECZTRA 2, the efficacy and safety was investigated in AD patients over the age of 18 and in ECZTRA 6 in the age group of 12-17-year-old AD patients [13,14]. Tralokinumab is also well tolerated with a similar spectrum of side effects (local reactions, conjunctivitis) as dupilumab [4].

Below is a brief overview of other promising biologics for AD that are currently (as of 23.08.2024) not approved in Switzerland for this indication.

• Lebrikizumab: this IL-13 inhibitor is approved in the EU for the treatment of AD. In the two randomized controlled trials ADvocate1 and ADvocate2 , a significantly larger proportion of patients with lebrikizumab achieved an IGA score of 0 or 1 by week 16 compared to placebo and a reduction of ≥2 points on the itch scale compared to baseline [15]. Conjunctivitis, exacerbation of dermatitis and skin infections were reported as undesirable side effects of lebrikizumab [15].
• Nemolizumab: the target of this monoclonal antibody is the IL-31-A receptor. IL-31-RA is considered a key factor in the itch-scratch circuit associated with AD [16]. IL-31 is a known pruritogenic inflammatory cytokine that binds to IL-31-RA and maintains the itch-scratch cycle [16,17]. Nemolizumab is approved in Switzerland for the treatment of prurigo nodularis, but is currently (as of 23.8.2024) not approved for the indication AD [4]. In the phase II XCIMA study (nemolizumab in the context of AD proved to be clearly superior to placebo in terms of both itching (VAS) and EASI [18]. Overall, nemolizumab showed a favorable safety profile; the most common adverse events included mild to moderate injection site reactions and signs of upper respiratory tract infections [17].
• Rocatinlimab: inhibits OX40-expressing cells and reduces their number. The interaction between the co-stimulatory T cell receptor OX40 and its ligand OX40L has been shown to play an important role in the pathogenesis of AD, with OX40L-induced signaling promoting the survival and activation of various T helper (Th) cells involved in the pathogenesis of atopic dermatitis [19]. By blocking OX40, these signals are suppressed, which inhibits inflammation [19]. In a phase IIb study, a significant reduction in the EASI score was observed in all rocatinlimab groups at week 16 [19]. The most common side effects included pyrexia, nasopharyngitis, chills, headache, aphthae and nausea [19]. Rocatinlimab is currently approved for AD in the USA (as of 23.8.24).

Janus kinase inhibitors

Some of the pro-inflammatory cytokines involved in the pathogenesis of AD activate the JAK-STAT signaling pathway via their receptors and thus trigger a cytokine response. The intracellular signal transduction of numerous cytokines is mediated by Janus kinases (JAK1, JAK2, JAK3 and TYK2) [20]. The pathogenesis of AD is associated with enhanced Th2 immunity driven by key cytokines such as IL-4, IL-5 and IL-13, which are downstream of JAK-STAT signaling [21]. Based on these findings, JAK inhibitors have emerged as an innovative therapeutic approach for AD. In summary, their efficacy is based on the fact that they suppress the intracellular cytokine response [20,22].

Baricitinib: this JAK1/JAK2 inhibitor was shown to be superior to placebo plus TCS in the BREEZE-AD4 study in combination with topical corticosteroids (TCS) in patients with moderate to severe AD for whom ciclosporin treatment was ineffective at 4 mg compared to placebo plus TCS, both in terms of EASI75 at week 16 and in terms of a ≥4-point improvement on the NRS for pruritus [23]. Baricitinib is being tested in the ongoing BREEZE-AD-PEDS study in children and adolescents [24]. The interim results at week 16 were promising at the 4 mg dose.

The most common side effects included abdominal pain, acne, headaches, diarrhea, nasopharyngitis and upper respiratory tract infections [24].

Upadacitinib: this selective JAK1 inhibitor achieved the efficacy and safety endpoints as monotherapy (15 mg or 30 mg) in the Measure Up 1 and Measure Up 2 studies [25]. In the AD Up study, upadacitinib in combination with TCS in both doses proved to be superior to the placebo in terms of EASI-75 [26]. The most common adverse effects observed with upadacitinib were upper respiratory tract infections and acne [2].

Abrocitinib: this is also a selective JAK1 inhibitor, for which study results from JADE MONO 1 and JADE MONO 2, among others, are available [27,28]. In these studies, abrocitinib (100 mg or 200 mg) proved to be superior to placebo at week 12 with regard to IGA and EASI-75. Upper respiratory tract infections, nausea and elevated liver enzyme levels were reported as common side effects [27].

In addition to the JAK inhibitors baricitinib, upadactinib and abrocitinib, which are approved for the treatment of AD in Switzerland and many other countries, another drug candidate from this drug group, ruxolitinib, is currently at an advanced stage of clinical development. The effects of this JAK1/JAK2 inhibitor in AD were investigated in the TRuE-AD study, for example [29].

Conclusion

The market approval of biologics** and Janus kinase (JAK) ^inhibitors& has set new standards in the treatment of atopic dermatitis (AD) and raised the therapeutic goals to an unprecedented level. The main aim of any therapy is to relieve itching and inflammatory skin changes. In order to achieve this, a severity-adapted approach according to a step-by-step scheme is recommended [2]. Basic care is still the basis of any AD therapy and topical anti-inflammatory preparations can also be used for a short time in parallel with systemic therapy. Phototherapy remains another important treatment modality. Validated objective scores (oSCORAD, EASI) are available for recording the severity of atopic eczema. The use of the DLQI has proven its worth in assessing the impact on quality of life. Furthermore, the PO-SCORAD offers a practice-oriented severity assessment over time and the POEM is suitable for assessing symptoms from a subjective perspective.

** Biologics currently approved in Switzerland for the treatment of AD (as of 23.08.2024) are dupilumab and tralokinumab [4].
& JAK inhibitors currently approved in Switzerland for the treatment of AD (as of 23.08.2024) are abrocitinib, baricitinib and upadacitinib [4].

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