Basile Darbellay, MD, MD-PhD (Cabinet Dr. Basile Darbellay Orsières) & Prof. Christoph Schlapbach, MD, PhD (Inselspital Bern)
Atopic dermatitis is characterized by eczematous skin lesions, severe pruritus, and great heterogeneity in clinical features and severity [1]. Targeted systemic immunotherapies are now available for patients with moderate to severe AD [2]. In this CME, the most important pivotal studies on these modern therapeutic approaches will be presented.
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in the developed world with increasing prevalence especially in middle and low income countries [1, 3]. The disease can occur at any age but begins in the first five years of life in 85% of affected individuals and is typically seen in infancy [4, 5]. In Switzerland, about 20% of all children are affected by AD. Among adults, it is between 4% to 5% [4]. AD is characterized by marked heterogeneity in clinical features, severity, and course. Typical symptoms include severe pruritus, general skin dryness, and chronic or recurrent eczematous house lesions, which vary in location depending on age [1].
The eczematous skin lesions and severe itching can lead to sleep deprivation, psychological stress, stigmatization, and low self-esteem in AD patients. As a result, depression, anxiety disorders, and an increased risk of suicidal ideation may occur [1]. This is compounded by the increasing limitation of work capacity with increasing AD severity [6, 7]. Overall, then, AD severely affects the quality of life of those affected and their families. This was also shown in a just-published Swedish epidemiological study that, based on data collection since birth, demonstrated a negative effect of AD on health-related quality of life (HRQoL) in adolescents into adulthood. In addition, study data suggest that despite limited HRQoL, individuals rarely seek medical advice, which may lead to delayed diagnosis of AD and consequent undertreatment [8].
AD is associated with various allergic, autoimmune, and cardiovascular comorbidities [1]. Allergic comorbidities, such as food allergies, asthma, and allergic rhinitis, often develop gradually after the onset of AD in childhood as part of the so-called atopic march [9]. The exact mechanisms behind the progression of atopic march are not yet understood. It is still unclear whether early effective therapeutic intervention can halt it, although some studies suggest that it can [10].
How do you determine the severity of AD?
The selection of the appropriate therapy depends primarily on the clinical severity of the disease, which is measured and recorded by different “scores”. These evaluate objective signs as well as the patient’s subjective feelings and should be used in combination [11]. A selection of the relevant scores is summarized below:
- EASI(Eczema Area and Severity Index): Exclusively for grading lesions, not for patient-subjective symptoms [11]; EASI 0 = asymptomatic; 0.1-5.9 = mild; 6.0 – 22.9 = moderate; 23-72 = severe. [12]
- SCORAD(Scoring of Atopic Dermatitis) [11]: Includes extent, intensity, and subjective symptoms pruritus and insomnia [13]; SCORAD <25 = mild; 25-50 = moderate; >50-103 = severe [11]
- PO-SCORAD (patient-oriented SCORAD): severity of AD determined independently by physician, correlates with SCORAD [11, 14].
- POEM(Patient-Oriented Eczema Measures for Eczema): Used to measure subjective symptoms, not objective signs of disease in clinical trials. [11]
- IGA(Investigators Global Assessment): Global assessment of an attending physician [11]; uses 4- to 7-item scales. [15]
- WP-NRS(Worst Pruritus Numerical Rating Scale): scale (0-10) to assess the highest intensity of pruritus in adult patients with moderate to severe AD. [16]
Which treatment for which severity? The graduated treatment!
Based on the classification into mild, moderate, and severe AD, a graded treatment plan is recommended in the 2018 European consensus-based treatment guidelines. Therapeutic options range from topical corticosteroids (TCS) or calcineurin inhibitors to antiseptics, phototherapy, drape therapy, and systemic immunosuppression or modulation [11]. A specific Swiss guideline does not exist, but the German S2k guideline was updated in 2021 and now includes the monoclonal antibody dupilumab (DUPI), the first biologic treatment option in Switzerland, in the staged therapy plan for moderate to severe AD [17, 18].
Current European and German guidelines recommend oily or moisturizing skin creams, bath oils, and avoidance of clinically relevant allergens as basic therapy(Figure 1, Level 1). Appropriate educational programs to identify and avoid trigger factors support the measures [4, 11]. In mild AD (SCORAD <25, transient eczema, stage 2) reactive therapy with rather weak-potent TCS (class II-III) or with topical calcineurin inhibitors and antiseptics is recommended. Moderate/moderate AD (SCORAD 25-50, recurrent eczema, stage 3) is treated with proactive therapy consisting of stronger-potent TCS (class II/III) or the topical calcineurin inhibitor tacrolimus, cloth or phototherapy. Psychosomatic counseling and climate therapy are also considered. In severe AD (SCORAD >50, persistent eczema, stage 4), hospitalization may be reasonable and immunosuppression with cyclosporine A, azathioprine, methotrexate, or mycophenolate mofetil may be indicated [11, 17]. In Switzerland, of these options, only cyclosporine A is approved for AD [19]. In adults, short-term use of oral glucocorticosteroids, rarely PUVA, or alitretinoin may also be considered [11, 17].

Figure 1: Four-stage treatment recommendations for AD, depending on disease severity. *Phototherapy is often indicated from stage 2, but only in adults and not in children; **First-line therapy consists of TCS, in case of intolerance or lack of efficacy and in specific sites (face, intertriginous skin sites, genital areas, scalp in children) topical calcineurin inhibitors are used, ***Additional use of antipruritic and antiseptic drugs may be considered. Not all treatment options from the recommendations are presented. Adapted from [11, 17].
Since these guidelines are not up to date with newly available therapies, the clinical stance in Switzerland is based on the guidelines of the Federal Office of Public Health (FOPH). If first-line (various topical agents) and second-line (phototherapy, systemic immunosuppressants, of which only cyclosporine is approved for AD in Switzerland) treatments fail after at least one month due to contraindications or side effects, third-line therapies can be used for severe AD (SCORAD > 50, EASI > 21, IGA 4, DLQI > 10). Third-line AD therapy includes the monoclonal antibodies dupilumab and tralokinumab and the JAK inhibitors abrocitinib, baricitinib, and upadacitinib.
Unmet Needs
Conventional systemic therapies often have limited efficacy in moderate to severe AD or must be discontinued because of side effects. In addition, long-term use of topical corticosteroids may be associated with a number of local and systemic side effects [20]. This not infrequently leads to “corticosteroid anxiety” in patients, which in turn results in poor adherence and a reduction in disease control [21]. In an observational study of more than 800 adult patients with moderate-to-severe AD on conventional systemic therapies, 81% of patients experienced at least one disease flare in the month before the interview, 58% reported moderate-to-severe symptoms in the last week, and persistent pruritus and sleep disturbances were also common. In addition, a strong impairment of quality of life as well as productivity at work could be observed [22]. These findings highlight the unmet need for new therapeutic options in AD [7, 22]. An adaptation of the treatment guidelines, which takes into account the new therapy options, also seems reasonable.
Targeted treatment options for moderate to severe AD.
Based on the improved understanding of the pathophysiology(Box 1) of chronic inflammatory skin diseases, targeted immunomodulatory therapies have been developed in recent years [2]. Thus, the biologics DUPI since April 2019 and tralokinumab (TRALO) since February 2022 can be used in Switzerland as therapy for moderate to severe AD when treatment with prescription topical medications does not provide adequate disease control or is contraindicated [18, 23]. As the newest treatment options in the therapeutic landscape for moderate-to-severe AD, the oral JAK inhibitors (JAKi) upadacitinib (UPA) and baricitinib (BARI) have been approved in Switzerland since 2021 and abrocitinib (ABRO) since 2022 [23-25]. DUPI is recommended in the 2021 update of the S2k guidelines with strong consensus for patients with moderate-to-severe AD, but the other therapies are not yet mentioned there [17]. Recommendations for the use of JAKi in AD are expected to enter the treatment guidelines with the next updates. In the following, the most important pivotal studies – and predominantly the therapy-relevant dose results – of these three modern systemic therapies are presented. The focus will first be on the latest therapeutic approaches for AD based on inhibition of JAK signaling molecules. Subsequently, biologics that block the inflammatory cascade by binding specific cytokines or cytokine receptors will be discussed [2].
Pathophysiology of AD The pathophysiology of AD is complex and not yet understood in all aspects. Basically, the disease is thought to be characterized by a complex interplay of three factors: impaired skin barrier function, alterations in the skin microbiome, and dysregulation in the Th2-based immune response [2]. In addition, genetic and environmental factors play a role. The following risk factors for AD are known [1]:
The largest known genetic risk factor for the development of AD is variants in the FLG gene, which encodes the protein filaggrin. Filaggrin is produced by keratinocytes during the cornification process and plays an important role in maintaining the skin barrier. Approximately 30% of patients have such FLG mutations[1]. Environmental factors can also negatively affect the barrier function of the skin [2, 26]. Due to the reduced barrier function of the skin, the penetration of antigens and irritants, such as allergens from the air or environmental toxins, is increased. This leads to activation of a Th2-based immune response, secreting cytokines IL-4, IL-5, and IL-13 and stimulating IgE production in B cells. Cytokines bind to cytokine receptors to activate the JAK/STAT signaling cascade of target cells. The binding of IL-4 and IL-13 to their receptors on sensory neurons, as well as IgE-mediated effects, are associated with AD-typical itch [2]. Activated keratinocytes in the skin also secrete proinflammatory signals such as IL-33 or thymic stromal lymphopoietin (TSLP), which contribute to the decreased barrier function of the skin and stimulate the recruitment of additional type 2 immune cells [1, 2]. Constant scratching further destroys the skin barrier, promoting the entry of allergens and other irritants, which in turn increases the immunological response [1]. The skin of AD patients is also more colonized by Staphylococcus aureus than is the case in healthy individuals [2, 27]. It is debated whether the proliferation of S. aureus on the skin possibly contributes to the reduced barrier function and eczema formation or is merely a secondary consequence of these very phenomena. Animal studies indicate a stronger eczematous inflammatory response when S. aureus is overrepresented in the microbiome [27]. At the same time, the cytokines secreted in AD reduce the barrier function of the skin and thus increase colonization with S. aureus [2]. |
Specific inhibition of the JAK signal transduction chain.
Through the JAK-STAT signaling pathway, extracellular factors such as cytokines can control gene expression and thus regulate cell growth and differentiation. In humans, there are four JAK signaling molecules-JAK1, JAK2, JAK3, and TYK2-which bind to different receptors and thus have different physiological roles [28]. Signal transduction involving JAK1 after type I or type II cytokine receptor activation plays an important role in immune dysregulation in AD. JAKi UPA, BARI and ABRO target this mechanism [2].
- Upadacitinib (Rinvoq®)
UPA (Rinvoq®) is an oral JAKi that acts specifically on JAK1 rather than JAK2, JAK3 or TYK2. The active ingredient can be used in the dosage 15 mg once daily since January 2020 in rheumatoid arthritis and since March 2021 in axial spondyloarthritis as well as psoriatic arthritis and since November 2021 is also indicated for the treatment of adults with moderate to severe AD when therapy with conventional topical drugs does not provide adequate disease control or could not be used [24].
The randomized, double-blind, placebo-controlled Phase III AD Up trial evaluated UPA in combination with TCS in patients with moderate-to-severe AD. The total of 901 patients between 12 and 75 years of age received either 15 mg UPA, 30 mg UPA, or placebo orally once daily, each plus TCS; primary endpoints of the study were EASI 75 response* and improvement in vIGA-AD score** after 16 weeks [29]. With once-daily oral 15 mg UPA + TCS, 39.6% (95% CI: 34.1-45.2) of patients achieved a vIGA of 0 or 1, compared with 10.9% (95% CI: 7.4-14.4; p<0.0001) with placebo + TCS. EASI 75 response under 15 mg UPA + TCS was also significantly higher (64.6%; 95% CI: 59.1-70.0) than in the placebo group (26.4%; 95% CI: 21.5-31.4; p<0.0001). In addition, a rapid response to treatment with UPA + TCS was observed – already after 2 weeks, significantly more patients on UPA treatment had achieved an EASI 75 response (p<0.0001) or vIGA-AD improvement (p<0.01) than in the placebo group [29]. In the long-term follow-up of this study, 50.8% of patients on 15 mg UPA + TCS continued to show an EASI 75 response after 52 weeks, and 33.5% of patients had a vIGA-AD of 0 or 1 [30].
The randomized, double-blind, placebo-controlled phase III MEASURE Up-1 and MEASURE Up-2 studies investigated the efficacy and tolerability of once-daily oral 15 mg or 30 mg UPA as monotherapy. Again, EASI 75 response and vIGA-AD improvement at 16 weeks were considered co-primary endpoints. In both studies with a total of 1683 patients, these endpoints were met. More than 40% of patients, 53% in MEASURE Up-1 and 42% in MEASURE Up-2, under 15 mg UPA also achieved an EASI 90 response and 52% and 42% of patients, respectively, achieved significant relief of pruritus, i.e., an improvement of at least 4 points on the WP-NRS. In the placebo groups, only about one in ten patients succeeded in doing both [20]. After 52 weeks, in an integrated analysis of the two studies, 81% of patients on 15 mg UPA showed an EASI 75 response, 62% showed an EASI 90 response, and 65% showed a significant improvement in pruritus [31]. A rapid response to UPA was also observed in MEASURE Up-1 and MEASURE Up-2: After only two days, significantly more patients on UPA than on placebo reported significant relief of itch (p<0.0001)[20].
The efficacy and safety of UPA and DUPI were directly compared in the randomized phase III HEADS UP study of 692 adult patients with moderate-to-severe AD who were eligible for systemic therapy. For this purpose, patients took UPA at the dosage – not approved in Switzerland – of 30 mg 1x daily, while DUPI was injected subcutaneously at a starting dose of 600 mg followed by 300 mg biweekly. After only one week, more patients in the UPA group showed significantly clinically meaningful improvement in itch than in the DUPI group, illustrating the rapid response to UPA. At 16 weeks, significantly more patients had achieved an EASI 75 response under UPA than under DUPI (71% vs. 61%; P=0.006), meeting the primary study end point. UPA also showed significantly better results than DUPI in terms of EASI 90 and EASI 100 response and improvement in itch. The most common adverse events during the first 16 weeks of treatment were acne under UPA (16% vs. 3% under DUPI) and conjunctivitis under DUPI (8% vs. 1% under UPA). Serious treatment-associated adverse effects leading to study discontinuation occurred in 3% of patients on UPA and in 1% of patients on DUPI [32]. The long-term response beyond 4 months of UPA and DUPI is likely to be assumed comparable based on current data.
The safety profile of UPA has been extensively characterized in 4 indications. Compared with clinical trials in rheumatoid arthritis, ankylosing spondyloarthritis, and psoriatic arthritis, acne occurred more frequently in AD trials, but in most cases with a mild course [20]. The integrated 52-week analysis of MEASURE Up-1 and -2 with a total of 797 patients and 953.3 patient-years on 15 mg UPA showed an acne rate of 13.1 per 100 patient-years. The rate of herpes zoster in this analysis was 3.6 per 100 patient-years. Malignancies occurred extremely rarely at a rate of 0.2 per 100 patient-years. Serious cardiovascular events (MACE) and venous thromboembolism (VTE) were each observed in a patient on 15 mg UPA who had at least one cardiovascular risk factor [31].
- Baricitinib(Olumiant®)
BARI(Olumiant®) is a JAKi that shows selective inhibition of JAK1 and JAK2 signaling molecules. The agent is used in rheumatoid arthritis and is now approved for the treatment of adult patients with moderate to severe AD when therapy with topical medications does not provide adequate disease control or is not recommended [25]. Based on BREEZE-AD1, 2, 3, 4, and 7 pivotal studies, BARI is used as a 4 mg tablet once daily or a 2 mg tablet twice daily. If no treatment success is visible after 8 weeks, the therapy must be discontinued. Patients who have sustained control of disease symptoms with 4 mg may switch to once-daily therapy with 2 mg BARI [22].
The randomized, double-blind, placebo-controlled phase III BREEZE-AD1, BREEZE-AD2, and BREEZE-AD7 studies evaluated the efficacy and tolerability of once-daily oral 1 mg, 2 mg, and 4 mg BARI for 16 weeks in a total of 1568 patients with moderate-to-severe AD and inadequate response or intolerance to topical drugs [33-35]. In the BREEZE AD-1 and AD-2 trials, BARI was used once daily as monotherapy; the primary endpoint was an IGA score of 0/1 and an improvement of at least 2 points on the IGA scale. After 16 weeks, 17% of patients in BREEZE-AD1 and 14% of patients in BREEZE-AD2 taking 4 mg BARI showed improvement in IGA compared to 5% (both p<0.001) in the respective placebo arm. An EASI 75 response was achieved with the highest dose as monotherapy in 25% of patients in BREEZE-AD1 and in 21% of patients in BREEZE-AD2. In the placebo group, this was achieved by only 6-9% of patients (both p≤0.001). Improvement in itch occurred with the 4 mg dose of BARI as early as 1 week, as did improvements in sleep patterns and quality of life (p≤0.05 for all comparisons) [33]. In the BREEZE-AD7 trial, a dose of 4 mg BARI was then also tested in combination with TCS and was shown to improve IGA scores in 31% of patients after 16 weeks, compared to 15% in the placebo group (p=0.004) [35].
In the BREEZE-AD3 extension study, patients from the BREEZE-AD1 and -AD2 trials who had demonstrated a complete or partial response to treatment were treated with BARI for up to 68 weeks [36]. The primary endpoint was IGA improvement at 16, 36, and 52 weeks of the extension study. Thereby, the IGA response to 4 mg BARI was stable over the duration of treatment. At the start of the BREEZE-AD3 study, 46% of patients had an IGA score of 0 or 1; at the end of the study, after a total of 68 weeks of treatment, this figure was 47%. The reduction in pruritus was also kept stable over the duration of therapy with 4 mg BARI. There was a slight decrease over time in EASI 75 response – 70% of patients showed an EASI 75 response with 4 mg BARI at the start of BREEZE-AD3, compared with 56% after 68 weeks of treatment [36].
In the randomized, double-blind, placebo-controlled phase III BREEZE-AD4 trial with 462 participants, BARI + TCS were also tested in patients with moderate-to-severe AD and intolerance or contraindication to oral cyclosporine treatment. In the study, 13% of patients receiving treatment with 4 mg BARI + TCS and 13% receiving placebo + TCS achieved an IGA score of 0 or 1 and an improvement on the IGA scale of at least 2 points after 16 weeks (p≤0.05). An EASI 75 response was achieved by 28% of patients taking 4 mg BARI + TCS and 15% taking placebo + TCS (p≤0.05) [25, 37].
According to an integrated long-term safety analysis of eight clinical trials involving a total of 2531 patients and 2247 patient-years on BARI, serious and opportunistic infections and conjunctivitis occurred infrequently and at a frequency similar to placebo at the 2 mg and 4 mg doses. The incidence of herpes zoster was 2.3/100 000 for both doses combined, and that of herpes simplex was 10.3. Malignancies were rare with an incidence of 0.2, and MACE and VTE were also observed in only two patients each [38].
- Abrocitinib (Cibinqo®)
The oral JAKi ABRO (Cibinqo®) predominantly inhibits JAK1 and can be used at the dose of 100 mg once daily since April 2022 for the treatment of adults with moderate-to-severe AD when therapy with topical medications does not provide adequate disease control or cannot be used. If there is insufficient improvement after 12 weeks of treatment, the drug should be discontinued [39].
The randomized, double-blind, placebo-controlled phase III JADE MONO-1, MONO-2, and COMPARE trials evaluated the efficacy and safety of ABRO as monotherapy compared with placebo or DUPI [40-42]. The JADE MONO-1 trial enrolled 387 patients 12 years of age and older with moderate-to-severe AD and received placebo, 100 mg, or 200 mg ABRO once daily for 12 weeks. Co-primary endpoints were an IGA score of 0/1 or improvement on the IGA scale by at least 2 points and an EASI 75 response at 12 weeks. Significantly more patients in the 100 mg ABRO group (24%) than in the placebo group (8%) achieved an IGA response (p=0.0037). An EASI 75 response was achieved by 40% of patients on 100 mg ABRO and 12% of patients on placebo (p<0.0001). Serious adverse events were reported in 3% of patients receiving 100 mg ABRO and in 4% of patients receiving placebo [40]. The JADE MONO-2 study, with the same study design as JADE MONO-1, enrolled 391 patients. Here, with 100 mg ABRO, 28% of patients achieved an improvement in IGA score and 45% of those achieved an EASI 75 response compared with 9% and 10% of patients on placebo, respectively (p each <0.001). Also in this study, the incidence of serious adverse events was comparable in the 100 mg ABRO and placebo groups (3.2% versus 1.3%). A reduced platelet count and laboratory values indicative of thrombocytopenia were demonstrated in the 200 mg ABRO group [41].
In the double-blind phase III JADE COMPARE study, 838 patients were treated with oral 100 mg or 200 mg ABRO once daily for 12 weeks, received placebo, or received subcutaneous 300 mg DUPI every 2 weeks after an initial dose of 600 mg. Here, the primary endpoints of vIGA improvement and EASI 75 response as in the JADE MONO-1 and -2 trials were met at 12 weeks by 37%, 37% and 14% and 59%, 58% and 27% of patients in the 100 mg ABRO group, DUPI group and placebo group, respectively (p<0.001 for ABRO vs. placebo in IGA and EASI 75). Under 100 mg ABRO, nausea occurred in 4.2% of patients and acne occurred in 2.9% of patients [42].
A pooled analysis of the JADE MONO-1 and MONO-2 trials and the phase IIb trial also examined patient-reported outcomes (PROs) with ABRO treatment. The analysis included 942 patients. On 100 mg ABRO, 43% of patients showed improvement in nocturnal itch(Night Time Itch Scale improvement ≥ 4 points) and 65% showed improvement of one point in thePruritus and Symptoms Assessment for AD (PSAAD) score compared with 13% and 34% in the placebo group. Patients’ mental status also improved after 12 weeks on 100 mg ABRO, with a reduction of 1.7 for anxiety and of 1.3 for depression on the Hospital Anxiety and Depression Scales (HADS) compared with 1.0 and 0.1 in the placebo group [43].
General application-relevant information on JAKi:
- Taken as a tablet, independent of meals [24, 25].
- In combination with TCS or as monotherapy [24, 25].
- Do not combine with other potent immunosuppressants, such as cyclosporine, biologic immunomodulators, or JAKi [24, 25].
- Nicht empfohlen bei [24, 25]
- Hypersensitivity to the active substance or one of the excipients
- severe liver dysfunction
- active tuberculosis or serious infections
- Pregnancy or during breastfeeding
- an absolute lymphocyte count (ALC) < than 500 cells/mm3
- an absolute neutrophil count (ANC) < 1000 cells/mm3
- a hemoglobin level < 8 g/dL
- an estimated glomerular filtration rate <30 ml/min/1.73m2 (BARI).[25]
- UPA not studied in ESRD patients. [24]
- Update vaccination status, including herpes zoster vaccination, according to current vaccination guidelines before starting treatment [24, 25].
- Exclusion of chronic infections before therapy and regular blood controls during therapy [44]
Targeted inhibition of the IL-4 receptor and IL-13 signaling molecule.
- Dupilumab (Dupixent®)
DUPI (Dupixent®) is a human monoclonal antibody that specifically binds to the IL-4 type I and IL-4/IL-13 type II receptors, inhibiting IL-4 and IL-13 mediated signal transduction. DUPI finds an application as an ad-on maintenance therapy in severe asthma and is also indicated as an add-on therapy in chronic rhinosinusitis with nasal polyps. In Switzerland, the compound has been approved since 2019 for the treatment of moderate-to-severe AD in adult patients and adolescents 12 years of age and older when therapy with prescription topical medications does not provide adequate disease control or is not recommended. DUPI is available as a pre-filled syringe in 200 mg and 300 mg doses and has been studied in the three pivotal trials SOLO 1, SOLO 2 and CHRONOS. Based on these studies, DUPI is applicable as monotherapy as well as in combination with TCS. For patients who do not respond to treatment after 16 weeks, consider discontinuation [18].
In the parallel randomized, double-blind, placebo-controlled phase III SOLO 1 and SOLO 2 studies, DUPI was evaluated as monotherapy in a total of 1379 patients with moderate-to-severe AD who had failed or failed adequately to respond to topical medications. Patients received a starting dose of 600 mg DUPI followed by 300 mg DUPI weekly (qw) or every two weeks (q2w); primary endpoint was improvement in vIGA-AD score and secondary endpoint was EASI 75 response at 16 weeks [45, 46]. In Switzerland, only q2w treatment with DUPI is approved [18]. With this, 37% of patients achieved improvement in vIGA-AD and 48% achieved an EASI 75 response, as shown in a pooled analysis of the two studies. In the placebo group, this was achieved by only 9.3% and 13% of the patients, respectively (p<0.0001) [46]. DUPI also showed a rapid significant improvement in itching as early as 4 days compared to the placebo arm (p<0.0001) [46].
In the randomized, double-blind, placebo-controlled Phase III CHRONOS trial, DUPI was studied in combination with TCS. Patients with moderate-to-severe AD and an inadequate response to TCS were treated with 300 mg DUPI qw or q2w for 52 weeks and also received TCS as indicated based on disease severity [47]. The co-primary endpoints were an IGA score of 0/1 and an improvement in IGA score of at least 2 points and an EASI 75 response. After 16 weeks, 39% of patients with q2w DUPI + TCS treatment and only 12% in the placebo group had reached the IGA endpoint (p<0.0001). An EASI 75 response occurred in 69% of these patients and in 23% of patients on placebo (p<0.0001). Efficacy was stable over 52 weeks – 36% of patients on q2w DUPI + TCS had met the IGA endpoint and 65% had met the EASI 75 endpoint at the end of the study (p<0.0001) [47].
Reactions at the injection site as well as conjunctivitis, nasopharyngitis, and upper respiratory tract infections were side effects of DUPI therapy [45, 47]. However, there was a higher rate of serious adverse events and study discontinuations as a result of adverse events in the placebo + TCS group from the CHRONOS study compared with the DUPI therapy arms [47].
- Tralokinumab (Adtralza®)
The human antibody TRALO (Adtralza®) specifically binds to IL-13 and thereby inhibits the activation of the IL-13Rα1/IL-4Rα receptor complex. As of February 2022, TRALO is approved in Switzerland for the treatment of adult patients with moderate-to-severe AD when therapy with prescription topical medications does not provide adequate disease control or is not recommended. A starting dose of 600 mg TRALO as a subcutaneous injection followed by biweekly injections of 300 mg TRALO is recommended. Dosage may be reduced to one subcutaneous injection every four weeks when the patient has achieved complete or near-complete healing of the skin [23].
Three randomized, placebo-controlled, double-blind phase III studies, ECZTRA 1, ECZTRA 2, and ECZTRA 3, evaluated the efficacy and safety of TRALO in a total of 1976 adults with moderate-to-severe AD [23, 48, 49]. In the ECZTRA 1 study of 802 patients and the ECZTRA 2 study of 794 patients, TRALO was used as monotherapy at the doses described above and compared with placebo. Primary endpoints were IGA improvement and EASI 75 response at 16 weeks. Patients who met at least one of these primary endpoints were randomized to receive a dose of 300 mg TRALO or placebo either every 2 or every 4 weeks for an additional 36 weeks after 16 weeks in a second phase of the study. After 16 weeks, 16% and 22% of patients on TRALO and 7% and 11% of patients on placebo in ECZTRA 1 (p=0.002) and ECZTRA 2 (p<0.001), respectively, had achieved IGA improvement. An EASI 75 response was seen in 25% and 33% of patients on TRALO compared to 13% and 11% of the placebo group in the ECZTRA 1 (p<0.001) and ECZTRA 2 (<0.001) trials, respectively. PROs illustrated early improvement in patients’ pruritus, sleep, and quality of life, and response to TRALO treatment persisted in the majority of patients for up to 52 weeks. Treatment was well tolerated for up to 52 weeks, and adverse events occurred in 76% and 62% of the TRALO group and 77% and 66% of the placebo group, respectively, in both studies [48].
The ECZTRA 3 study evaluated the efficacy and safety of TRALO in combination with TCS compared to placebo + TCS. The study design over a total of 32 weeks was similar to that of the first two Phase III studies, with the exception that the second phase with patients who had responded to treatment lasted only an additional 16 weeks. With a biweekly injection of 300 mg TRALO + TCS as needed, 39% of patients achieved IGA improvement and 56% of patients achieved an EASI 75 response at 16 weeks. In the placebo + TCS group, this was achieved by 26% (p=0.015) and 36% (p<0.001) of patients, respectively. At 32 weeks, 90% and 93% of patients with biweekly TRALO injections and 78% and 91% of patients with four-weekly TRALO injections maintained an improvement in IGA and an EASI 75 response, respectively. The incidence of adverse events was again comparable between groups. Upper respiratory tract infections, conjunctivitis, headache, and injection site reactions were common adverse events that occurred more often with TRALO than with placebo [49].
Application-relevant information on DUPI and TRALO [18, 23]:
- Application as subcutaneous injection
- In combination with TCS or as monotherapy
- Not recommended for
- Hypersensitivity to the active substance or one of the excipients
- Acute asthma symptoms, acute exacerbations, acute bronchospasm, or status asthmaticus (for DUPI).
- Helminthosis
- Pregnancy
- Not or hardly investigated in
- Patients with impaired liver function
- Patients with severe renal insufficiency
- Women during breastfeeding
- Update vaccination status, including herpes zoster vaccination, according to current vaccination guidelines before starting treatment
AD therapeutics in the pipeline [50] More than 80 new treatments are in the pipeline for AD. The mechanisms of action of these therapies in development range from modifying the skin microbiome to restoring the skin’s barrier function and targeting the excess immune response. Therapies in development from Phase II upward are listed in the following table [50]: ![]() Legend: AhR, aryl hydrocarbon receptor; CCR4, C- C chemokine receptor 4; GPCR19, G protein-coupled receptor 19; H4R, type 4 histamine receptor; IL-4Rα, α-chain of IL-4 receptor; IL-5Rα, α-chain of IL-5 receptor; IL-13Rα1, α1 chain of IL-13 receptor; IL-22R1, IL-22 receptor 1; JAK, Janus kinase; NA, not applicable; OX40L, OX40 ligand; PDE4, phosphodiesterase 4; S1PR1, sphingosine 1- phosphate receptor 1; TSLP, thymic stromal lymphopoietin. |
Take Home Messages
- The pathophysiology of AD is a complex interplay of impaired skin barrier function, alterations in the skin microbiome, and dysregulation in the Th2-based immune response.
- Advances in the understanding of the immunological basis of AD enable the development of targeted immunotherapies, of which, in addition to the injectable biologics dupilumab and tralokinumab, the oral JAKi upadacitinib, baricitinib and abrocitinib have been approved in Switzerland to date.
- Immunotherapies show good efficacy and a good tolerability profile, also in long-term studies.
- The heterogeneity of the disease means that there is no “one-fits-all” treatment, even with immunotherapies.
*EASI 75 response: 75% reduction in EASI score compared to baseline.
** Improvement vIGA-AD value: a vIGA-AD value of 0 or 1 with ≥2 levels of improvement compared with baseline.
Literature