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Address correspondence to Yayoi Tada M.D., Ph.D. Department of Dermatology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan, TEL +81-3-3964-1211, FAX +81-3-3814-1503,
Recently, Janus kinase (JAK) inhibitors such as baricitinib, upadacitinib, and abrocitinib were approved for the treatment of atopic dermatitis (AD) in addition to biologics, including dupilumab, tralokinumab, and nemolizumab. The increase in treatment options can be benefit to AD patients. Meanwhile, it could make it difficult for physicians to choose the best treatment among those treatment options. Biologics and JAK inhibitors differ in efficacy, safety, route of administration, and whether or not there is a concern about immunogenicity in addition to the evidence on comorbidities. Among the three JAK inhibitors, the degree of inhibition of signal transducer and activator of transcription differs in each JAK inhibitor. Therefore, the efficacy and safety profiles of the three JAK inhibitors are different. Physicians who treat AD patients with JAK inhibitors and biologics need to understand the current evidence and choose the best treatment for individual patients. In this review we discuss how integrating a knowledge of the mechanisms of action of JAK inhibitors and biologics, the potential significant adverse events of these drugs and the age and comorbidities of the patient can help achieve optimal clinical benefit for patients with moderate-to-severe AD refractory to topical agents.
Atopic dermatitis (AD) is a chronic inflammatory skin disease with pruritus, characterized by recurrent eczema with exacerbations and remissions, impairs patients’ quality of life, and places a heavy burden. Although most of patients are successfully treated with topical therapy including corticosteroid, tacrolimus (a calcineurin inhibitor) (
Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study.
), some of patients need phototherapy or systemic therapy such as oral corticosteroid, cyclosporine, and methotrexate. However, the effectiveness of phototherapy and these conventional systemic treatments is insufficient in certain patients. Furthermore, due to the safety concerns, some of them are not approved for the treatment of AD in some countries, and even in the countries where they have been approved, they are recommended to be used for the short-term (
). Insufficiency of effectiveness and safety concerns of the conventional systemic therapy were unmet needs in AD treatment.
Recently, new biologics and oral drugs with high efficacy and tolerable safety have been approved for the treatment of AD. At present, JAK inhibitors such as baricitinib, upadacitinib, and abrocitinib are available for patients with AD in addition to dupilumab, an anti-interleukin (IL)-4 receptor α antibody, tralokinumab, an anti-IL-13 antibody, and nemolizumab, an anti-IL-31 receptor A antibody. The increase in treatment options can be of benefit to AD patients. Meanwhile, it could make it difficult for physicians to choose the best treatment among those treatment options. Biologics and JAK inhibitors differ in efficacy, safety, route of administration, and whether or not there is a concern about immunogenicity in addition to the evidence on comorbidities. Among the three JAK inhibitors, the degree of inhibition of signal transducer and activator of transcription (STAT) differs in each JAK inhibitor. Therefore, the efficacy and safety profiles are different among the JAK inhibitors. Physicians who treat AD patients with JAK inhibitors and biologics need to understand the current evidence and select the best treatment for individual patients. In this review we discuss how integrating a knowledge of the mechanisms of action of JAK inhibitors and biologics, the potential significant adverse events of these drugs, and the age and comorbidities of the patient can help achieve optimal clinical benefit for patients with moderate-to-severe AD.
1-1. Cytokines and Janus kinases in the pathogenesis of atopic dermatitis, the immune response, and homeostasis
AD is characterized by complex interactions between genetic and environmental factors, such as skin barrier dysfunction, allergy/immunity, and pruritus (
). A variety of cytokines are involved in the pathogenesis of AD. IL-4 and IL-13 suppress expression of filaggrin, resulting in skin barrier dysfunction. IL-31, thymic stromal lymphopoietin, IL-4, and IL-13 are involved in pruritus. IL-5 activates eosinophils. IL-22 drives proliferation of keratinocytes in the chronic phase. Those cytokines bind to specific receptors and allow activation of JAK, inducing phosphorylation of STAT (JAK-STAT signaling pathway). Since JAK1 is involved in the signaling pathway of those key cytokines for AD (
), inhibition of JAK leads to improvement of AD. JAK inhibitors inhibit a wider range of signaling pathway of these AD-associated cytokines, whereas dupilumab, tralokinumab, or nemolizumab does so of only IL-4 and IL-13, IL-13, or IL-31, respectively (Figure 1). However, JAK is expressed not only in receptors of cytokines associated with AD, but also in receptors of cytokines that contribute to homeostasis and the immune response (
JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib.
). For instance, interferon (IFN)-α plays an important role in the innate immune response, and its receptor harbors JAK1 and TYK2. IFN-γ is associated with innate antiviral defense, and its receptor harbors JAK1 and JAK2. Granulocyte macrophage colony-stimulating factor and erythropoietin are involved in erythropoiesis, myelopoiesis, and platelet production, and their receptors harbor JAK2. Therefore, strong inhibition of JAK1 and JAK2 could cause adverse events including herpes and anemia in addition to amelioration of AD.
Figure 1Differenet mechanisms of action of JAK inhibitors and biologics in the treatment of atopic dermatitis. JAK inhibitors inhibit a wider range of signaling pathway of atopic dermatitis-associated cytokines, whereas dupilumab, tralokinumab, or nemolizumab does so of only IL-4 and IL-13, IL-13, or IL-31, respectively. JAK, Janus kinase; IL, interleukin.
1-2. Differences among Janus kinase inhibitors for atopic dermatitis
The three JAK inhibitors are not the same. First, the selectivity of inhibition of JAK is different. Baricitinib is a JAK1,2-selective inhibitor, while upadacitinib and abrocitinib are JAK1-selective inhibitors. However, we should be aware that the selectivity of inhibition of JAK is relative. Increased dose of administration can inhibit other JAKs. For instance, although upadacitinib is a JAK1-selective inhibitor, clinical trials demonstrated that the incidence of anemia, which is one of the adverse effects of JAK2 inhibition, was higher in patients treated with 30 mg of upadacitinib (1.4%) than in those treated with 15 mg of upadacitinib (0.3%) or placebo (0.4%) during 0-16 weeks (AbbVie_GK., 2021). Furthermore, the degree of JAK-STAT inhibition is not the same among these JAK inhibitors. Traves et al. compared the degree of JAK-STAT inhibition by JAK inhibitors, utilizing peripheral blood mononuclear cells and whole blood from healthy donors and patients with rheumatoid arthritis (RA) (
JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib.
). Inhibition of STAT was generally stronger in cells treated with upadacitinib than in those treated with baricitinib, indicating that the degree of STAT inhibition by individual JAK inhibitors is different. Indeed, reflecting these results, the efficacy for AD and safety profiles were different in clinical trials of each JAK inhibitor (Tables 1 and 2). Although baricitinib inhibits JAK2 in addition to JAK1, the degree of inhibition is relatively mild. Clinical trials of baricitinib demonstrated mild efficacy with tolerable safety. Regarding anemia, one of the possible adverse effects caused by JAK2 inhibition, severe anemia (grade 3 or more) was not observed in the pooled safety data from eight clinical trials of baricitinib (
In general, low-molecular-weight compounds inhibit a wide range of signaling pathways, whereas biologics inhibit specific cytokine signaling pathways. Therefore, strong potency or a high dose of low-molecular-weight compounds is associated with safety concerns, which is applicable to JAK inhibitors for AD. JAK inhibitors with high efficacy showed higher incidences of specific adverse events including herpes zoster (Tables 1 and 2). Regarding efficacy, a network meta-analysis demonstrated that 30 mg of upadacitinib had the highest efficacy, followed by 200 mg of abrocitinib and 15 mg of upadacitinib, then 100mg of abrocitinib, 4 mg of baricitinib, and 2 mg of baricitinib in terms of the eczema area and severity index (EASI)-75 at week 12-16 (
Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review and Network Meta-Analysis.
). Although dupilumab or tralokinumab is not a JAK inhibitor, the efficacy of dupilumab was similar to that of 15 mg of upadacitinib, and that of tralokinumab was to that of baricitinib. As for adverse events observed in clinical trials of monotherapy, the incidence of any adverse event was higher in clinical trials of upadacitinib and abrocitinib than in clinical trials of baricitinib and biologics. A similar trend was observed in other network meta-analyses (
Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network Meta-analysis.
). In contrast, biologics such as dupilumab and tralokinumab specifically inhibits IL-13 and/or IL-4, and showed relatively high efficacy with good safety profiles, although they have other concerns including conjunctivitis.
2. Material and Methods
In order to evaluate efficacy and safety, we identified articles on clinical trials of baricitinib, abrocitinib, upadacitinib, dupilumab, tralokinumab, and nemolizumab for AD from the PubMed database. Regarding efficacy, we mainly selected the clinical trials of those drugs in which patients did not use topical agents. Head-to-head comparison clinical trials were also included. In terms of safety, articles on analyses of data pooled from some clinical trials were selected preferentially. Data on safety were also collected from new drug application review reports issued by the Pharmaceuticals and Medical Devices Agency in Japan and proper use guides from pharmaceutical companies. In addition, the latest data presented at international conferences were collected. Real-world evidence was also identified from the PubMed database.
3. Results
3-1. Efficacy and safety of JAK inhibitors for atopic dermatitis
Before focusing on the characteristics of individual JAK inhibitors, we mention the safety of JAK inhibitors. Baricitinib and upadacitinib are also used for the treatment of RA. However, their safety profiles in clinical trials of AD patients were different from their safety profiles in clinical trials of RA patients probably due to the differences in age and immune conditions of the patients. Generally, the safety profiles of drugs in AD patients are better than those in RA patients when the same drugs are administered. When explaining the characteristics of JAK inhibitors to AD patients, the explanation should be based on the evidence of clinical trials in AD patients (real-world data are lacking as of now) instead of those in patients with RA or other diseases. Clinical trials of tofacitinib, a JAK1,2,3 inhibitor, raised potential safety concerns of increased risks of serious infection, malignancy, cardiovascular events, thrombosis/embolism, and gastrointestinal perforation (
Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study.
). However, increased risks of these events have not been reported in clinical trials of baricitinib, upadacitinib, or abrocitinib in AD patients to date, although a few cases were observed. It is important not to choose JAK inhibitors for patients who are at risk for these diseases, but deprival of the benefits of JAK inhibitors by overestimating the risks should be avoided. We should understand the safety evidence of individual JAK inhibitors, know which patients are at high risk for adverse events, and not administer JAK inhibitors as a first-line therapy for those patients. The right choice of drugs leads to maximizing benefits and minimizing risks. However, safety data on long-term use of JAK inhibitors in AD patients are limited. Only safety data of administration of JAK inhibitors to AD patients for a period of approximately one year have been published to date. Meanwhile, safety data of administration of upadacitinib and baricitinib to RA patients for a longer period of time are available. Considering that the safety profiles in AD patients are better than those in RA patients, the safety profiles in RA patients could be useful for dermatologists who treat AD patients with the same JAK inhibitor, especially for long-term use.
Several clinical trials of JAK inhibitors have been conducted. Herein, we mainly mention the results of monotherapy clinical trials (without topical corticosteroid). The results described below are all from multicenter, double-blind, randomized, placebo-controlled phase III trials.
3-1-1. Baricitinib
Moderate-to-severe adult AD patients were enrolled in the BREEZE-AD1 trial of baricitinib. The percentage of AD patients achieving investigator's global assessment score of 0/1 at 16 weeks was 16.8% among patients receiving 4 mg of baricitinib, 11.4% among those receiving 2 mg of baricitinib, and 4.85% among those receiving the placebo (
Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.
). The percentage of patients achieving EASI-75 was 24.8%, 18.7%, and 8.8%, respectively. Reduction rates of numerical rating scale (NRS) scores of pruritus were 36.6%, 29.4%, and 12.0%, respectively. Baricitinib significantly improved dermatitis and pruritus in AD patients. In addition, amelioration of sleep disorder and pain was observed. Another clinical trial, the BREEZE-AD2 trial, demonstrated similar results as the BREEZE-AD1 trial. Improvement of depression and anxiety at 16 weeks in patients receiving baricitinib has been reported (
Long-term Efficacy of Baricitinib in Adults With Moderate to Severe Atopic Dermatitis Who Were Treatment Responders or Partial Responders: An Extension Study of 2 Randomized Clinical Trials.
Long-term Efficacy of Baricitinib in Adults With Moderate to Severe Atopic Dermatitis Who Were Treatment Responders or Partial Responders: An Extension Study of 2 Randomized Clinical Trials.
). A total of 2,531 patients (2,247 per person-year; median time of observation, 310 days) were analyzed. The incidences of serious adverse events were almost the same between patients receiving baricitinib and those receiving placebo during 0-16 weeks. Under long-term administration, the incidence of herpes zoster was 2.3 events per 100 person-year, indicating a slightly increased risk of herpes zoster. In the Japanese population, it was 2.7 events per 100 person-year (Pharmaceuticals_and_Medical_Devices_Agency, 2022c). Laboratory tests showed slightly elevated serum levels of creatine kinase (CPK), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, and slightly decreased hemoglobin. Elevated liver enzymes were observed in less than 2% of patients. Although severe adverse events are rare except in patients with renal dysfunction and elderly patients, regular monitoring is necessary especially in patients taking baricitinib over a long period of time.
As for long-term use of baricitinib, the safety of baricitinib in 3770 patients with RA over a median of 4.6 years and up to 9.3 years of treatment has been published (
Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database.
), although there are no data in AD patients. Baricitinib maintained a similar safety profile as that in earlier analyses. No new safety signals were identified. Analysis of the Japanese RA population revealed that age over 50 years was a risk factor for the development of herpes zoster during treatment with baricitinib (hazard ratio; HR 1.94, 95% confidence interval; CI 1.49-2.52) (
Incidence of herpes zoster in patients with rheumatoid arthritis treated during barictinib treatment and the characteristics of those patients: Results of clinical trials including Japanese patients with moderate-to-severe active rheumatoid arthritis.
Abstracts of the 65th Annual General Assembly and Scientific Meeting of the Japan College of Rheumatology.2021; : 345
). Furthermore, Harigai et al. demonstrated that the live vaccine against herpes zoster did not have any preventive effect on the development of herpes zoster while RA patients were receiving baricitinib. No evidence on the preventive effect of the subunit vaccine against herpes zoster has been reported yet.
Real-world data of short-term use of baricitinib (
) showed effectiveness and tolerable safety similar to the results of clinical trial data, although they are limited. Concomitant strong topical corticosteroid and/or prior use of dupilumab in certain patients could account for the subtle difference in effectiveness of real-world data from the efficacy of clinical trials.
Baricitinib is mainly excreted by the kidneys. In patients with renal impairment, dose reduction of baricitinib or avoiding baricitinib is recommended according to the severity of renal impairment (Pharmaceuticals_and_Medical_Devices_Agency, 2022b).
3-1-2. Abrocitinib
Moderate-to-severe AD patients over 12 years old were enrolled in the JADE MONO-1 trial of abrocitinib. The percentage of patients achieving EASI-75 at week 12 was 63% among patients treated with 200 mg of abrocitinib, 40% among those treated with 100 mg of abrocitinib, and 12% among those treated with placebo (
Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.
). The percentage of patients achieving EASI-90 at week 12 was 39%, 19%, and 5%, respectively. Abrocitinib significantly improved pruritus. Similar results were observed in the JADE MONO-2 trial (
), the percentage of patients achieving EASI-75 at week 12 was 70.3% among patients treated with 200 mg of abrocitinib, 58.7% among those treated with 100 mg of abrocitinib, 58.1% among those treated with dupilumab, and 27.1% among those treated with placebo. Although statistical evaluation was not conducted, 200 mg of abrocitinib could be superior in efficacy to dupilumab. Furthermore, another article (
Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: a randomised, double-blind, multicentre phase 3 trial.
) reported that 200 mg of abrocitinib induced earlier reduction of itch and AD sings than dupilumab (proportions of patients reaching a 4 point or higher improvement from baseline in peak pruritus-numerical rating scale [PP-NRS4] at week 2, 48% in patients treated with abrocitinib, 26% in those with dupilumab; EASI-90 at week 4, 29%, 15%, respectively). The efficacy of these indexes reached almost the same levels at week 26 (PP-NRS4, 68%, 63%; EASI-90, 55%, 48%, respectively (Table 3).
Table 3Comparison of 200 mg of abrocitinib with dupilumab (
Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: a randomised, double-blind, multicentre phase 3 trial.
Safety: TEAE through week 26 and up to 28 days after last dose of study drug (%)
Severe AE
3
2
Serious AE
2
2
Nausea
19
2
Headache
13
7
Acne or folliculitis
13
3
Conjunctivitis
3
11
Herpes Zoster
2
<1
PP-NRS4, a 4 point or higher improvement from baseline in peak pruritus-numerical rating scale; EASI, eczema area and severity index; TEAE, treatment-emergent adverse event; AE, adverse event.
Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program.
). Nausea (14.6% in patients treated with 200 mg of abrocitinib, 6.1% in those treated with 100 mg of abrocitinib, 2.0% in those treated with placebo), headache (7.8%, 5.9%, 3.5%), and acne (4.7%, 1.6%, 0%) were observed in a dose-dependent manner. The incidence of herpes zoster was 4.34 per 100 patient-year in those treated with 200 mg of abrocitinib and 2.04 in those treated with 100 mg of abrocitinib. Multivariate analysis found that abrocitinib 200 mg, age ≥ 65 years and severe disease at baseline were associated with higher risk of herpes zoster (
Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program.
). In the Japanese population, the incidence of herpes zoster was 9.80 and 5.36 in those treated with 200 mg or 100 mg of abrocitinib, respectively (Ito et al., 2022). Five venous thromboembolism events occurred (0.30 per 100 patient-year), all in the 200-mg group. Laboratory findings showed a slight decrease in platelets and increases in serum levels of CPK, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, without any clinical consequences. The incidence of serious adverse events was higher in elderly patients (aged 65 years or above, 22.8 per 100 patient-year in patients treated with 200 mg of abrocitinib, 16.5 in those with 100 mg) than in younger patients (under 18 years old, 5.1, 6.3; aged 18-64 years, 6.4, 6.4) (Pharmaceuticals_and_Medical_Devices_Agency, 2021b). In the clinical trial of 200 mg of abrocitinib versus 300 mg of dupilumab (
Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: a randomised, double-blind, multicentre phase 3 trial.
), the incidences of adverse events of nausea, headache, and acne/folliculitis were higher in patients receiving abrocitinib than in those treated with dupilumab (Table 3). The incidence of conjunctivitis was higher in patients receiving dupilumab.
The primary route of elimination of abrocitinib is via cytochrome P450 hepatic metabolism. Abrocitinib is not indicated for patients with severe hepatic impairment. In addition, dose reduction should be considered for patients with renal dysfunction (Pharmaceuticals_and_Medical_Devices_Agency, 2021a).
3-1-3. Upadacitinib
Moderate-to-severe AD patients over 12 years old were enrolled in the Measure Up 1 trial of upadacitinib. The percentage of patients achieving EASI-75 at 16 weeks was 79.7% in patients treated with 30 mg of upadacitinib, 69.6% in those treated with 15 mg of upadacitinib, and 16.3% in those treated with placebo (
Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials.
). The percentage of patients achieving EASI-90 was 65.8%, 53.1%, and 8.1%, respectively, and the percentage of patients achieving EASI-100 was 27.0%, 16.7%, and 1.8%, respectively. Significant improvement in pruritus was observed. The results of another clinical trial, Measure Up 2, were similar to those mentioned above. In the head-to-head trial of 30 mg of upadacitinib versus 300 mg of dupilumab (
), 61.1%, 38.7%, and 7.6% of patients treated with dupilumab showed EASI-75, EASI-90, and EASI-100, respectively, whereas 71.0%, 60.6%, and 27.9% of those treated with upadacitinib did so (Table 4). The percentage change from baseline of worst pruritus NRS was -8.8% in the dupilumab group and -31.4% in the upadacitinib group at 1 week, and -49.0% and -66.9%, respectively, at 16 weeks. This clinical trial revealed the superiority of upadacitinib to dupilumab in efficacy towards eruption and pruritus and rapid onset of efficacy of upadacitinib.
Table 4Comparison of 30 mg of updacitinib with dupilumab (
The analysis on integrated safety data from the phase 2 clinical trials and phase 3 trials (Measure Up 1, Measure Up 2, AD Up, and Rising Up) (AbbVie_GK., 2021,
A phase 3 randomized, multicenter, double-blind study to evaluate the safety of upadacitinib in combination with topical corticosteroids in adolescent and adult patients with moderate-to-severe atopic dermatitis in Japan (Rising Up): An interim 24-week analysis.
Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.
Efficacy and Safety of Upadacitinib in Patients With Moderate to Severe Atopic Dermatitis: Analysis of Follow-up Data From the Measure Up 1 and Measure Up 2 Randomized Clinical Trials.
) demonstrated no significant difference in the incidence of serious adverse events during 0-16 weeks between placebo and upadacitinib. Acne was observed in 15.5% of patients treated with 30 mg of upadacitinib, 9.9% of those treated with 15 mg of upadacitinib, and 2.5% of those treated with placebo. Elevated serum CPK levels (5.2%, 4.2%, 2.1%), anemia (1.4%. 0.3%, 0.4%), and neutropenia (3.0%, 1.1%, 0.3%) were reported in a dose-dependent manner (AbbVie_GK., 2021). Long-term safety data pooled from phase 3 clinical trials (Measure Up 1, Measure Up 2, AD Up, Rising Up, and Heads Up) up to 52 weeks (AbbVie_GK., 2021,
A phase 3 randomized, multicenter, double-blind study to evaluate the safety of upadacitinib in combination with topical corticosteroids in adolescent and adult patients with moderate-to-severe atopic dermatitis in Japan (Rising Up): An interim 24-week analysis.
Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.
Efficacy and Safety of Upadacitinib in Patients With Moderate to Severe Atopic Dermatitis: Analysis of Follow-up Data From the Measure Up 1 and Measure Up 2 Randomized Clinical Trials.
) showed that the incidence of acne was 23.2 events per 100 person-year in patients treated with 30 mg of upadacitinib and 14.5 in those treated with 15 mg of upadacitinib. The incidence of CPK elevation was 10.0 and 7.4, respectively, and that of herpes zoster was 5.8 and 3.7, respectively. The incidence of herpes zoster in the Japanese population of AD patients treated with 30 mg or 15 mg of upadacitinib was 14.7 and 7.2, respectively (
A phase 3 randomized, multicenter, double-blind study to evaluate the safety of upadacitinib in combination with topical corticosteroids in adolescent and adult patients with moderate-to-severe atopic dermatitis in Japan (Rising Up): An interim 24-week analysis.
). Elevated liver enzymes, anemia, and neutropenia were also reported in a few patients in the analysis of long-term safety data. In the clinical trial of 30 mg of upadacitinib versus 300 mg of dupilumab (
), the incidences of adverse events of serious infection, herpes simplex, herpes zoster and abnormality in laboratory data were higher in patients receiving upadacitinib than in those treated with dupilumab (Table 4). The incidence of conjunctivitis was higher in patients receiving dupilumab. A few patients injected with dupilumab showed injection-site reaction.
Regarding long-term use of upadacitinib, safety data in RA patients treated with 15 mg of upadacitinib (7023.8 person-year; median period of observation, 136 weeks) or 30 mg of upadacitinib (3091.6 person-year; median period of observation, 160 weeks) were presented (
). Serious infection (5.1 events per 100 person-year in patients treated with 30 mg of upadacitinib, 3.3 in those treated with 15 mg of upadacitinib), herpes zoster (5.9, 3.3), anemia (4.2, 3.3), neutropenia (4.6, 2.3), elevation of CPK (8.4, 4.9), and non-melanoma skin cancer (NMSC; 1.1, 0.3) were observed dose-dependently. The high incidence of NMSC in the upadacitinib 30 mg group was due in part to recurrent events (34%). The incidence of gastrointestinal perforation was 0.2 in patients treated with 30 mg of upadacitinib and 0.1 in those treated with 15 mg of upadacitinib (0.0 in those treated with methotrexate, 0.0 in those treated with adalimumab and methotrexate). The incidence of major adverse cardiac events was 0.6 in patients treated with 30 mg of upadacitinib and 0.4 in those treated with 15 mg of upadacitinib (0.3 in those treated with methotrexate, 0.3 in those treated with adalimumab and methotrexate). The incidence of those adverse events increased or seemed to increase in a dose-dependent manner. Further accumulation of evidence on adverse effects of long-term use of JAK inhibitors in AD patients is definitely needed.
) showed that age over 50 years old and a history of herpes zoster were risk factors for the development of herpes zoster during upadacitinib treatment (HR 1.78, 95% CI 1.23-2.57; 18.20, 1.23-2.57). Furthermore, a history of live vaccine against herpes zoster did not reduce the incidence of herpes zoster during upadacitinib treatment (HR 1.08, 95% CI 0.59-1.98), similar to the data from RA patients treated with baricitinib. No data on the subunit vaccine against herpes zoster have been reported yet.
Real-world data of short-term use of upadacitinib (
) revealed that baseline total eosinophil count was positively correlated with the percent reduction of EASI at week 4, suggesting that baseline total eosinophil could be a biomarker reflecting therapeutic effects in upadacitinib treatment for AD. Napolitano et al. (
) reported that the decrease of pruritus at week 16 was higher in their patients population (96.62%) than that reported in clinical trials for upadacitinib 30 mg. Chiricozzi et al. (
) confirmed elevated effectiveness and favorable safety of upadacitinib in patients unresponsive to dupilumab.
Upadacitinib is metabolized mainly by cytochrome P450 3A hepatic metabolism (Pharmaceuticals_and_Medical_Devices_Agency). Upadacitinib is not indicated for patients with severe hepatic impairment. Dose reduction should be considered for patients with severe renal dysfunction.
3-2. Efficacy and safety of biologics for atopic dermatitis
3-2-1. Dupilumab
The efficacy and safety of dupilumab in clinical trials and effectiveness and safety profiles in real-world settings are described in our previous article (
Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2).
). The percentage of patients achieving an IGA score of 0 or 1 at 16 weeks was 15.8% in patients treated subcutaneously with tralokinumab 300 mg every 2 weeks vs. 7.1% in those with placebo in ECZTRA 1, and 22.2% vs. 10.9% in ECZTRA 2. The percentage of patients achieving EASI-75 at 16 weeks was 25.0% vs. 12.7%, and 33.2% vs. 11.4%, respectively. Reduction of weekly average worst daily pruritus NRS by ≥ 4 points from baseline to week 16 was achieved by 20.0% with tralokinumab vs. 10.3% with placebo in ECZTRA 1 and by 25.0% vs. 9.5% in ECZTRA 2. With 2 years of tralokinumab with topical corticosteroid, improvements in extent and severity of AD were sustained, with EASI-75 in 82.5% of participants (
Long-term 2-year safety and efficacy of tralokinumab in adults with moderate-to-severe atopic dermatitis: Interim analysis of the ECZTEND open-label extension trial.
Pooled safety analysis of patients with tralokinumab every 2 weeks (N = 1605; 473.19 patient-year) and those with placebo (N = 680; 193.1 patient-year) revealed tolerable safety (
). As safety concerns of interest, the incidence of eye disorders including conjunctivitis, keratoconjunctivitis, and keratitis was higher in patients treated with tralokinumab than in those with placebo (7.9%, 31.1 events per 100 person-year vs. 3.4%, 12.9, respectively) in addition to injection site reaction (3.5%, 22.9 vs. 0.3%, 4.0). That of eczema herpeticum was lower (0.3%, 1.2 vs. 1.5%, 5.2). That of skin infections requiring systemic treatment was also lower (2.6%, 9.7 vs. 5.5%, 22.8). Long-term use of tralokinumab (over 2 years) was well tolerated with a safety profile (N = 1174; 1235.7 patient-year). The incidences of eye disorders, eczema herpeticum, and skin infections requiring systemic treatment were 6.6%, 7.8 events per 100 patient-year; 0.9%, 0.8; 1.8%, 2.2, respectively. Regarding conjunctivitis, results from five tralokinumab clinical trials including 2285 adult AD patients up to 16 weeks were analyzed (
). The incidence of conjunctivitis was higher (7.5%) with tralokinumab than with placebo (3.2%). Most events were mild or moderate in severity. An increased incidence of conjunctivitis, regardless of treatment group, was associated with more severe baseline AD, and history of allergic conjunctivitis/atopic keratoconjunctivitis, as well as the number of atopic comorbidities.
3-2-3. Nemolizumab
AD patients ≥ 18 years of age with inadequate pruritic response to topical corticosteroid for at least 4 weeks and to oral antihistamines administered for at least 2 week, and with pruritus visual analogue scale (VAS) score of 50 or more (maximum 100) and an EASI score of 10 or more, were included in the clinical trial of nemolizumab (
). At week 16, the mean percent change in the VAS score was -42.8% in patients treated subcutaneously with nemolizumab 60 mg every 4 weeks and -21.4% in those treated with placebo. The mean percent change in the EASI score was -45.9% with nemolizumab and -33.2% with placebo. The percentage of patients with a dermatology life quality index score of 4 or less was 40% in the nemolizumab group and 22% in the placebo group. The incidence of injection-site reactions was greater with nemolizumab than with placebo (8%, 3%).
4. Discussion
4-1. Differences between biologics and JAK inhibitors
Since the difference in the mean percent change in the EASI score at week 16 between nemolizumab and placebo was subtle, we would not expect so much improvement in AD signs from nemolizumab as from other biologics and JAK inhibitors, although nemolizumab demonstrated significant improvement in pruritus. In this point of view, the characteristics of nemolizumab are different from other biologics and JAK inhibitors. Therefore, in this section, we mainly discuss the differences between JAK inhibitors and biologics except nemolizumab, namely, dupilumab and tralokinumab. We include nemolizumab in the following discussion section, “optimal use of biologics and JAK inhibitors.”
There are some differences between biologics and JAK inhibitors in addition to the route of administration (subcutaneous versus oral) and mode of action (Figure 1).
Biologics have possible concerns about immunogenicity (
). Although the incidence was quite low (less than 0.6% of patients), anti-drug antibodies could affect the pharmacokinetics and effectiveness of dupilumab in patients with a high titer of over 10,000 (Pharmaceuticals_and_Medical_Devices_Agency, 2022a). Since low trough plasma dupilumab levels are associated with the development of AD (
Efficacy and Safety of Multiple Dupilumab Dose Regimens After Initial Successful Treatment in Patients With Atopic Dermatitis: A Randomized Clinical Trial.
). Dupilumab and tralokinumab are suitable for maintaining remission in addition to inducing remission. In contrast, oral JAK inhibitors do not have issues of immunogenicity, which allows for short-term use. The flexibility of administration of JAK inhibitors, e.g., temporary use, withdrawal, and re-initiation, is one of the strong points of JAK inhibitors. Discontinuation after short-term use could result in rapid loss of efficacy (Guttman-Yassky et al., 2018, Reich, 2021). However, re-initiation brings efficacy to the same extent (
Guttman-Yassky E, Beck LA, Anderson JK, Hu X, Gu Y, Teixeira HD, et al. Upadacitinib treatment withdrawal and retreatment in patients with moderate-to-severe atopic dermatitis from a phase 2b, randomized, controlled trial. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY: MOSBY-ELSEVIER 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA; 2019. p. AB294-AB.
, Reich, 2021). To date, data on whether efficacy will be maintained after withdrawal of JAK inhibitors that have been administered for a long period of time have not been reported yet.
The elimination half-life of biologics, for instance dupilumab (5.13 ± 1.42 days) (Pharmaceuticals_and_Medical_Devices_Agency, 2022a), is much longer than that of JAK inhibitors (several hours) (Pharmaceuticals_and_Medical_Devices_Agency, 2021a, 2022b, 2022 May). Regarding the occurrence of adverse events, discontinuation of JAK inhibitors results in rapid reduction of the adverse effects of these drugs, whereas adverse effects could last for a while even after withdrawal of dupilumab. Although it is based on our personal experience and needs to be confirmed by clinical trials, when switching from a JAK inhibitor to dupilumab or tralokinumab, careful attention needs to be paid due to the differences in elimination half-times and rapidity of onset of efficacy. Since the effects of JAK inhibitors wear off rapidly and since it usually takes several days or a few weeks for dupilumab and tralokinumab to exert their effects, a temporary flare can occur. Therefore, strengthening topical therapy, concomitant administration of a JAK inhibitor and biologics for a short period of time, or temporary use of cyclosporine for the flare should be considered. Regarding the safety of concomitant administration of a JAK inhibitor and biologics, although it is considered tolerable, a JAK inhibitor and biologics should be administered concomitantly for only a short period of time since data are limited. Conversely, switching from dupilumab or tralokinumab to a JAK inhibitor can usually be performed without inducing flares. During the first few weeks after switching from dupilumab or tralokinumab to a JAK inhibitor, both drugs are having an effect due to the long elimination half-life of biologics. Immunologically, IL-13 and/or IL-4 are inhibited strongly and/or for a long period of time by dupilumab or tralokinumab in addition to short-term inhibition of a wider range of cytokines by a JAK inhibitor, which might affect the immune response to parasites regarding safety. However, parasitic infection rarely becomes a problem in countries where a JAK inhibitor is approved due to good hygienic environments. It is speculated that short-term concomitant administration of a JAK inhibitor and biologics such as dupilumab and tralokinumab would not cause serious adverse events, which is supported by the fact that no additional adverse events were observed in patients who switched from dupilumab to upadacitinib at 24 weeks in a clinical trial (Blauvelt, 2021). Furthermore, in this trial, intriguingly, the percentage of patients achieving EASI-90 was numerically higher in those who switched from dupilumab to upadacitinib at 24 weeks than in those treated with only upadacitinib (87.8%, 73.4% at 4 weeks after switching, or 28 weeks after initiation of upadacitinib; 89.1%, 71.8% at 8 weeks after switching, or 32 weeks after initiation of upadacitinib; 87.7%, 73.6% at 16 weeks after switching, or 40 weeks after initiation of upadacitinib). This additional effectiveness suggests that the inhibition of IL-4 and IL-13 signaling pathways by dupilumab could be longer and/or stronger than the inhibition of JAK-1/2 by JAK inhibitors. Further research is needed to elucidate this.
The differences in efficacy and onset of action between JAK inhibitors and biologics are described above. Abrocitinib and upadacitinib are superior in rapid onset of efficacy to dupilumab. Dupilumab has concerns of conjunctivitis and facial redness, the details of which are described in our previous article (
), whereas JAK inhibitors do not increase the risks of conjunctivitis. Dupilumab reduces the risks of cutaneous infections including eczema herpeticum (
Fleming P, Drucker AM. Risk of infection in patients with atopic dermatitis treated with dupilumab: A meta-analysis of randomized controlled trials. J Am Acad Dermatol 2018;78(1):62-9.e1.
Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.
Hirano I, Dellon ES, Hamilton JD, Collins MH, Peterson K, Chehade M, et al. Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis. Gastroenterology 2020;158(1):111-22.e10.
Long-term 2-year safety and efficacy of tralokinumab in adults with moderate-to-severe atopic dermatitis: Interim analysis of the ECZTEND open-label extension trial.
). Tralokinumab showed the tendency of reduced risks of cutaneous infection including eczema herpeticum, although statistical analysis has not been conducted. The ages of patients for whom JAK inhibitors and biologics are approved differ according to the drug and country. In Japan, dupilumab, tralokinumab, baricitinib, and 30 mg of upadacitinib are approved for moderate-to-severe AD patients who are no less than 15 years old; nemolizumab is approved for those who are no less than 13 years old; and abrocitinib and 15 mg of upadacitinib are approved for those who are no less than 12 years old, as of December 2022.
4-2. Optimal use of biologics and JAK inhibitors (Figure 2)
Figure 2Optimal use of biologics and JAK inhibitors for atopic dermatitis. The schematic illustrates how to choose JAK inhibitors and biologics for patients with moderate-to-severe AD refractory to topicl agents. AD, atopic dermatitis; JAK, Janus kinase.
Nemolizumab demonstrated significant efficacy for pruritus in AD patients. However, its efficacy for AD signs was not strong. Therefore, other biologics or JAK inhibitors should be considered for AD patients with severe AD signs. Other biologics and JAK inhibitors are efficacious for both pruritus and AD signs. In Japan, nemolizumab has been approved for AD patients with an EASI score of 10 or above who suffer from severe pruritus, whereas other biologics and JAK inhibitor can be prescribed to AD patients with an EASI score of 16 or above. AD patients have heterogeneous clinical phenotypes, including different combinations of itch and lesional severity (
). Some patients suffer from severe pruritus with mild-to-moderate AD sings. Nemolizumab can be considered for those patients, for instance, patients with an EASI score of 10-16 and severe pruritus. EASI scores in some patients with prurigo nodularis-like phenotype in AD are low due to small areas of affected lesions. These patients are also candidates for nemolizumab.
Dupilumab, tralokinumab and JAK inhibitors are treatment options, apart from patients suitable for nemolizumab. Although oral medicine is generally preferred to injection, JAK inhibitors have some safety concerns compared with dupilumab and tralokinumab. First, dupilumab or tralokinumab is preferred for patients who have, had, or have risks of malignancy, cardiovascular diseases, deep vein thrombosis, pulmonary embolism, gastrointestinal perforation, or diverticulitis. Patients with renal or hepatic impairment can receive JAK inhibitors at reduced doses according to the degree of impairment or physicians can choose the appropriate drugs considering their metabolism and excretion; however, dupilumab or tralokinumab is a better option for patients with severe comorbidities in terms of safety. Among patients treated with upadacitinib, the incidences of serious or severe adverse events and anemia were higher in elderly patients than in younger patients (AbbVie_GK., 2021). Among patients treated with abrocitinib the incidences of serious adverse events was also higher in elderly patients than in younger patients (Pharmaceuticals_and_Medical_Devices_Agency, 2021b). Therefore, in elderly patients and those in whom safety is prioritized, dupilumab or tralokinumab can be the first line as a systemic therapy for AD. As stated above, age over 50 years is one of the risk factors for the development of herpes zoster in RA patients treated with baricitinib (
Incidence of herpes zoster in patients with rheumatoid arthritis treated during barictinib treatment and the characteristics of those patients: Results of clinical trials including Japanese patients with moderate-to-severe active rheumatoid arthritis.
Abstracts of the 65th Annual General Assembly and Scientific Meeting of the Japan College of Rheumatology.2021; : 345
Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program.
). Dupilumab or tralokinumab is recommended in patients at higher risk of herpes zoster such as elderly patients and those with a history of herpes zoster. Since dupilumab was shown to be associated with a reduced risk of cutaneous infections (
Fleming P, Drucker AM. Risk of infection in patients with atopic dermatitis treated with dupilumab: A meta-analysis of randomized controlled trials. J Am Acad Dermatol 2018;78(1):62-9.e1.
Long-term 2-year safety and efficacy of tralokinumab in adults with moderate-to-severe atopic dermatitis: Interim analysis of the ECZTEND open-label extension trial.
), dupilumab or tralokinumab should be considered instead of JAK inhibitors in AD patients with repeated skin infections including eczema herpeticum. Dupilumab is preferred in AD patients with asthma, eosinophilic esophagitis, and/or chronic rhinosinusitis with nasal polyps due to the efficacy of dupilumab for patients with these conditions. Dupilumab can be the first-line option of treatment for AD patients with the above-mentioned conditions (Figure 2).
A JAK inhibitor is one of the systemic treatment options in patients without the conditions mentioned above (Figure 2). JAK inhibitors are favored, especially for patients with a fear of needles (trypanophobia) or who prefer oral medicine to injection. Since JAK inhibitors demonstrated significant improvement in pruritus from one day after initiating the drug, and a rapid onset of efficacy in eruption, JAK inhibitors are suitable for patients who suffer from severe pruritus and/or who wish a rapid onset of efficacy. JAK inhibitors should also be considered for patients who cannot continue systemic therapies for a long period of time due to economic reasons, those who experience temporary exacerbation, for instance, at a certain season, and those who need or want to receive systemic therapy over the short term for any reason. Patients with a history of conjunctivitis and/or elevated serum levels of thymus and activation-regulated chemokine (over 3,000 pg/ml) and immunoglobulin E (IgE) (over 11,000 IU/ml) are at high risk for developing conjunctivitis during dupilumab treatment (
Conjunctivitis in patients with atopic dermatitis treated with dupilumab is associated with higher baseline serum levels of immunoglobulin E and thymus and activation-regulated chemokine but not clinical severity in a real-world setting.
), although the results vary depending on the report. JAK inhibitors could be considered first for those patients. In AD patients treated with dupilumab or tralokinumab who suffer from severe or persistent conjunctivitis and/or facial redness, switching to a JAK inhibitor is one of the options. Although there is insufficient evidence, cases successfully treated by switching from dupilumab to a JAK inhibitor have been reported (
) gives a choice of switching to upadacitinib in patients who are refractory to dupilumab. Although it is rare, there are a few cases who developed alopecia areata or arthritis/enthesitis during dupilumab treatment (
). Changing dupilumab to a JAK inhibitor should be considered in those patients.
4-3. Optimal use of dupilumab and tralokinumab: Which to choose
Since evidence of tralokinumab is limited, it is difficult to compare dupilumab and tralokinumab at present. As a head-to-head clinical trial has never been conducted, this discussion includes speculation and expectation. Tralokinumab seems to show a slower onset of efficacy than dupilumab but to reach almost the same levels after the long-term use with topical corticosteroid. The incidences of conjunctivitis and facial redness might be lower in tralokinumab than in dupilumab, although there is no evidence supporting this concept and accumulation of evidence is needed. Considering them, tralokinumab might be one of good options for patients who prioritize safety over a rapid onset of efficacy. As stated above, dupilumab demonstrated decreased risks of cutaneous infection and tralokinumab showed the same trend, although the evidence level is different between them. Dupilumab is efficacious for asthma, eosinophilic esophagitis, and/or chronic rhinosinusitis with nasal polyps, whereas tralokinumab has no evidence on it. Dupilumab should be considered for AD patients with asthma, eosinophilic esophagitis, and/or chronic rhinosinusitis with nasal polyps instead of tralokinumab. Further accumulation of evidence is needed to clarify the differences between them.
4-4. Optimal use of JAK inhibitors: Which JAK inhibitor to choose
As stated above, JAK inhibitors with higher efficacy are accompanied by more safety concerns including herpes zoster. Therefore, we should consider the balance of efficacy and safety, namely, the risks and benefits when choosing a JAK inhibitor. Since most AD patients are young and have no comorbidities, even 30 mg of upadacitinib is relatively safe in most cases. However, in patients at high risk for the specific concerns discussed above, the choice of JAK inhibitor should be made carefully. In terms of efficacy, baricitinib can be considered for patients with moderate AD. In severe AD patients, upadacitinib or abrocitinib is favored. JAK inhibitors are recommended for induction of remission. As for maintaining remission, safety data on long-term use of JAK inhibitors in AD patients are limited. Long-term use for up to one year can be considered based on the results of clinical trials of JAK inhibitors for AD. Use of a JAK inhibitor for more than one year needs careful consideration due to the lack of evidence. Since safety data of baricitinib in RA patients over a median of 4.6 years demonstrated that no new safety signals were identified (
Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database.
), baricitinib could be tolerable for long-term use. As of now, data on long-term use of abrocitinib for more than 2 years have not been reported yet. According to the safety data of RA patients treated with upadacitinib for a median of 2-3 years (
), in treating AD patients with 30 mg upadacitinib for the long term, we may want to consider reducing the dose to 15 mg once AD is well-controlled since the incidence of some adverse effects increased or seemed to increase in a dose-dependent manner. Further accumulation of evidence on long-term use of JAK inhibitors is needed, especially in view of safety.
5. Conclusions
Understanding the characteristics of biologics and differences in the efficacy and safety profiles of JAK inhibitors is essential in order to choose the right treatment option for individual AD patients. A knowledge of the mechanisms of action of JAK inhibitors and biologics, the potential significant adverse events of these drugs, and the age and comorbidities of the patient can help achieve optimal clinical benefit for patients with moderate-to-severe AD. This article was written based on the updated current evidence. We need to be informed of updated data and provide the best treatment for individual patients.
Blauvelt A. Efficacy and Safety of Switching from Dupilumab to Upadacitinib in Moderate-to-Severe Atopic Dermatitis: Results from an Open-Label Extension Trial. EADV Congress 20212021. p. D1T01.
Guttman-Yassky E, Silverberg J, Nemoto O, Forman S, Wilke A, Prescilla R. Efficacy and safety of upadacitinib treatment over 32 weeks for patients with atopic dermatitis from a phase 2b, randomized, placebo-controlled trial [abstract]. EADV Congress 20182018.
Ito T, Okubo U, Kataoka Y, Simpson E, Valdez H, Johnson S, et al. Safety of abroctinitib for moderate-to-severe atopic dermaitis: Analyses on the Japanese population. The Annual Meetin of the Japanese Dermatological Association. Kyoto2022.
Pharmaceuticals_and_Medical_Devices_Agency. Japan phamaceutical reference of Cibinqo® (abrocitinib) https://www.info.pmda.go.jp/go/pdf/672212_4490037F1026_1_02; 2021a [accessed on September 8, 2022].
Pharmaceuticals_and_Medical_Devices_Agency. Japne phamaceutical reference of Dupixent® (dupilumab), https://www.info.pmda.go.jp/go/pdf/780069_4490405G2020_1_04; 2022a [accessed on September 8, 2022].
Pharmaceuticals_and_Medical_Devices_Agency. Japne phamaceutical reference of Olumiant® (baricitinib), https://www.info.pmda.go.jp/go/pdf/530471_3999043F1020_1_10; 2022b [accessed on September 8, 2022].
Reich K. Efficacy with continuous dosing, down-titration, or treatment withdrawal after successful treatment with baricitinib in patients with moderate-to-severe atopic dermatitis [abstract]. 50th Annual ESDR Meeting 20212021. p. 30-.
Pharmaceuticals_and_Medical_Devices_Agency. Japne phamaceutical reference of Rinvoq® (upadacitinib) https://www.info.pmda.go.jp/go/pdf/112130_3999048G2024_1_09; 2022 May [accessed on September 8, 2022].
Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.
Blauvelt A. Efficacy and Safety of Switching from Dupilumab to Upadacitinib in Moderate-to-Severe Atopic Dermatitis: Results from an Open-Label Extension Trial. EADV Congress 20212021. p. D1T01.
Long-term 2-year safety and efficacy of tralokinumab in adults with moderate-to-severe atopic dermatitis: Interim analysis of the ECZTEND open-label extension trial.
Fleming P, Drucker AM. Risk of infection in patients with atopic dermatitis treated with dupilumab: A meta-analysis of randomized controlled trials. J Am Acad Dermatol 2018;78(1):62-9.e1.
Guttman-Yassky E, Beck LA, Anderson JK, Hu X, Gu Y, Teixeira HD, et al. Upadacitinib treatment withdrawal and retreatment in patients with moderate-to-severe atopic dermatitis from a phase 2b, randomized, controlled trial. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY: MOSBY-ELSEVIER 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA; 2019. p. AB294-AB.
Guttman-Yassky E, Silverberg J, Nemoto O, Forman S, Wilke A, Prescilla R. Efficacy and safety of upadacitinib treatment over 32 weeks for patients with atopic dermatitis from a phase 2b, randomized, placebo-controlled trial [abstract]. EADV Congress 20182018.
Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials.
Incidence of herpes zoster in patients with rheumatoid arthritis treated during barictinib treatment and the characteristics of those patients: Results of clinical trials including Japanese patients with moderate-to-severe active rheumatoid arthritis.
Abstracts of the 65th Annual General Assembly and Scientific Meeting of the Japan College of Rheumatology.2021; : 345
Hirano I, Dellon ES, Hamilton JD, Collins MH, Peterson K, Chehade M, et al. Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis. Gastroenterology 2020;158(1):111-22.e10.
Ito T, Okubo U, Kataoka Y, Simpson E, Valdez H, Johnson S, et al. Safety of abroctinitib for moderate-to-severe atopic dermaitis: Analyses on the Japanese population. The Annual Meetin of the Japanese Dermatological Association. Kyoto2022.
A phase 3 randomized, multicenter, double-blind study to evaluate the safety of upadacitinib in combination with topical corticosteroids in adolescent and adult patients with moderate-to-severe atopic dermatitis in Japan (Rising Up): An interim 24-week analysis.
Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study.
Short-Term Effectiveness and Safety of Biologics and Small Molecule Drugs for Moderate to Severe Atopic Dermatitis: A Systematic Review and Network Meta-Analysis.
Pharmaceuticals_and_Medical_Devices_Agency. Japan phamaceutical reference of Cibinqo® (abrocitinib) https://www.info.pmda.go.jp/go/pdf/672212_4490037F1026_1_02; 2021a [accessed on September 8, 2022].
Pharmaceuticals_and_Medical_Devices_Agency. Japne phamaceutical reference of Dupixent® (dupilumab), https://www.info.pmda.go.jp/go/pdf/780069_4490405G2020_1_04; 2022a [accessed on September 8, 2022].
Pharmaceuticals_and_Medical_Devices_Agency. Japne phamaceutical reference of Olumiant® (baricitinib), https://www.info.pmda.go.jp/go/pdf/530471_3999043F1020_1_10; 2022b [accessed on September 8, 2022].
Pharmaceuticals_and_Medical_Devices_Agency. Japne phamaceutical reference of Rinvoq® (upadacitinib) https://www.info.pmda.go.jp/go/pdf/112130_3999048G2024_1_09; 2022 May [accessed on September 8, 2022].
Reich K. Efficacy with continuous dosing, down-titration, or treatment withdrawal after successful treatment with baricitinib in patients with moderate-to-severe atopic dermatitis [abstract]. 50th Annual ESDR Meeting 20212021. p. 30-.
Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.
Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: a randomised, double-blind, multicentre phase 3 trial.
Comparative Efficacy of Targeted Systemic Therapies for Moderate to Severe Atopic Dermatitis without Topical Corticosteroids: Systematic Review and Network Meta-analysis.
Long-term Efficacy of Baricitinib in Adults With Moderate to Severe Atopic Dermatitis Who Were Treatment Responders or Partial Responders: An Extension Study of 2 Randomized Clinical Trials.
Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.
Efficacy and Safety of Upadacitinib in Patients With Moderate to Severe Atopic Dermatitis: Analysis of Follow-up Data From the Measure Up 1 and Measure Up 2 Randomized Clinical Trials.
Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program.
Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.
Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database.
JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib.
Conjunctivitis in patients with atopic dermatitis treated with dupilumab is associated with higher baseline serum levels of immunoglobulin E and thymus and activation-regulated chemokine but not clinical severity in a real-world setting.
Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2).
Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study.
Efficacy and Safety of Multiple Dupilumab Dose Regimens After Initial Successful Treatment in Patients With Atopic Dermatitis: A Randomized Clinical Trial.
Funding sources: This article has no funding source.
Conflict of interest: M.K. received honoraria for lectures from AbbVie and Eli Lilly. Y.T. received grants for research from AbbVie and Eli Lilly, and honoraria for lectures from AbbVie and Eli Lilly.
Contribution to the submitted work: M.K. writing-original draft; Y.T. supervision, writing-review & editing.
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