Aislyn Oulee, BS

To the Editor:

Brodalumab, a monoclonal antibody targeting IL-17RA, was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of moderate to severe chronic plaque psoriasis. The drug is the only biologic agent available for the treatment of psoriasis for which a psoriasis area severity index score of 100 is a primary end point.^1,2 Brodalumab is associated with an FDA boxed warning due to an increased risk for suicidal ideation and behavior (SIB), including completed suicides, during clinical trials.

We sought to characterize national utilization of this effective yet underutilized drug among Medicare beneficiaries by surveying the Medicare Part D Prescriber dataset.³ We tabulated brodalumab utilization statistics and characteristics of high-volume prescribers who had 11 or more annual claims for brodalumab.

Despite its associated boxed warning, the number of Medicare D claims for brodalumab increased by 1756 from 2017 to 2019, surpassing $7 million in costs by 2019. The number of beneficiaries also increased from 11 to 292—a 415.2% annual increase in beneficiaries for whom brodalumab was prescribed (Table 1).

In addition, states in the West and South had the highest utilization rates of brodalumab in 2019. There also was an increasing trend toward high-volume prescribers of brodalumab, with private practice clinicians constituting the majority (Table 2).

There was a substantial increase in advanced practice providers including nurse practitioners and physician assistants who were brodalumab prescribers. Although this trend might promote greater access to brodalumab, it is vital to ensure that advanced practice providers receive targeted training to properly understand the complexities of treatment with brodalumab.

Although the utilization of brodalumab has increased since 2017 (P<.001), it is still underutilized compared to the other IL-17 inhibitors secukinumab and ixekizumab. Secukinumab was FDA approved for the treatment of moderate to severe plaque psoriasis in 2015, followed by ixekizumab in 2016.⁴

According to the Medicare Part D database, both secukinumab and ixekizumab had a higher number of total claims and prescribers compared to brodalumab in the years of their debut.³ In 2015, there were 3593 claims for and 862 prescribers of secukinumab; in 2016, there were 1731 claims for and 681 prescribers of ixekizumab. In contrast, there were only 29 claims for and 11 prescribers of brodalumab in 2017, the year that the drug was approved by the FDA. During the same 3-year period, secukinumab and ixekizumab had a substantially greater number of claims—totals of 176,823 and 55,289, respectively—than brodalumab. The higher number of claims for secukinumab and ixekizumab compared to brodalumab may reflect clinicians’ increasing confidence in prescribing those drugs, given their long-term safety and efficacy. In addition, secukinumab and ixekizumab do not require completion of a Risk Evaluation and Mitigation Strategy (REMS) program, which makes them more readily prescribable.³

Overall, most experts agree that there is no increase in the risk for suicide associated with brodalumab compared to the general population. A 2-year pharmacovigilance report on brodalumab supports the safety of this drug.⁵ All participants who completed suicide during the clinical trials harbored an underlying psychiatric disorder or stressor(s).⁶

Although causation between brodalumab and SIB has not been demonstrated, it remains imperative that prescribers diligently assess patients’ risk of SIB and subsequently their access to appropriate psychiatric services as a precaution, if necessary. This is particularly important for private practice prescribers, who constitute the majority of Medicare D brodalumab claims, because they must ensure collaboration with a multidisciplinary team involving mental health providers. Lastly, considering that the highest number of brodalumab Medicare D claims were in western and southern states, it is critical to note that those 2 regions also harbor comparatively fewer mental health facilities that accept Medicare than other regions of the country.⁷ Prescribers in western and southern states must be mindful of mental health coverage limitations when treating psoriasis patients with brodalumab.

The increase in the number of claims, beneficiaries, and prescribers of brodalumab during its first 3 years of availability might be attributed to its efficacy and safety. On the other hand, the boxed warning and REMS associated with brodalumab might have led to underutilization of this drug compared to other IL-17 inhibitors.

Our analysis is limited by its representative restriction to Medicare patients. There also are limited data on brodalumab given its novelty. Individual attributes of prescribers with fewer than 11 annual claims for brodalumab could not be obtained because of dataset regulations; however, aggregated utilization statistics provide an indication of brodalumab prescribing patterns among all providers. Furthermore, during this analysis, data on the Medicare D database were limited to 2013 through 2020. Studies are needed to determine prescribing patterns of brodalumab since this study period.

To the Editor:

Brodalumab, a monoclonal antibody targeting IL-17RA, was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of moderate to severe chronic plaque psoriasis. The drug is the only biologic agent available for the treatment of psoriasis for which a psoriasis area severity index score of 100 is a primary end point.^1,2 Brodalumab is associated with an FDA boxed warning due to an increased risk for suicidal ideation and behavior (SIB), including completed suicides, during clinical trials.

We sought to characterize national utilization of this effective yet underutilized drug among Medicare beneficiaries by surveying the Medicare Part D Prescriber dataset.³ We tabulated brodalumab utilization statistics and characteristics of high-volume prescribers who had 11 or more annual claims for brodalumab.

Despite its associated boxed warning, the number of Medicare D claims for brodalumab increased by 1756 from 2017 to 2019, surpassing $7 million in costs by 2019. The number of beneficiaries also increased from 11 to 292—a 415.2% annual increase in beneficiaries for whom brodalumab was prescribed (Table 1).

In addition, states in the West and South had the highest utilization rates of brodalumab in 2019. There also was an increasing trend toward high-volume prescribers of brodalumab, with private practice clinicians constituting the majority (Table 2).

There was a substantial increase in advanced practice providers including nurse practitioners and physician assistants who were brodalumab prescribers. Although this trend might promote greater access to brodalumab, it is vital to ensure that advanced practice providers receive targeted training to properly understand the complexities of treatment with brodalumab.

Although the utilization of brodalumab has increased since 2017 (P<.001), it is still underutilized compared to the other IL-17 inhibitors secukinumab and ixekizumab. Secukinumab was FDA approved for the treatment of moderate to severe plaque psoriasis in 2015, followed by ixekizumab in 2016.⁴

According to the Medicare Part D database, both secukinumab and ixekizumab had a higher number of total claims and prescribers compared to brodalumab in the years of their debut.³ In 2015, there were 3593 claims for and 862 prescribers of secukinumab; in 2016, there were 1731 claims for and 681 prescribers of ixekizumab. In contrast, there were only 29 claims for and 11 prescribers of brodalumab in 2017, the year that the drug was approved by the FDA. During the same 3-year period, secukinumab and ixekizumab had a substantially greater number of claims—totals of 176,823 and 55,289, respectively—than brodalumab. The higher number of claims for secukinumab and ixekizumab compared to brodalumab may reflect clinicians’ increasing confidence in prescribing those drugs, given their long-term safety and efficacy. In addition, secukinumab and ixekizumab do not require completion of a Risk Evaluation and Mitigation Strategy (REMS) program, which makes them more readily prescribable.³

Overall, most experts agree that there is no increase in the risk for suicide associated with brodalumab compared to the general population. A 2-year pharmacovigilance report on brodalumab supports the safety of this drug.⁵ All participants who completed suicide during the clinical trials harbored an underlying psychiatric disorder or stressor(s).⁶

Although causation between brodalumab and SIB has not been demonstrated, it remains imperative that prescribers diligently assess patients’ risk of SIB and subsequently their access to appropriate psychiatric services as a precaution, if necessary. This is particularly important for private practice prescribers, who constitute the majority of Medicare D brodalumab claims, because they must ensure collaboration with a multidisciplinary team involving mental health providers. Lastly, considering that the highest number of brodalumab Medicare D claims were in western and southern states, it is critical to note that those 2 regions also harbor comparatively fewer mental health facilities that accept Medicare than other regions of the country.⁷ Prescribers in western and southern states must be mindful of mental health coverage limitations when treating psoriasis patients with brodalumab.

The increase in the number of claims, beneficiaries, and prescribers of brodalumab during its first 3 years of availability might be attributed to its efficacy and safety. On the other hand, the boxed warning and REMS associated with brodalumab might have led to underutilization of this drug compared to other IL-17 inhibitors.

Our analysis is limited by its representative restriction to Medicare patients. There also are limited data on brodalumab given its novelty. Individual attributes of prescribers with fewer than 11 annual claims for brodalumab could not be obtained because of dataset regulations; however, aggregated utilization statistics provide an indication of brodalumab prescribing patterns among all providers. Furthermore, during this analysis, data on the Medicare D database were limited to 2013 through 2020. Studies are needed to determine prescribing patterns of brodalumab since this study period.

To the Editor:

Brodalumab, a monoclonal antibody targeting IL-17RA, was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of moderate to severe chronic plaque psoriasis. The drug is the only biologic agent available for the treatment of psoriasis for which a psoriasis area severity index score of 100 is a primary end point.^1,2 Brodalumab is associated with an FDA boxed warning due to an increased risk for suicidal ideation and behavior (SIB), including completed suicides, during clinical trials.

We sought to characterize national utilization of this effective yet underutilized drug among Medicare beneficiaries by surveying the Medicare Part D Prescriber dataset.³ We tabulated brodalumab utilization statistics and characteristics of high-volume prescribers who had 11 or more annual claims for brodalumab.

Despite its associated boxed warning, the number of Medicare D claims for brodalumab increased by 1756 from 2017 to 2019, surpassing $7 million in costs by 2019. The number of beneficiaries also increased from 11 to 292—a 415.2% annual increase in beneficiaries for whom brodalumab was prescribed (Table 1).

In addition, states in the West and South had the highest utilization rates of brodalumab in 2019. There also was an increasing trend toward high-volume prescribers of brodalumab, with private practice clinicians constituting the majority (Table 2).

There was a substantial increase in advanced practice providers including nurse practitioners and physician assistants who were brodalumab prescribers. Although this trend might promote greater access to brodalumab, it is vital to ensure that advanced practice providers receive targeted training to properly understand the complexities of treatment with brodalumab.

Although the utilization of brodalumab has increased since 2017 (P<.001), it is still underutilized compared to the other IL-17 inhibitors secukinumab and ixekizumab. Secukinumab was FDA approved for the treatment of moderate to severe plaque psoriasis in 2015, followed by ixekizumab in 2016.⁴

According to the Medicare Part D database, both secukinumab and ixekizumab had a higher number of total claims and prescribers compared to brodalumab in the years of their debut.³ In 2015, there were 3593 claims for and 862 prescribers of secukinumab; in 2016, there were 1731 claims for and 681 prescribers of ixekizumab. In contrast, there were only 29 claims for and 11 prescribers of brodalumab in 2017, the year that the drug was approved by the FDA. During the same 3-year period, secukinumab and ixekizumab had a substantially greater number of claims—totals of 176,823 and 55,289, respectively—than brodalumab. The higher number of claims for secukinumab and ixekizumab compared to brodalumab may reflect clinicians’ increasing confidence in prescribing those drugs, given their long-term safety and efficacy. In addition, secukinumab and ixekizumab do not require completion of a Risk Evaluation and Mitigation Strategy (REMS) program, which makes them more readily prescribable.³

Overall, most experts agree that there is no increase in the risk for suicide associated with brodalumab compared to the general population. A 2-year pharmacovigilance report on brodalumab supports the safety of this drug.⁵ All participants who completed suicide during the clinical trials harbored an underlying psychiatric disorder or stressor(s).⁶

Although causation between brodalumab and SIB has not been demonstrated, it remains imperative that prescribers diligently assess patients’ risk of SIB and subsequently their access to appropriate psychiatric services as a precaution, if necessary. This is particularly important for private practice prescribers, who constitute the majority of Medicare D brodalumab claims, because they must ensure collaboration with a multidisciplinary team involving mental health providers. Lastly, considering that the highest number of brodalumab Medicare D claims were in western and southern states, it is critical to note that those 2 regions also harbor comparatively fewer mental health facilities that accept Medicare than other regions of the country.⁷ Prescribers in western and southern states must be mindful of mental health coverage limitations when treating psoriasis patients with brodalumab.

The increase in the number of claims, beneficiaries, and prescribers of brodalumab during its first 3 years of availability might be attributed to its efficacy and safety. On the other hand, the boxed warning and REMS associated with brodalumab might have led to underutilization of this drug compared to other IL-17 inhibitors.

Our analysis is limited by its representative restriction to Medicare patients. There also are limited data on brodalumab given its novelty. Individual attributes of prescribers with fewer than 11 annual claims for brodalumab could not be obtained because of dataset regulations; however, aggregated utilization statistics provide an indication of brodalumab prescribing patterns among all providers. Furthermore, during this analysis, data on the Medicare D database were limited to 2013 through 2020. Studies are needed to determine prescribing patterns of brodalumab since this study period.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting 7% of adults and 13% of children in the United States.^1,2 Atopic dermatitis is characterized by pruritus, dry skin, and pain, all of which can negatively impact quality of life and put patients at higher risk for psychiatric comorbidities such as anxiety and depression.³ The pathogenesis of AD is multifactorial, involving genetics, epidermal barrier dysfunction, and immune dysregulation. Overactivation of helper T cell (T_H2) pathway cytokines, including IL-4, IL-13, and IL-31, is thought to propagate both inflammation and pruritus, which are central to AD. The JAK-STAT signaling pathway plays a pivotal role in the immune system dysregulation and exaggeration of T_H2 cell response, making JAK-STAT inhibitors (or JAK inhibitors) strong theoretical candidates for the treatment of AD.⁴ In humans, the Janus kinases are composed of 4 different members—JAK1, JAK2, JAK3, and tyrosine kinase 2—all of which can be targeted by JAK inhibitors.⁵

JAK inhibitors such as tofacitinib have already been approved by the US Food and Drug Administration (FDA) to treat various inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, and psoriatic arthritis; other JAK inhibitors such as baricitinib are only approved for patients with rheumatoid arthritis.^6,7 The success of these small molecule inhibitors in these immune-mediated conditions make them attractive candidates for the treatment of AD. Several JAK inhibitors are in phase 2 and phase 3 clinical trials as oral therapies (moderate to severe AD) or as topical treatments (mild to moderate AD). Currently, ruxolitinib (RUX) is the only topical JAK inhibitor that is FDA approved for the treatment of AD in the United States.⁸ In this editorial, we focus on recent trials of JAK inhibitors tested in patients with AD, including topical RUX, as well as oral abrocitinib, upadacitinib, and baricitinib.

Topical RUX in AD

Ruxolitinib is a topical JAK1/2 small molecule inhibitor approved by the FDA for the treatment of AD in 2021. In a randomized trial by Kim et al⁹ in 2020, all tested regimens of RUX demonstrated significant improvement in eczema area and severity index (EASI) scores vs vehicle; notably, RUX cream 1.5% applied twice daily achieved the greatest mean percentage change in baseline EASI score vs vehicle at 4 weeks (76.1% vs 15.5%; P<.0001). Ruxolitinib cream was well tolerated through week 8 of the trial, and all adverse events (AEs) were mild to moderate in severity and comparable to those in the vehicle group.⁹

Topical JAK inhibitors appear to be effective for mild to moderate AD and have had an acceptable safety profile in clinical trials thus far. Although topical corticosteroids and calcineurin inhibitors can have great clinical benefit in AD, they are recommended for short-term use given side effects such as thinning of the skin, burning, or telangiectasia formation.^10,11 The hope is that topical JAK inhibitors may be an alternative to standard topical treatments for AD, as they can be used for longer periods due to a safer side-effect profile.

Oral JAK Inhibitors in AD

Several oral JAK inhibitors are undergoing investigation for the systemic treatment of moderate to severe AD. Abrocitinib is an oral JAK1 inhibitor that has demonstrated efficacy in several phase 3 trials in patients with moderate to severe AD. In a 2021 trial, patients were randomized in a 2:2:2:1 ratio to receive abrocitinib 200 mg daily, abrocitinib 100 mg daily, subcutaneous dupilumab 300 mg every other week, or placebo, respectively.¹² Patients in both abrocitinib groups showed significant improvement in AD vs placebo, and EASI-75 response was achieved in 70.3%, 58.7%, 58.1%, and 27.1% of patients, respectively (P<.001 for both abrocitinib doses vs placebo). Adverse events occurred more frequently in the abrocitinib 200-mg group vs placebo. Nausea, acne, nasopharyngitis, and headache were the most frequently reported AEs with abrocitinib.¹² Another phase 3 trial by Silverberg et al¹³ (N=391) had similar treatment results, with 38.1% of participants receiving abrocitinib 200 mg and 28.4% of participants receiving abrocitinib 100 mg achieving investigator global assessment scores of 0 (clear) or 1 (almost clear) vs 9.1% of participants receiving placebo (P<.001). Abrocitinib was well tolerated in this trial with few serious AEs (ie, herpangina [0.6%], pneumonia [0.6%]).¹³ In both trials, there were rare instances of laboratory values indicating thrombocytopenia with the 200-mg dose (0.9%¹² and 3.2%¹³) without any clinical manifestations. Although a decrease in platelets was observed, no thrombocytopenia occurred in the abrocitinib 100-mg group in the latter trial.¹³

Baricitinib is another oral inhibitor of JAK1 and JAK2 with potential for the treatment of AD. One randomized trial (N=329) demonstrated its efficacy in combination with a topical corticosteroid (TCS). At 16 weeks, a higher number of participants treated with baricitinib and TCS achieved investigator global assessment scores of 0 (clear) or 1 (almost clear) compared to those who received placebo and TCS (31% with baricitinib 4 mg + TCS, 24% with baricitinib 2 mg + TCS, and 15% with placebo + TCS).¹⁴ Similarly, in BREEZE-AD5,another phase 3 trial (N=440), baricitinib monotherapy demonstrated a higher rate of treatment success vs placebo.¹⁵ Specifically, 13% of patients treated with baricitinib 1 mg and 30% of those treated with baricitinib 2 mg achieved 75% or greater reduction in EASI scores compared to 8% in the placebo group. The most common AEs associated with baricitinib were nasopharyngitis and headache. Adverse events occurred with similar frequency across both experimental and control groups.¹⁵ Reich et al¹⁴ demonstrated a higher overall rate of AEs—most commonly nasopharyngitis, upper respiratory tract infections, and folliculitis—in baricitinib-treated patients; however, serious AEs occurred with similar frequency across all groups, including the control group.

The selective JAK1 inhibitor upadacitinib also is undergoing testing in treating moderate to severe AD. In one trial, 167 patients were randomized to once daily oral upadacitinib 7.5 mg, 15 mg, or 30 mg or placebo.¹⁶ All doses of upadacitinib demonstrated considerably higher percentage improvements from baseline in EASI scores compared to placebo at 16 weeks with a clear dose-response relationship (39%, 62%, and 74% vs 23%, respectively). In this trial, there were no dose-limiting safety events. Serious AEs were infrequent, occurring in 4.8%, 2.4%, and 0% of upadacitinib groups vs 2.5% for placebo. The serious AEs observed with upadacitinib were 1 case of appendicitis, lower jaw pericoronitis in a patient with a history of repeated tooth infections, and an exacerbation of AD.¹⁶

Tofacitinib, another JAK inhibitor, has been shown to increase the risk for blood clots and death in a large trial in the treatment of rheumatoid arthritis. Following this study, the FDA is requiring black box warnings for tofacitinib and also for the 2 JAK inhibitors baricitinib and upadacitinib regarding the risks for heart-related events, cancer, blood clots, and death. Given that these medications share a similar mechanism of action to tofacitinib, they may have similar risks, though they have not yet been fully evaluated in large safety trials.¹⁷

With more recent investigation into novel therapeutics for AD, oral JAK inhibitors may play an important role in the future to treat patients with moderate to severe AD with inadequate response or contraindications to other systemic therapies. In trials thus far, oral JAK inhibitors have exhibited acceptable safety profiles and have demonstrated treatment success in AD. More randomized, controlled, phase 3 studies with larger patient populations are required to confirm their potential as effective treatments and elucidate their long-term safety.

Deucravacitinib in Psoriasis

Deucravacitinib is a first-in-class, oral, selective TYK2 inhibitor currently undergoing testing for the treatment of psoriasis. A randomized phase 2 trial (N=267) found that deucravacitinib was more effective than placebo in treating chronic plaque psoriasis at doses of 3 to 12 mg daily.¹⁸ The percentage of participants with a 75% or greater reduction from baseline in the psoriasis area and severity index score was 7% with placebo, 9% with deucravacitinib 3 mg every other day (P=.49 vs placebo), 39% with 3 mg once daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). The most commonly reported AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection. Adverse events occurred in 51% of participants in the control group and in 55% to 80% of those in the experimental groups. Additionally, there was 1 reported case of melanoma (stage 0) 96 days after the start of treatment in a patient in the 3-mg once-daily group. Serious AEs occurred in only 0% to 2% of participants who received deucravacitinib.¹⁸

Two phase 3 trials—POETYK PSO-1 and POETYK PSO-2 (N=1686)—found deucravacitinib to be notably more effective than both placebo and apremilast in treating psoriasis.¹⁹ Among participants receiving deucravacitinib 6 mg daily, 58.7% and 53.6% in the 2 respective trials achieved psoriasis area and severity index 75 response vs 12.7% and 9.4% receiving placebo and 35.1% and 40.2% receiving apremilast. Overall, the treatment was well tolerated, with a low rate of discontinuation of deucravacitinib due to AEs (2.4% of patients on deucravacitinib compared to 3.8% on placebo and 5.2% on apremilast). The most frequently observed AEs with deucravacitinib were nasopharyngitis and upper respiratory tract infection. The full results of these trials are expected to be published soon.^19,20

Final Thoughts

Overall, JAK inhibitors are a novel class of therapeutics that may have further success in the treatment of other dermatologic conditions that negatively affect patients’ quality of life and productivity. We should look forward to additional successful trials with these promising medications.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting 7% of adults and 13% of children in the United States.^1,2 Atopic dermatitis is characterized by pruritus, dry skin, and pain, all of which can negatively impact quality of life and put patients at higher risk for psychiatric comorbidities such as anxiety and depression.³ The pathogenesis of AD is multifactorial, involving genetics, epidermal barrier dysfunction, and immune dysregulation. Overactivation of helper T cell (T_H2) pathway cytokines, including IL-4, IL-13, and IL-31, is thought to propagate both inflammation and pruritus, which are central to AD. The JAK-STAT signaling pathway plays a pivotal role in the immune system dysregulation and exaggeration of T_H2 cell response, making JAK-STAT inhibitors (or JAK inhibitors) strong theoretical candidates for the treatment of AD.⁴ In humans, the Janus kinases are composed of 4 different members—JAK1, JAK2, JAK3, and tyrosine kinase 2—all of which can be targeted by JAK inhibitors.⁵

JAK inhibitors such as tofacitinib have already been approved by the US Food and Drug Administration (FDA) to treat various inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, and psoriatic arthritis; other JAK inhibitors such as baricitinib are only approved for patients with rheumatoid arthritis.^6,7 The success of these small molecule inhibitors in these immune-mediated conditions make them attractive candidates for the treatment of AD. Several JAK inhibitors are in phase 2 and phase 3 clinical trials as oral therapies (moderate to severe AD) or as topical treatments (mild to moderate AD). Currently, ruxolitinib (RUX) is the only topical JAK inhibitor that is FDA approved for the treatment of AD in the United States.⁸ In this editorial, we focus on recent trials of JAK inhibitors tested in patients with AD, including topical RUX, as well as oral abrocitinib, upadacitinib, and baricitinib.

Topical RUX in AD

Ruxolitinib is a topical JAK1/2 small molecule inhibitor approved by the FDA for the treatment of AD in 2021. In a randomized trial by Kim et al⁹ in 2020, all tested regimens of RUX demonstrated significant improvement in eczema area and severity index (EASI) scores vs vehicle; notably, RUX cream 1.5% applied twice daily achieved the greatest mean percentage change in baseline EASI score vs vehicle at 4 weeks (76.1% vs 15.5%; P<.0001). Ruxolitinib cream was well tolerated through week 8 of the trial, and all adverse events (AEs) were mild to moderate in severity and comparable to those in the vehicle group.⁹

Topical JAK inhibitors appear to be effective for mild to moderate AD and have had an acceptable safety profile in clinical trials thus far. Although topical corticosteroids and calcineurin inhibitors can have great clinical benefit in AD, they are recommended for short-term use given side effects such as thinning of the skin, burning, or telangiectasia formation.^10,11 The hope is that topical JAK inhibitors may be an alternative to standard topical treatments for AD, as they can be used for longer periods due to a safer side-effect profile.

Oral JAK Inhibitors in AD

Several oral JAK inhibitors are undergoing investigation for the systemic treatment of moderate to severe AD. Abrocitinib is an oral JAK1 inhibitor that has demonstrated efficacy in several phase 3 trials in patients with moderate to severe AD. In a 2021 trial, patients were randomized in a 2:2:2:1 ratio to receive abrocitinib 200 mg daily, abrocitinib 100 mg daily, subcutaneous dupilumab 300 mg every other week, or placebo, respectively.¹² Patients in both abrocitinib groups showed significant improvement in AD vs placebo, and EASI-75 response was achieved in 70.3%, 58.7%, 58.1%, and 27.1% of patients, respectively (P<.001 for both abrocitinib doses vs placebo). Adverse events occurred more frequently in the abrocitinib 200-mg group vs placebo. Nausea, acne, nasopharyngitis, and headache were the most frequently reported AEs with abrocitinib.¹² Another phase 3 trial by Silverberg et al¹³ (N=391) had similar treatment results, with 38.1% of participants receiving abrocitinib 200 mg and 28.4% of participants receiving abrocitinib 100 mg achieving investigator global assessment scores of 0 (clear) or 1 (almost clear) vs 9.1% of participants receiving placebo (P<.001). Abrocitinib was well tolerated in this trial with few serious AEs (ie, herpangina [0.6%], pneumonia [0.6%]).¹³ In both trials, there were rare instances of laboratory values indicating thrombocytopenia with the 200-mg dose (0.9%¹² and 3.2%¹³) without any clinical manifestations. Although a decrease in platelets was observed, no thrombocytopenia occurred in the abrocitinib 100-mg group in the latter trial.¹³

Baricitinib is another oral inhibitor of JAK1 and JAK2 with potential for the treatment of AD. One randomized trial (N=329) demonstrated its efficacy in combination with a topical corticosteroid (TCS). At 16 weeks, a higher number of participants treated with baricitinib and TCS achieved investigator global assessment scores of 0 (clear) or 1 (almost clear) compared to those who received placebo and TCS (31% with baricitinib 4 mg + TCS, 24% with baricitinib 2 mg + TCS, and 15% with placebo + TCS).¹⁴ Similarly, in BREEZE-AD5,another phase 3 trial (N=440), baricitinib monotherapy demonstrated a higher rate of treatment success vs placebo.¹⁵ Specifically, 13% of patients treated with baricitinib 1 mg and 30% of those treated with baricitinib 2 mg achieved 75% or greater reduction in EASI scores compared to 8% in the placebo group. The most common AEs associated with baricitinib were nasopharyngitis and headache. Adverse events occurred with similar frequency across both experimental and control groups.¹⁵ Reich et al¹⁴ demonstrated a higher overall rate of AEs—most commonly nasopharyngitis, upper respiratory tract infections, and folliculitis—in baricitinib-treated patients; however, serious AEs occurred with similar frequency across all groups, including the control group.

The selective JAK1 inhibitor upadacitinib also is undergoing testing in treating moderate to severe AD. In one trial, 167 patients were randomized to once daily oral upadacitinib 7.5 mg, 15 mg, or 30 mg or placebo.¹⁶ All doses of upadacitinib demonstrated considerably higher percentage improvements from baseline in EASI scores compared to placebo at 16 weeks with a clear dose-response relationship (39%, 62%, and 74% vs 23%, respectively). In this trial, there were no dose-limiting safety events. Serious AEs were infrequent, occurring in 4.8%, 2.4%, and 0% of upadacitinib groups vs 2.5% for placebo. The serious AEs observed with upadacitinib were 1 case of appendicitis, lower jaw pericoronitis in a patient with a history of repeated tooth infections, and an exacerbation of AD.¹⁶

Tofacitinib, another JAK inhibitor, has been shown to increase the risk for blood clots and death in a large trial in the treatment of rheumatoid arthritis. Following this study, the FDA is requiring black box warnings for tofacitinib and also for the 2 JAK inhibitors baricitinib and upadacitinib regarding the risks for heart-related events, cancer, blood clots, and death. Given that these medications share a similar mechanism of action to tofacitinib, they may have similar risks, though they have not yet been fully evaluated in large safety trials.¹⁷

With more recent investigation into novel therapeutics for AD, oral JAK inhibitors may play an important role in the future to treat patients with moderate to severe AD with inadequate response or contraindications to other systemic therapies. In trials thus far, oral JAK inhibitors have exhibited acceptable safety profiles and have demonstrated treatment success in AD. More randomized, controlled, phase 3 studies with larger patient populations are required to confirm their potential as effective treatments and elucidate their long-term safety.

Deucravacitinib in Psoriasis

Deucravacitinib is a first-in-class, oral, selective TYK2 inhibitor currently undergoing testing for the treatment of psoriasis. A randomized phase 2 trial (N=267) found that deucravacitinib was more effective than placebo in treating chronic plaque psoriasis at doses of 3 to 12 mg daily.¹⁸ The percentage of participants with a 75% or greater reduction from baseline in the psoriasis area and severity index score was 7% with placebo, 9% with deucravacitinib 3 mg every other day (P=.49 vs placebo), 39% with 3 mg once daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). The most commonly reported AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection. Adverse events occurred in 51% of participants in the control group and in 55% to 80% of those in the experimental groups. Additionally, there was 1 reported case of melanoma (stage 0) 96 days after the start of treatment in a patient in the 3-mg once-daily group. Serious AEs occurred in only 0% to 2% of participants who received deucravacitinib.¹⁸

Two phase 3 trials—POETYK PSO-1 and POETYK PSO-2 (N=1686)—found deucravacitinib to be notably more effective than both placebo and apremilast in treating psoriasis.¹⁹ Among participants receiving deucravacitinib 6 mg daily, 58.7% and 53.6% in the 2 respective trials achieved psoriasis area and severity index 75 response vs 12.7% and 9.4% receiving placebo and 35.1% and 40.2% receiving apremilast. Overall, the treatment was well tolerated, with a low rate of discontinuation of deucravacitinib due to AEs (2.4% of patients on deucravacitinib compared to 3.8% on placebo and 5.2% on apremilast). The most frequently observed AEs with deucravacitinib were nasopharyngitis and upper respiratory tract infection. The full results of these trials are expected to be published soon.^19,20

Final Thoughts

Overall, JAK inhibitors are a novel class of therapeutics that may have further success in the treatment of other dermatologic conditions that negatively affect patients’ quality of life and productivity. We should look forward to additional successful trials with these promising medications.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting 7% of adults and 13% of children in the United States.^1,2 Atopic dermatitis is characterized by pruritus, dry skin, and pain, all of which can negatively impact quality of life and put patients at higher risk for psychiatric comorbidities such as anxiety and depression.³ The pathogenesis of AD is multifactorial, involving genetics, epidermal barrier dysfunction, and immune dysregulation. Overactivation of helper T cell (T_H2) pathway cytokines, including IL-4, IL-13, and IL-31, is thought to propagate both inflammation and pruritus, which are central to AD. The JAK-STAT signaling pathway plays a pivotal role in the immune system dysregulation and exaggeration of T_H2 cell response, making JAK-STAT inhibitors (or JAK inhibitors) strong theoretical candidates for the treatment of AD.⁴ In humans, the Janus kinases are composed of 4 different members—JAK1, JAK2, JAK3, and tyrosine kinase 2—all of which can be targeted by JAK inhibitors.⁵

JAK inhibitors such as tofacitinib have already been approved by the US Food and Drug Administration (FDA) to treat various inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, and psoriatic arthritis; other JAK inhibitors such as baricitinib are only approved for patients with rheumatoid arthritis.^6,7 The success of these small molecule inhibitors in these immune-mediated conditions make them attractive candidates for the treatment of AD. Several JAK inhibitors are in phase 2 and phase 3 clinical trials as oral therapies (moderate to severe AD) or as topical treatments (mild to moderate AD). Currently, ruxolitinib (RUX) is the only topical JAK inhibitor that is FDA approved for the treatment of AD in the United States.⁸ In this editorial, we focus on recent trials of JAK inhibitors tested in patients with AD, including topical RUX, as well as oral abrocitinib, upadacitinib, and baricitinib.

Topical RUX in AD

Ruxolitinib is a topical JAK1/2 small molecule inhibitor approved by the FDA for the treatment of AD in 2021. In a randomized trial by Kim et al⁹ in 2020, all tested regimens of RUX demonstrated significant improvement in eczema area and severity index (EASI) scores vs vehicle; notably, RUX cream 1.5% applied twice daily achieved the greatest mean percentage change in baseline EASI score vs vehicle at 4 weeks (76.1% vs 15.5%; P<.0001). Ruxolitinib cream was well tolerated through week 8 of the trial, and all adverse events (AEs) were mild to moderate in severity and comparable to those in the vehicle group.⁹

Topical JAK inhibitors appear to be effective for mild to moderate AD and have had an acceptable safety profile in clinical trials thus far. Although topical corticosteroids and calcineurin inhibitors can have great clinical benefit in AD, they are recommended for short-term use given side effects such as thinning of the skin, burning, or telangiectasia formation.^10,11 The hope is that topical JAK inhibitors may be an alternative to standard topical treatments for AD, as they can be used for longer periods due to a safer side-effect profile.

Oral JAK Inhibitors in AD

Several oral JAK inhibitors are undergoing investigation for the systemic treatment of moderate to severe AD. Abrocitinib is an oral JAK1 inhibitor that has demonstrated efficacy in several phase 3 trials in patients with moderate to severe AD. In a 2021 trial, patients were randomized in a 2:2:2:1 ratio to receive abrocitinib 200 mg daily, abrocitinib 100 mg daily, subcutaneous dupilumab 300 mg every other week, or placebo, respectively.¹² Patients in both abrocitinib groups showed significant improvement in AD vs placebo, and EASI-75 response was achieved in 70.3%, 58.7%, 58.1%, and 27.1% of patients, respectively (P<.001 for both abrocitinib doses vs placebo). Adverse events occurred more frequently in the abrocitinib 200-mg group vs placebo. Nausea, acne, nasopharyngitis, and headache were the most frequently reported AEs with abrocitinib.¹² Another phase 3 trial by Silverberg et al¹³ (N=391) had similar treatment results, with 38.1% of participants receiving abrocitinib 200 mg and 28.4% of participants receiving abrocitinib 100 mg achieving investigator global assessment scores of 0 (clear) or 1 (almost clear) vs 9.1% of participants receiving placebo (P<.001). Abrocitinib was well tolerated in this trial with few serious AEs (ie, herpangina [0.6%], pneumonia [0.6%]).¹³ In both trials, there were rare instances of laboratory values indicating thrombocytopenia with the 200-mg dose (0.9%¹² and 3.2%¹³) without any clinical manifestations. Although a decrease in platelets was observed, no thrombocytopenia occurred in the abrocitinib 100-mg group in the latter trial.¹³

Baricitinib is another oral inhibitor of JAK1 and JAK2 with potential for the treatment of AD. One randomized trial (N=329) demonstrated its efficacy in combination with a topical corticosteroid (TCS). At 16 weeks, a higher number of participants treated with baricitinib and TCS achieved investigator global assessment scores of 0 (clear) or 1 (almost clear) compared to those who received placebo and TCS (31% with baricitinib 4 mg + TCS, 24% with baricitinib 2 mg + TCS, and 15% with placebo + TCS).¹⁴ Similarly, in BREEZE-AD5,another phase 3 trial (N=440), baricitinib monotherapy demonstrated a higher rate of treatment success vs placebo.¹⁵ Specifically, 13% of patients treated with baricitinib 1 mg and 30% of those treated with baricitinib 2 mg achieved 75% or greater reduction in EASI scores compared to 8% in the placebo group. The most common AEs associated with baricitinib were nasopharyngitis and headache. Adverse events occurred with similar frequency across both experimental and control groups.¹⁵ Reich et al¹⁴ demonstrated a higher overall rate of AEs—most commonly nasopharyngitis, upper respiratory tract infections, and folliculitis—in baricitinib-treated patients; however, serious AEs occurred with similar frequency across all groups, including the control group.

The selective JAK1 inhibitor upadacitinib also is undergoing testing in treating moderate to severe AD. In one trial, 167 patients were randomized to once daily oral upadacitinib 7.5 mg, 15 mg, or 30 mg or placebo.¹⁶ All doses of upadacitinib demonstrated considerably higher percentage improvements from baseline in EASI scores compared to placebo at 16 weeks with a clear dose-response relationship (39%, 62%, and 74% vs 23%, respectively). In this trial, there were no dose-limiting safety events. Serious AEs were infrequent, occurring in 4.8%, 2.4%, and 0% of upadacitinib groups vs 2.5% for placebo. The serious AEs observed with upadacitinib were 1 case of appendicitis, lower jaw pericoronitis in a patient with a history of repeated tooth infections, and an exacerbation of AD.¹⁶

Tofacitinib, another JAK inhibitor, has been shown to increase the risk for blood clots and death in a large trial in the treatment of rheumatoid arthritis. Following this study, the FDA is requiring black box warnings for tofacitinib and also for the 2 JAK inhibitors baricitinib and upadacitinib regarding the risks for heart-related events, cancer, blood clots, and death. Given that these medications share a similar mechanism of action to tofacitinib, they may have similar risks, though they have not yet been fully evaluated in large safety trials.¹⁷

With more recent investigation into novel therapeutics for AD, oral JAK inhibitors may play an important role in the future to treat patients with moderate to severe AD with inadequate response or contraindications to other systemic therapies. In trials thus far, oral JAK inhibitors have exhibited acceptable safety profiles and have demonstrated treatment success in AD. More randomized, controlled, phase 3 studies with larger patient populations are required to confirm their potential as effective treatments and elucidate their long-term safety.

Deucravacitinib in Psoriasis

Deucravacitinib is a first-in-class, oral, selective TYK2 inhibitor currently undergoing testing for the treatment of psoriasis. A randomized phase 2 trial (N=267) found that deucravacitinib was more effective than placebo in treating chronic plaque psoriasis at doses of 3 to 12 mg daily.¹⁸ The percentage of participants with a 75% or greater reduction from baseline in the psoriasis area and severity index score was 7% with placebo, 9% with deucravacitinib 3 mg every other day (P=.49 vs placebo), 39% with 3 mg once daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). The most commonly reported AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection. Adverse events occurred in 51% of participants in the control group and in 55% to 80% of those in the experimental groups. Additionally, there was 1 reported case of melanoma (stage 0) 96 days after the start of treatment in a patient in the 3-mg once-daily group. Serious AEs occurred in only 0% to 2% of participants who received deucravacitinib.¹⁸

Two phase 3 trials—POETYK PSO-1 and POETYK PSO-2 (N=1686)—found deucravacitinib to be notably more effective than both placebo and apremilast in treating psoriasis.¹⁹ Among participants receiving deucravacitinib 6 mg daily, 58.7% and 53.6% in the 2 respective trials achieved psoriasis area and severity index 75 response vs 12.7% and 9.4% receiving placebo and 35.1% and 40.2% receiving apremilast. Overall, the treatment was well tolerated, with a low rate of discontinuation of deucravacitinib due to AEs (2.4% of patients on deucravacitinib compared to 3.8% on placebo and 5.2% on apremilast). The most frequently observed AEs with deucravacitinib were nasopharyngitis and upper respiratory tract infection. The full results of these trials are expected to be published soon.^19,20

Final Thoughts

Overall, JAK inhibitors are a novel class of therapeutics that may have further success in the treatment of other dermatologic conditions that negatively affect patients’ quality of life and productivity. We should look forward to additional successful trials with these promising medications.