Commentary: Abrocitinib, Malignancy Risk, and S aureus in AD, August 2023

The excellent short-term efficacy of the drug was well maintained up to 48 weeks, with only a slight loss of efficacy over time. Abrocitinib is a small molecule. We wouldn't expect a loss of efficacy due to the anti-drug antibodies that we see for large-molecule biologic drugs. I suspect that the slight loss of efficacy over time is a form of tachyphylaxis that is, to my thinking, probably due to poor adherence. Shocking, I know! Patients may not be fully adherent to treatment, even in a clinical trial. I think we should encourage patients to use 7-day pill boxes to aid better long-term adherence and outcomes.

Long-term safety is a critical issue with any new drug, certainly with a Janus kinase (JAK) inhibitor. Reich and colleagues concluded, "The long-term safety profile was manageable and consistent with previous reports." That conclusion seems reasonable to me. The most common side effects were upper respiratory tract infections. There may be a slight signal for increased risk for oral herpes infection, particularly at the higher dose. If this safety profile endures with longer-term data in larger numbers of people, it will be very reassuring.

The study by Wan and colleagues is another extremely well-done, important study by the premier dermatoepidemiology research team at the University of Pennsylvania. The study used an outstanding database from the United Kingdom that encompassed the clinical care experience of hundreds of thousands of children and adults with atopic dermatitis and millions of control patients without atopic dermatitis. With this many patients, the study has tremendous power to detect risk differences between groups.

With all that power, this study’s findings are very reassuring that there is no meaningful overall increased risk for malignancy in children or adults with atopic dermatitis. And while there was a statistically significant increased risk for lymphoma in children with severe atopic dermatitis, that risk is small … very small. Similarly, adults with severe AD had a twofold higher risk for noncutaneous T-cell lymphoma (CTCL), but since non-CTCL is rare, patients with severe AD shouldn't lose any sleep over it..

Simpson and colleagues' study of the effect of dupilumab on Staphylococcus aureus surprised me. Of course, we could expect that S aureus counts would be reduced with dupilumab; as barrier function is restored, surely S aureus counts would go down too. But, fascinatingly, with dupilumab treatment, S aureus counts decreased almost immediately, at both 3 and 7 days, before there was apparent clinical improvement in the skin rash. Simpson and colleagues suggest that the drop in S aureus counts could be due to improvement in immune function when interleukins 4 and 13 are blocked. Whether or not that is true, it is striking how fast S aureus counts improved, long before normal skin barrier function is restored.

Here's a fun fact: Atopic dermatitis is a little less common, about 10% less common, in people born second or later in the birth order. Lisik and colleagues did a meta-analysis of 114 studies and found this marginally lower rate in those born second or later compared with those born first. I'm not sure that there is any clinically meaningful significance to this, but I found it interesting (even though I was born first, and my younger brother had atopic dermatitis).

The excellent short-term efficacy of the drug was well maintained up to 48 weeks, with only a slight loss of efficacy over time. Abrocitinib is a small molecule. We wouldn't expect a loss of efficacy due to the anti-drug antibodies that we see for large-molecule biologic drugs. I suspect that the slight loss of efficacy over time is a form of tachyphylaxis that is, to my thinking, probably due to poor adherence. Shocking, I know! Patients may not be fully adherent to treatment, even in a clinical trial. I think we should encourage patients to use 7-day pill boxes to aid better long-term adherence and outcomes.

Long-term safety is a critical issue with any new drug, certainly with a Janus kinase (JAK) inhibitor. Reich and colleagues concluded, "The long-term safety profile was manageable and consistent with previous reports." That conclusion seems reasonable to me. The most common side effects were upper respiratory tract infections. There may be a slight signal for increased risk for oral herpes infection, particularly at the higher dose. If this safety profile endures with longer-term data in larger numbers of people, it will be very reassuring.

The study by Wan and colleagues is another extremely well-done, important study by the premier dermatoepidemiology research team at the University of Pennsylvania. The study used an outstanding database from the United Kingdom that encompassed the clinical care experience of hundreds of thousands of children and adults with atopic dermatitis and millions of control patients without atopic dermatitis. With this many patients, the study has tremendous power to detect risk differences between groups.

With all that power, this study’s findings are very reassuring that there is no meaningful overall increased risk for malignancy in children or adults with atopic dermatitis. And while there was a statistically significant increased risk for lymphoma in children with severe atopic dermatitis, that risk is small … very small. Similarly, adults with severe AD had a twofold higher risk for noncutaneous T-cell lymphoma (CTCL), but since non-CTCL is rare, patients with severe AD shouldn't lose any sleep over it..

Simpson and colleagues' study of the effect of dupilumab on Staphylococcus aureus surprised me. Of course, we could expect that S aureus counts would be reduced with dupilumab; as barrier function is restored, surely S aureus counts would go down too. But, fascinatingly, with dupilumab treatment, S aureus counts decreased almost immediately, at both 3 and 7 days, before there was apparent clinical improvement in the skin rash. Simpson and colleagues suggest that the drop in S aureus counts could be due to improvement in immune function when interleukins 4 and 13 are blocked. Whether or not that is true, it is striking how fast S aureus counts improved, long before normal skin barrier function is restored.

Here's a fun fact: Atopic dermatitis is a little less common, about 10% less common, in people born second or later in the birth order. Lisik and colleagues did a meta-analysis of 114 studies and found this marginally lower rate in those born second or later compared with those born first. I'm not sure that there is any clinically meaningful significance to this, but I found it interesting (even though I was born first, and my younger brother had atopic dermatitis).

The excellent short-term efficacy of the drug was well maintained up to 48 weeks, with only a slight loss of efficacy over time. Abrocitinib is a small molecule. We wouldn't expect a loss of efficacy due to the anti-drug antibodies that we see for large-molecule biologic drugs. I suspect that the slight loss of efficacy over time is a form of tachyphylaxis that is, to my thinking, probably due to poor adherence. Shocking, I know! Patients may not be fully adherent to treatment, even in a clinical trial. I think we should encourage patients to use 7-day pill boxes to aid better long-term adherence and outcomes.

Long-term safety is a critical issue with any new drug, certainly with a Janus kinase (JAK) inhibitor. Reich and colleagues concluded, "The long-term safety profile was manageable and consistent with previous reports." That conclusion seems reasonable to me. The most common side effects were upper respiratory tract infections. There may be a slight signal for increased risk for oral herpes infection, particularly at the higher dose. If this safety profile endures with longer-term data in larger numbers of people, it will be very reassuring.

The study by Wan and colleagues is another extremely well-done, important study by the premier dermatoepidemiology research team at the University of Pennsylvania. The study used an outstanding database from the United Kingdom that encompassed the clinical care experience of hundreds of thousands of children and adults with atopic dermatitis and millions of control patients without atopic dermatitis. With this many patients, the study has tremendous power to detect risk differences between groups.

With all that power, this study’s findings are very reassuring that there is no meaningful overall increased risk for malignancy in children or adults with atopic dermatitis. And while there was a statistically significant increased risk for lymphoma in children with severe atopic dermatitis, that risk is small … very small. Similarly, adults with severe AD had a twofold higher risk for noncutaneous T-cell lymphoma (CTCL), but since non-CTCL is rare, patients with severe AD shouldn't lose any sleep over it..

Simpson and colleagues' study of the effect of dupilumab on Staphylococcus aureus surprised me. Of course, we could expect that S aureus counts would be reduced with dupilumab; as barrier function is restored, surely S aureus counts would go down too. But, fascinatingly, with dupilumab treatment, S aureus counts decreased almost immediately, at both 3 and 7 days, before there was apparent clinical improvement in the skin rash. Simpson and colleagues suggest that the drop in S aureus counts could be due to improvement in immune function when interleukins 4 and 13 are blocked. Whether or not that is true, it is striking how fast S aureus counts improved, long before normal skin barrier function is restored.

Here's a fun fact: Atopic dermatitis is a little less common, about 10% less common, in people born second or later in the birth order. Lisik and colleagues did a meta-analysis of 114 studies and found this marginally lower rate in those born second or later compared with those born first. I'm not sure that there is any clinically meaningful significance to this, but I found it interesting (even though I was born first, and my younger brother had atopic dermatitis).