The Safety of New Systemics

The approvals of various systemic therapies for skin conditions over the past few years have transformed dermatologists’ ability to treat patients. Instead of “mopping up the mess” by treating symptoms, we can now “turn off the faucet” by targeting the cells that cause these conditions. Despite this massive progress, however, too many clinicians are still hesitant to take advantage of these new systemic therapies—especially Janus Kinase (JAK) inhibitors. The same patients with moderate disease whom we have freely prescribed topical and systemic steroids over the years now are often considered to not have severe enough symptoms for targeted therapies, and the patients with more severe symptoms are often being referred to other specialists. We are risking the loss of medical dermatology as we continue this trend.

Despite black box warnings, the risks of treating otherwise healthy patients for skin conditions with systemic therapies have proven repeatedly in studies to be quite low. Considering that JAK inhibitors, for example, do not inhibit cellular functions, are targeting cytokine processes, and are dedicated to certain enzymatic profiles, how can therapies such as cyclosporine, methotrexate, and systemic corticosteroids that are cytotoxic or truly immunosuppressive be considered safer? The evidence, in fact, has shown that they are not.¹

Meanwhile, the consequences of not utilizing the most effective therapies can be significant. The impact of depression and anxiety are pivotal in addressing the entire patient outcome. The cost of being unable to focus at work, school, and home cannot be measured. Additionally, dermatologists are best equipped to treat these skin conditions, so unnecessarily referring patients to other specialists creates potential safety concerns.

Black box warnings indicating higher rates of adverse events having been observed with JAK inhibitors are deceiving because they do not specify that those adverse events were observed in a study comparing tofacitinib with tumor necrosis factor (TNF) alpha inhibitors in patients with rheumatoid arthritis who were older than 50 and had at least one additional cardiovascular risk factor.² Importantly, contraindications for JAK inhibitors do exist, so patient selection is important.³ However, adverse events of interest in trials for skin conditions have been sparse by comparison.⁴

SAFETY DATA

The efficacy of various JAK inhibitors, including Bruton tyrosine kinase inhibitors (BTK), tyrosine kinase 2 inhibitors (TYK2), and tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitors, for dermatologic conditions such as atopic dermatitis (AD), psoriasis, alopecia areata, and vitiligo has been widely accepted. While the questions surrounding most of these drugs generally focus on their safety profiles, it is important to understand that these have mostly been well established also.

Upadacitinib (oral JAK1)

In a study assessing the efficacy and safety of upadacitinib compared with placebo for the treatment of moderate-to-severe AD, the incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among all groups.⁵

A phase 2 trial on adults with moderate-to-severe hidradenitis suppurativa found a safety profile consistent with previous reports on upadacitinib for dermatologic conditions.⁶

Ritlecitinib (oral JAK3/TEC)

In a study of the efficacy and safety of ritlecitinib in patients with alopecia areata, the incidence of each adverse event was similar between groups, and no major adverse cardiovascular events (MACE), deaths, or opportunistic infections were reported.⁷

A phase 2b trial evaluating the efficacy and safety of ritlecitinib in patients with active nonsegmental vitiligo found no dose-dependent trends in treatment-emergent or serious adverse events across the 48-week treatment.⁸

Abrocitinib (oral JAK1)

In a study of the efficacy and safety of abrocitinib in adolescents and adults with moderate-to-severe AD, serious adverse events were reported through 12 weeks for two of 155 patients (1.3%) in the 200-mg group, five of 158 (3.2%) in the 100-mg group, and one of 78 (1.3%) in the placebo group.9 Just last year, a new study aimed to provide updated integrated long-term safety results for abrocitinib from available data accrued up to a maximum of almost 4 years in patients with moderate-to-severe atopic dermatitis from the JADE clinical development program, and it showed a consistent profile with no new safety signals; the authors of the study wrote that it “continues to support that abrocitinib has a manageable long-term safety profile in patients with moderate-to-severe atopic dermatitis.”¹⁰ The most frequent serious infection with consistent-dose abrocitinib 200 mg and 100 mg in that safety analysis was herpes zoster (0.5% and 0.2%, respectively), risk factors for which were a history of herpes zoster, abrocitinib 200-mg dose, age ≥65 years, absolute lymphocyte count < 1 x 103/mm³ before the event, and residing in Asia. For serious infections, >100 kg body weight was a risk factor.

Baricitinib (oral JAK1/JAK2)

A study of the efficacy and safety of baricitinib in patients with moderate-to-severe AD found that the only treatment-emergent adverse events that were prevalent in higher percentages of the baricitinib groups vs placebo were headache, blood creatine phosphokinase increase, and nasopharyngitis.¹¹

Another study evaluating the efficacy and safety of baricitinib for severe AA through 104 weeks of continuous therapy found that incidence rates of serious infections, MACE, deep vein thrombosis/pulmonary embolism, and malignancies were within the background rates in AA.¹²

Deuruxolitinib (oral JAK1/JAK2)

Pooled results from two studies evaluating the safety and efficacy of deuruxolitinib in adult patients with AA found that both 8-mg and 12-mg twice-daily doses were generally well-tolerated through 24 weeks; most treatment-emergent adverse events (> 95%) were mild to moderate in severity, treatment discontinuations due to treatment-emergent adverse events were uncommon, and no thromboembolic events or deaths were observed during the trial periods through 24 weeks (drug-related thromboembolic events have been reported with the 12-mg twice-daily dose beyond 12 months of treatment in open label extension studies).¹³

Povorcitinib (oral JAK1)

A study assessing the efficacy and safety of povorcitinib in hidradenitis suppurativa resulted in no deaths and lower rates of serious treatment-emergent adverse events in the patients treated with povorcitinib than placebo.¹⁴ Phase 3 trials are underway.

Remibrutinib (oral BTK)

A phase 2b trial aiming to evaluate the efficacy and safety of remibrutinib in chronic spontaneous urticaria treatment and characterize the dose–response found that most adverse events were mild or moderate, with no dose-dependent pattern.¹⁵ Phase 3 studies are ongoing.

Deucravacitinib (oral TYK2)

In an integrated analysis of phase 3 trials involving patients with moderate-to-severe plaque psoriasis treated through 3 years with one or more doses of deucravacitinib, no new safety signals were observed compared with the first year.¹⁶

In a trial assessing the efficacy and safety of deucravacitinib in adult patients with active systemic lupus erythematosus, rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment; rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported.¹⁷

Delgocitinib (topical pan-JAK)

Two studies to assess the efficacy and safety of twice-daily applications of the topical pan-JAK inhibitor delgocitinib cream 20 mg/g versus cream vehicle in adults with moderate-to-severe chronic hand eczema found that most frequent adverse events occurring in at least 2% of patients were similar in both treatment groups and included COVID-19 and nasopharyngitis.¹⁸ Delgocitinib cream also is FDA-approved to treat vitiligo.

Ruxolitinib (topical JAK1/JAK2)

Two phase 3 trials have studied ruxolitinib cream, 1.5%, for patients 12 or older who had nonsegmental vitiligo with depigmentation covering 10% or less of total body-surface area, but they concluded that larger and longer trials are required to determine safety.¹⁹

Studies of ruxolitinib for hidradenitis suppurativa²⁰ and lichen planus²¹ also have found it to be well tolerated thus far, and the drug also has been studied for psoriasis. 

ENDLESS POSSIBILITIES

With the abundance of data supporting the safety of JAK inhibitors and similar drugs, dermatologists should feel as comfortable prescribing them as they have prescribing biologics such as dupilumab, guselkumab, risankizumab, lebrikizumab, tralokinumab, and nemolizumab.

Clearly, the enemies are steroids or immunosuppressants—not JAK inhibitors. Black box warnings provide guidance, but the indications for dermatology involve fewer risks as most patients are otherwise healthy. Clinicians should still check laboratory results, but to reduce risks, not to create concerns.

The potential applications are endless if we match the mechanism of action to the building blocks of disease. Trials are in motion for the topical JAK inhibitors cerdulatinib and ifidancitinib for vitiligo, the BTK inhibitor rilzabrutinib for atopic dermatitis and pemphigus, the JAK1/TYK2 inhibitor brepocitinib for dermatomyositis and systemic lupus erythematosus, the TYK2 inhibitor ropsacitinib for dermatomyositis, the JAK1 inhibitor INCB054707 for hidradenitis suppurativa, the TYK2 inhibitor TAK-279 for psoriasis, and more. Targeted therapy against signaling does not involve direct cellular suppression or dendritic cell surveillance of antigens. Turning off the faucet, to revisit the earlier analogy, is safer than mopping up the mess.

Black box warnings for drugs with low adverse event reporting should not scare us off from doing what is best for patients. JAK inhibitors, as a class, are safe, swift, and impactful. Along with biologics, they are are some of our safest and most effective treatments for the marathon. As dermatologists, we must be comfortable treating patients with serious diseases, and these therapeutic options are often the best ways to do that. n

Dr. Bhatia reports affiliations with Abbvie, Advanced Derm Solutions, Almirall, Arcutis, Beiersdorf, Biofrontera, BMS, BI, Ferndale, Galderma, InCyte, ISDIN, J&J, LaRoche-Posay, Leo, Lilly, Novartis, Ortho, Pfizer, Regeneron, Sanofi, SunPharma, and Verrica.

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