Reviewing Complex Cases: Navigating Biologics and JAK Inhibitors

In the second round of breakout sessions at the Horizons in Advanced Practice meeting in Las Vegas, Nevada, Omar Noor, MD, FAAD; Douglas DiRuggiero, DMSc, MHS, PA-C; and Lakshi Aldredge, MSN, ANP-BC, DCNP, FAANP, focused on common challenges and innovations in treating plaque psoriasis and atopic dermatitis (AD). To foster collaboration and discussion around the cases, the meeting attendees were divided into 3 groups, with each Horizons chair moderating a session. DiRuggiero presented the first case of a woman aged 27 years who had eczematous lesions covering more than 20% of her body surface area.

Navigating Biologics and JAK Inhibitors

Because each patient brings a unique set of complications, history, and treatment goals, Noor shared a different example with his breakout group. Here, the attendees considered the case of a woman aged 25 years who presented with erythematous and scaly patches on her face, neck, and upper trunk. The patient also had moderate lichenification on antecubital and popliteal fossae. This patient similarly reported issues with quality of life. Specifically, she noted she has persistent pruritus that affects her sleep and activities of daily living.

A medical history revealed that she had AD since she was a child. She reported allergic reactions to dust mites and some foods (ie, peanuts and eggs). The patient noted that stress, like college exams, exacerbates her condition.

Addressing Inadequate Response

Initial treatment included a 600-mg subcutaneous loading dose of dupilumab followed by treatment once every 2 weeks, Noor told attendees. She continued daily emollient and was prescribed topical tacrolimus 0.1% ointment. At her 16-week follow-up appointment, there was a 30% reduction in EASI score, noting moderate AD severity improvement. She reported some reduction in pruritus but said it remained significant. At 6 months, the patient appeared to hit a treatment plateau. She remained at 30% improvement from baseline as measured by EASI scores. However, the persistent moderate pruritus continued to impact her quality of life. Frustrated, she was looking for quick and improved symptomology and better overall disease control.

Empathetic to her plight, Noor asked attendees questions to elicit a discussion around solutions for such a patient, including issues defining response/nonresponse and strategies around switching treatments.

Mechanism of Action, Efficacy, and Safety

To determine the next best treatment option to initiate, Noor reviewed the mechanisms of action of the available treatments. Dupilumab, he explained, binds at IL-4α, which blocks IL-4 and IL-13 signaling. Meanwhile, tralokinumab​ binds at IL-13. This prevents IL-13 from binding to IL-13Rα1 and IL-13Rα2 decoy receptor. As such, it blocks IL-13 signaling as well as endogenous IL-13 regulation. Finally, lebrikizumab​ binds IL-13, which prevents the formation of IL-13Rα1/IL-4Rα complex. In turn, this blocks downstream signaling.¹ 

With that in mind, Noor asked attendees which factors, including safety and efficacy, might determine whetherthe patient should be switched to another systemic therapy (eg, anti–IL-13) or if another class of therapeutics (eg, oral JAK inhibitor) should be considered. He asked in general whether there was evidence to suggest an optimal sequence for introducing and using biologics.

To provide perspective, Nood shared results from the Heads Up trial (NCT03738397). This was a 24-week, head-to-head phase 3b, multicenter, randomized, double-blinded, double-dummy, active-controlled clinical trial comparing the safety and efficacy of upadacitinib (Rinvoq; AbbVie)(n = 342) with dupilumab (n = 331) in adults with moderate to severe AD.​ (The trial excluded patients with a history of dupilumab or JAK inhibitor use.) “Improvements in EASI 75 and WorstItch Numeric Rating Scale were seen as early as 1 week after treatment initiation,” Noor said of upadacitinib. He also reviewed the safety data. The trial found higher rates of serious infection, eczema herpeticum, and herpes zoster for patients who received upadacitinib. For those who received dupilumab, rates of conjunctivitis and injection-site reactions were higher.​²

Boxed Warnings in Perspective

Noor took a moment to review the boxed warnings for JAK inhibitors. There is an increased risk of serious infections that can lead to hospitalization or death. These can include active tuberculosis, invasive fungal infections (eg, candidiasis and pneumocystosis​), bacterial, viral (eg, herpes zoster), and other infections due to opportunistic pathogens​. In patients with rheumatologic arthritis, he said studies have indicated a higher rate of all-cause mortality with JAK inhibitors vs tumor necrosis factor blockers. He added that lymphoma and other malignancies, as well as thrombosis (ie, deep venous thrombosis, pulmonary embolism, and arterial thrombosis),​have been observed in patients with RA who are using JAK inhibitors. Finally, major cardiovascular events (eg, cardiovascular death, myocardial infarction, and stroke) have been associated with JAK inhibitors.

Noor further explored the risk of cardiovascular events and all-cause mortality in patients with skin diseases taking JAK inhibitors by looking at data from a recent meta-analysis of 35 randomized clinical trials with a total of 20,651 patients.JAK inhibitors included in the analysis were tofacitinib (Xeljanz; Pfizer), abrocitinib (Cibinqo; Pfizer), ​baricitinib (Olumiant; Eli Lilly and Incyte), upadacitinib, ritlecitinib (Litfulo; Pfizer), and delgocitinib (Anzupgo; LEO Pharma). In looking at major adverse cardiovascular events and all-cause mortality, the study failed to find a significant difference between JAK inhibitors and placebo/active comparator​ (OR, 0.83; 95% CI, 0.44-1.57; 30 trials)​. Similarly, they found no statistical difference between JAK inhibitors and placebo/active comparator​ for venous thromboembolism (OR, 0.52; 95% CI: 0.26-1.04; 30 trials)​. Finally, Noor reported that the study found oral and topical JAK inhibitors showed similar association without significant heterogeneity in endpoints.​ Thus, Noor added it is important to shed additional light and perspective on the boxed warnings when discussing treatment options with patients.³

Returning to the case, Noor reported the clinician and patient decided the best course was to switch to upadacitinib. Dupilumab was discontinued, and upadacitinib was initiated at 15 mg orally once daily. Emollient and topical tacrolimus were continued as needed.

Practice Issues

​Noor led the group in a discussion on related important topics. For instance, what is the appropriate washout period when switching from dupilumab to upadacitinib?​ If the response to upadacitinib is not adequate, what next steps can be taken? What are approaches to the concept of cycling through multiple biologics?​

Practical issues also need to be addressed, Noor told attendees. He led the conversation on navigating insurance and patient concerns over costs when prescribing biologics. As part of this, he discussed patient assistant programs, buy-and-bill practices, and the importance of biologics coordinators in navigating challenges to ensure patients receive the most appropriate treatments.

References

1. Haddad EB, Cyr SL, Arima K, McDonald RA, Levit NA, Nestle FO. Current and emerging strategies to inhibit type 2 inflammation in atopic dermatitis. Dermatol Ther (Heidelb). 2022;12(7):1501-1533. doi:10.1007/s13555-022-00737-7
2. Blauvelt A, Teixeira HD, Simpson EL, et al. Efficacy and safety of upadacitinib vs dupilumab in adults with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2021;157(9):1047-1055. doi:10.1001/jamadermatol.2021.3023
3. Ingrassia JP, Maqsood MH, Gelfand JM, et al. Cardiovascular and venous thromboembolic risk with JAK inhibitors in immune-mediated inflammatory skin diseases: a systematic review and meta-analysis. JAMA Dermatol. 2024;160(1):28-36. doi:10.1001/jamadermatol.2023.4090