Janus Kinase Inhibitors in the Treatment of Atopic Dermatitis: Military Considerations

The most frequently reported treatment-associated adverse events were nausea, nasopharyngitis, upper respiratory tract infection, and headache, and the percentages were similar among trial groups.⁹ Acne was more frequently reported in the abrocitinib groups compared with placebo and the dupilumab group, and conjunctivitis was more frequently reported in the dupilumab group. Herpesvirus cutaneous infections were rare in the abrocitinib groups, as were other serious infections. No deaths, major adverse cardiovascular events (MACEs), or venous thromboembolic events (VTEs) occurred during the trial. Dose-dependent increases in creatinine phosphokinase were seen in the abrocitinib groups, whereas dose-dependent decreases were seen in platelet counts, with no patient demonstrating a platelet count below 75,000/mm³ during the study.⁹ Low-density lipoprotein cholesterol levels and high-density lipoprotein cholesterol levels increased in a dose-dependent manner as well, but the ratios of low-density lipoprotein to high-density lipoprotein were unchanged.⁹ The results of a phase 3, 92-week extension study, JADE EXTEND, were recently published and demonstrated a role for abrocitinib as a treatment for patients with moderate to severe AD, regardless of prior dupilumab response status.¹²

Upadacitinib, another selective JAK1 inhibitor, was approved following data from 2 replicate double-blind, phase 3, randomized, controlled trials—Measure Up 1 and Measure Up 2.¹³ Results demonstrated that monotherapy with once-daily upadacitinib 15 mg or 30 mg is an effective and well-tolerated treatment option for patients with moderate to severe AD vs placebo. All coprimary end points at week 16 were achieved in the upadacitinib groups in both trials. Acne, upper respiratory tract infections, nasopharyngitis, headache, and increase in serum creatinine phosphokinase levels were the most frequently reported adverse events. Rates of herpes zoster infection in upadacitinib groups were low.¹³

In the subsequent phase 3 AD Up trial, researchers evaluated the safety and efficacy of combination therapy with topical corticosteroids in patients aged 12 to 75 years.¹⁴ Upadacitinib groups again achieved the identical coprimary end points that were present in the Measure Up trials¹³ as well as all key secondary end points.¹⁴ Additionally, significant differences in secondary end points, such as a 4-point improvement in the Worst Pruritus NRS vs placebo, were noticed in both upadacitinib treatment groups as early as 1 week into the study (P<.0001), with maintenance of the effect through to week 16 (P<.0001).¹⁴ AD Up was followed by the Heads Up trial, a 24-week, phase 3, multicenter, double-blind, randomized, controlled trial comparing safety and efficacy of upadacitinib with dupilumab among 692 adults with moderate to severe AD.¹⁵ At week 16, a higher percentage of patients in the upadacitinib group achieved EASI-75 vs the dupilumab group (71.0% vs 61.1%, respectively; P=.006). The difference noted at week 2 was even more impressive, with 43.7% of patients in the upadacitinib treatment group achieving EASI-75 compared with 17.4% in the dupilumab group (P<.001). No new safety-related events were registered compared with the already available data for both drugs.¹⁵

Ruxolitinib (RUX) is a topical JAK1 and JAK2 inhibitor that was FDA approved in September 2021 for the treatment of AD.¹⁶ In a phase 2 clinical trial of 307 adult patients with 3% to 20% body surface area (BSA) affected with AD, significant reductions in itch NRS scores were observed within 36 hours after the first application of RUX cream 1.5% twice daily (-1.8 vs -0.2, P<.0001).¹⁷ These decreases were noted within the first 2 weeks of treatment for all the RUX cream regimens and were sustained through to week 8, the end of the double-blind period. At 4 weeks, change in itch from baseline was significantly reduced in the RUX 1.5% twice-daily group compared with the triamcinolone ointment 0.1% group (−4 vs −2.5, P=.003). During the open-label treatment period from 8 to 12 weeks, all patients who switched to RUX cream 1.5% twice daily noted further reductions in itch, and those who continued it demonstrated additional improvement.¹⁷

The recent FDA approval was further backed by positive phase 3 trial data from the TRuE-AD1 and TRuE-AD2 studies.¹⁸ Patients in these trials were aged 12 years and older and had AD for 2 or more years with an IGA score of 2 or 3 and 3% to 20% affected BSA. Patients were randomized to twice-daily RUX cream 0.75%, RUX cream 1.5%, or vehicle cream, and the primary end point was an IGA score of 0 or 1 and an improvement of 2 or more points from baseline at week 8. Significantly more patients achieved IGA treatment success with RUX cream 0.75% (TRuE-AD1, 50.0%; TRuE-AD2, 39.0%) and RUX cream 1.5% (TRuE-AD1, 53.8%; TRuE-AD2, 51.3%) vs vehicle (TRuE-AD1, 15.1%; TRuE-AD2, 7.6%; P<.0001) at week 8. The RUX groups experienced dramatically reduced itch compared with vehicle, with a mean reduction of approximately 3 points on the NRS at 8 weeks. Additionally, statistically significant itch reductions vs vehicle were reported within 12 hours of first application of RUX cream 1.5% (P<.05). Application-site reactions including stinging and burning occurred in less than 1% of patients, and none were considered clinically significant. Mean plasma concentrations of RUX were monitored during the phase 2 and 3 AD studies and did not lead to any clinically meaningful changes in hematologic parameters. The low bioavailability following topical application of RUX cream (6% in the TRuE-AD studies) allows for a targeted delivery of the active drug to lesional skin while reducing the safety issues associated with oral administration of JAK inhibitors.¹⁸

Baricitinib is a predominantly JAK1 and JAK2 inhibitor that was the first JAK inhibitor to be approved for the treatment of moderate to severe AD in the European Union and Japan.¹⁹ Although the FDA’s decision on baricitinib has lagged behind market competitors, in 2 phase 3 clinical trials, BREEZE-AD1 and BREEZE-AD2, baricitinib demonstrated benefit over placebo on clinically important measures of disease severity. The primary end point—the proportion of patients achieving an IGA score of 0 or 1 with an improvement of 2 or more points from baseline at week 16—was met by both tested doses of baricitinib (2 mg and 4 mg) vs placebo in BREEZE-AD1 (2 mg, P≤.05; 4 mg, P≤.001) and BREEZE-AD2 (2 mg, P≤.05; 4 mg, P≤.001). In addition, baricitinib 4 mg consistently demonstrated significant benefit over placebo on other clinically important measures of disease severity at week 16 to include itch (BREEZE-AD1 and BREEZE-AD2, P≤.001), sleep disturbance (BREEZE-AD1, P≤.01; BREEZE-AD2, P≤.001), and skin pain (BREEZE-AD1, P≤.01; BREEZE-AD2, P≤.001). Nasopharyngitis, upper respiratory tract infections, creatine phosphokinase elevations, and headaches were the most frequently reported adverse events. During the 16-week treatment period in these trials, no deaths, MACEs, or VTEs occurred.¹⁹ Similar results were seen in a long-term extension study, BREEZE-AD3.²⁰ The combination of baricitinib and topical corticosteroids were evaluated in 2 additional phase 3 trials, BREEZE-AD4²¹ and BREEZE-AD7.²² Although only baricitinib 4 mg met the primary end point of EASI-75 at week 16 in both trials, both dosing regimens plus topical corticosteroids demonstrated notable reduction in multiple clinical and quality-of-life indices prior to week 2 when compared with placebo plus topical corticosteroids.^22,23

AD in Military Service Members

Atopic dermatitis is a common condition in the general population, with a prevalence of 7.3% (95% CI, 5.9-8.8) in a recent study of American adults.²⁴ Historically, the burden of AD that would be expected among active-duty military service members given the prevalence among the general population has not been observed, in part because of the disqualifying nature of AD for enlistment.²⁵ The Department of Defense Instruction 6130.03, Volume 1, Medical Standards for Military Service: Appointment, Enlistment, or Induction stipulates that a history of AD or eczema after the twelfth birthday or history of residual or recurrent lesions in characteristic areas (ie, face, neck, antecubital or popliteal fossae, occasionally wrists and hands) is disqualifying.²⁶ Specific military services possess additional standards that further define limits within the aforementioned Department of Defense instruction.²⁵ Additionally, there are service-specific policies in place that mandate medical evaluation boards to determine fitness for continued service in the event the condition interferes with the member’s ability to perform their duties. Insection 4.2 of the U.S. Navy Aeromedical Reference and Waiver Guide, further restrictions for aviation personnel are delineated: “Depending on the location of lesions, there can be interference with the wearing of flight gear. The symptoms, particularly itching, can be distracting in flight. Patients with atopic dermatitis are more susceptible to contact dermatitis due to irritants found in a military environment.” Ultimately, the document stipulates that symptom severity and the requirement for therapy will determine the aeromedical disposition. It specifically states that “[p]atients controlled on topical therapy over small areas and patients who are asymptomatic on stable doses of loratadine (Claritin) OR fexofenadine (Allegra) may be considered for waiver,” and “intermittent use of topical steroids over a limited area is compatible with waiver.”²⁷ It follows that limited use of topical JAK inhibitors, such as RUX, would be compatible with a waiver, given the favorable side effect profile and requirement for use in patients with 20% or lower affected BSA.¹⁶ This is just one example of duty-specific and service-specific medical standards that exist that could impact the use of both topical and oral JAK inhibitors.