Association of Atopic Dermatitis With Alopecia Areata: Targeting the Janus Kinase Pathway and the Managed Care Considerations

Abstract

Although treatment options for atopic dermatitis (AD) and alopecia areata (AA) exist, some patients experience inadequate response or intolerable adverse effects (AEs) that often negatively impact patient quality of life. Data from short-term phase 3 trials with the Janus kinase inhibitors (JAKi) in patients with AD and AA have demonstrated efficacy with limited serious AEs. However, recent clinical trial results with tofacitinib in rheumatoid arthritis indicated an increased risk of serious heart-related events, cancer, blood clots, and death, leading the United States Food and Drug Administration to require a black box warning for tofacitinib, baricitinib, upadacitinib, abrocitinib, and ruxolitinib (topical). Managed care pharmacists will need an expanded understanding of real-world data and the place in therapy of recently approved and emerging JAKi to best assist patients with AD and AA to navigate treatment options. Managed care organizations will play a pivotal role in developing appropriate utilization management strategies to ensure safe and cost-effective use to optimize patient outcomes.

What Is Atopic Dermatitis?

Atopic dermatitis (AD) is a common, chronic, or chronically reoccurring inflammatory skin condition accompanied by pruritus that negatively affects a patient’s quality of life (QOL).¹ AD affects up to 20% of children and 2% to 17% of adults (men and women equally), with the incident rate varying greatly by country.^1-4 AD typically starts in childhood, but about one-third of cases begin in adulthood. Most often, AD is mild, with fewer than 10% of patients experiencing severe disease. The disease has a genetic component and usually occurs in families with other atopic conditions, such as asthma or food allergies.¹

Although once believed to be primarily caused by an immune shift toward the T-helper (Th) 2 pathway and related cytokines (interleukin [IL]-4, IL-5, IL-10, IL-13, and IL-31), there is immunologic evidence linking AD to Th1 (interferon [IFN]-γ), Th17 (IL-17 or IL-22), and alarmin (IL-33).⁵ AD is characterized by skin barrier defects causing dry skin due to altered lipid metabolism and epidermal filaggrin expression. The increased production of inflammatory cells and defective skin barrier promotes microbial colonization of Staphylococcus aureus or Malassezia spp. This results in increased susceptibility to skin infections.¹

Disease Burden in AD

Studies have found that 91% of patients with AD experienced daily pruritus, and decreasing the amount of itch was the primary treatment goal for 36% of patients.⁶ A major consequence of pruritus is sleep disturbance, which is experienced by two-thirds of patients with AD and can lead to fatigue and increase the risk of attention-deficit/hyperactivity disorder, headaches, and short stature in children.⁶ Depression and anxiety have also been reported as comorbidities of AD.^6,7 Many studies have observed that QOL decreases as disease severity (itch and sleep disturbances) increases.⁸ Besides physical symptoms, AD can also affect social aspects of a patient’s life due to embarrassment from appearance and decreased self-esteem resulting in absenteeism from or decreased productivity at work or school. A study found that 12% and 2% of patients missed 1 to 2 days and 3 or more days of work due to AD, respectively.⁶ Unfortunately, the burden of AD is not only limited to the patients themselves, but also to the patient’s family and caregivers with their own sleep disturbed or caring for a child with AD.⁶

What Is Alopecia Areata?

Alopecia areata (AA) is a common disease that causes inflammatory, non-scarring hair loss. The cumulative lifetime incidence of AA is about 2% in the United States and globally, and the prevalence is approximately 0.1% to 0.2%.^9,10 AA affects men and women equally and is usually diagnosed in the third decade of life. AA may vary significantly in presentation.^9,11 Hair loss can range from small circular patches on the scalp or beard to all hair on the scalp (alopecia totalis [AT]) or the entire body (alopecia universalis [AU]).¹¹ AA often occurs with other autoimmune diseases including AD, asthma, and allergic rhinitis.¹²

There are 3 phases of hair growth. Anagen is the proliferation phase when the follicle is growing new hair. Catagen is considered the transition phase when cell division starts slowing down. Telogen is the resting phase where the hair is held in the follicle until it is shed so the anagen phase can begin again. The pathogenesis of AA is related to the disruption of immune privilege of the proximal part of the anagen hair follicle. An increase in major histocompatibility complexes 1 and 2 and adhesion molecules promote increased leukocyte trafficking in the dermis, causing antigen presentation and migration of CD8+and CD4+T cells to the hair follicle.¹³ CD8+ T cells produce IFN-γ, which increase IL-15 production through Janus activating kinase (JAK) 1 and JAK2 signaling.14,15 The binding of IL-15 to the surface of CD8+ T cells causes further IFN-γ production through JAK1 and JAK3 signaling. Infiltration of inflammatory immune cells in the bulb of the hair follicles leads to disrupted hair follicle cycling, causing a premature entry into the telogen phase.^16,17

Disease Burden in AA

Over 50% of patients with AA report poor QOL, with patients aged 20 to 50 years, women, and those reporting family or work stress, and those experiencing lightening of skin color or hair loss greater than 25% being at the highest risk for poor QOL. Psychiatric comorbidities including depression and anxiety have been reported in 66% to 74% of patients with AA.¹⁰ Similarly to AD, AA has a negative effect on a patient’s social well-being, with patients reporting decreased self-esteem, difficulty developing and maintaining relationships, and absenteeism.¹⁸

Cytokines and the JAK Pathway Connection Between AD and AA

The pathogenesis of AD and AA is regulated by a common intracellular mechanism involving JAKs and their associated signaling pathways (Figure 1⁵).^5,19 Cytokines, including ILs and IFNs, use the JAK-signal transducer and activator of transcription (JAK-STAT) pathway to transmit signals from the cell membrane to the nucleus to regulate gene expression.¹⁹ In AA, JAK-STAT−dependent cytokines (IFN-γ, IL-15) promote autoreactive T-cell activation and proliferation. Likewise, IL-4, IL-5, and IL-13 use the JAK-STAT signaling pathway to drive Th2 immunity in AD. Most cytokine receptors usually target a combination of JAK proteins (JAK1, JAK2, JAK3, and tyrosine kinase 2) for their activity, which may limit targeting a single JAK. However, pan-JAK inhibitors (JAKi) are associated with toxicities.⁵ Because the pathogenesis of AD and AA both involve JAKs and the JAK-STAT signaling pathway, JAKi are currently being investigated in clinical trials as a promising class of medications to treat AD and AA.

Figure 1. The JAK/STAT Pathway and the Role of JAKi5

Republished from Solimani F, et al. Front Immunol. 2019;10:2847, under the terms of the Creative Commons Attribution License (CC BY).

Current Treatment Guidelines and Therapies

AD

The American Academy of Dermatology last updated the AD clinical treatment guideline in 2014, so this guideline does not include recommendations for newer US Food and Drug Administration (FDA)-approved agents for AD, such as dupilumab (IL-4 receptor blocker approved in 2017), tralokinumab (IL-13 receptor blocker approved in 2021), ruxolitinib (topical JAKi approved in 2021), abrocitinib (oral JAKi approved in 2022), and upadacitinib (oral JAKi approved in 2022).^20-26 However, the more recent 2018 AD European Guideline contains recommendations for some newer agents.^1,27 The cornerstone of the AD treatment approach involves effective treatment and prevention of disease flares to improve itching, pain, and QOL.²¹ Patient age, disease severity, and symptom duration, reoccurrence, and persistence should guide treatment selection. The guideline recommends baseline maintenance therapy with moisturizers, education, and allergen avoidance for children and adults with AD (Figure 23).¹ For children and adults with transient or mild AD, defined as lower than 25 on the SCORing Atopic Dermatitis (SCORAD) index, as-needed treatment with moderate potency topical corticosteroids (TCS), topical calcineurin inhibitors (TCI [tacrolimus, pimecrolimus]), and certain antiseptics are recommended (Figure 13, Box 1^28-30).¹ Maintenance therapy with moderate to potent TCS or topical tacrolimus, UV therapy, counseling, climate therapy, and wet wrap therapy is recommended for children and adults with recurrent or moderate AD (SCORAD 25-50) (Figure 23).¹ In adults with persistent refractory or severe AD (SCORAD >50), the guideline recommends hospitalization and systemic immunosuppression (IMM) with a short course of oral corticosteroids (OCS), psoralen and UV-A (PUV-A), dupilumab, or other agents that are off-label in the United States (eg, methotrexate, azathioprine, mycophenolate mofetil, and alitretinoin) (Figure 23).¹ The recommendations for severe AD are the same for children, except they do not recommend a short course of OCS, dupilumab, PUV-A, or alitretinoin.¹ However, dupilumab is FDA approved in the United States and by the European Commission in Europe to treat patients 6 years and older with moderate to severe AD.^22,31

Figure 2. Stepwise Approach to Treating Atopic Dermatitis³

Republished from Salvati L, et al. Int J Mol Sci. 2021;19(10):10381, under the terms of the Creative Commons Attribution (CC BY) license.

Box 1. Clinical and Patient-Reported Outcomes Measurements for AD and AA^28-30

INSERT TABLE HERE

QOL, quality of life.

AA

Currently, there are no FDA-approved treatments for AA; however, the FDA did grant Breakthrough Therapy designation for baricitinib for the treatment of AA in March of 2020 based on preliminary data from the BRAVE clinical trials.^32,33 The most recent update to the United States National Alopecia Areata treatment guideline was published in 2010.^34,35 The Alopecia Areata Consensus of Experts released results from an expert opinion panel Delphi survey on treatments for AA in 2020. Experts agreed on using corticosteroids as first-line treatment, with route preference dependent on patient age, disease duration, and disease severity using a Severity of Alopecia Tool (SALT) score (63% consensus; [Box 128-30]). Intralesional corticosteroids were deemed more effective than ultrapotent TCS for regrowth and remission, but use was limited by the patient’s ability to tolerate multiple injections and the potential for skin atrophy. TCI could also be used to treat AA affecting the eyebrows, scalp, or beard (second-line topical treatment for beard AA [60% consensus]). Experts also endorsed the use of topical bimatoprost or latanoprost first-line for the treatment of eyelash AA (25% consensus). The panel advised treating children with AU, AT, or ophiasis withcontact immunotherapy before using systemic agents (33% consensus). Experts recommended using systemic therapy first-line in patients 13 years and older with severe AA with OCS. They also agreed on the efficacy of systemic monotherapy with OCS, cyclosporine, and JAKi therapy, as well as the combination therapy of OCS with cyclosporine or methotrexate. The lack of consensus recommendations on treatment reflected the scarcity of randomized controlled trial data to support recommendations at the time of the study.³⁶

Novel and Emerging JAKi for the Treatment of AD and AA

The unmet need for a safe and effective treatment option for AD and AA, accompanied by the increasing understanding of intracellular pathways involved in skin inflammation and immunity, led to the development of JAKi as a new treatment for chronic dermatologic inflammatory conditions.⁵ JAKi have been used to treat other autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis.³⁷ Cytokines related to the pathogenesis of AA and AD rely on JAKs and the JAK-STAT pathways for signal transduction. JAKi exert their therapeutic effects by inhibiting 1 or more of the JAK enzymes (JAK1, JAK2, JAK3, and TYK2), interfering with signal transduction and JAK-STAT−dependent cytokine-mediated inflammation.⁵ However, some serious safety concerns regarding the increased risk for serious heart-related events (ie, heart attack or stroke), cancer, blood clots, and death have surfaced with tofacitinib approved for the treatment of rheumatoid arthritis.³⁷ As a result, on September 1, 2021, the FDA required a black box warning on labeling for tofacitinib, baricitinib, and upadacitinib about these risks and limited the use to patients who have not responded to or are intolerant of 1 or more tumor necrosis factor blockers.³⁷ Furthermore, ruxolitinib topical, abrocitinib, and upadacitinib, recently approved for the treatment of AD, also carry a black box warning about these cardiovascular (CV) risks.^24-26 Clinical trial data from long-term safety and efficacy studies will determine their place in the AD and AA treatment landscape.

Novel JAKi for AD

Ruxolitinib Topical

Ruxolitinib 1.5% cream (Opzelura) is the first topical JAKi cream recently FDA approved for use in non-immunocompromised patients 12 years and older for the short-term and noncontinuous chronic treatment of mild to moderate AD that is not adequately controlled with topical prescription medications, or when such therapies are not advised.²⁴ The approval was based on the safety and efficacy data from 2 identically designed double-blind, vehicle-controlled, multicenter, randomized trials, TRuE-AD and TRuE-AD2.³⁸ Participants were randomized (2:2:1) to receive ruxolitinib 0.75% cream, 1.5% cream, or vehicle twice daily for 8 continuous weeks. A significantly greater proportion of participants in the ruxolitinib treatment arms achieved the Investigator’s Global Assessment (IGA) primary end point (IGA score of 0/1 and ≥2-grade improvement from baseline) and the Eczema Area and Severity Index (EASI)-75 secondary end point at week 8 (Table 1³⁸). Ruxolitinib was well tolerated with application site reactions (stinging, burning) infrequently occurring (<1%) in the ruxolitinib groups. Nasopharyngitis occurred more often in the ruxolitinib-treated groups (0.75% strength, 3%; 1.5% strength, 2.6%) versus the vehicle alone (0.8%). Although cytopenias have occurred with oral JAKi, they seem to be dependent on the duration of exposure (plasma concentrations). In the TRuE-AD and TRuE-AD2 studies, the mean plasma concentrations of ruxolitinib topical were low and did not lead to any clinically relevant hematologic changes.³⁸

Abrocitinib

Abrocitinib (Cibinqo) is an oral JAKi, recently FDA approved for use in adults with moderate to severe AD that is not adequately controlled with other systemic medications, or when such therapies are not advised.²⁵ The approval was based on the safety and efficacy data from the JADE studies (MONO-1, MONO-2, TEEN, COMPARE, EXTEND, and REGIMEN) that were multicenter, randomized, double-blinded trials in patients with moderate to severe AD. Co-primary end points measured in these studies were IGA response (0 [clear] or 1 [almost clear] with ≥2­grade improvement from baseline) and EASI-75 score (Box 128-30).^39-44

The JADE-MONO-1 and JADE-MONO-2 studies enrolled participants 12 years and older and randomly (2:2:1) assigned them to receive once-daily oral abrocitinib 200 mg, 100 mg, or placebo for 12 weeks. The percentage of participants achieving both co-primary end points was significantly greater in abrocitinib-treated groups than placebo at 12 weeks in both of these trials (Table 2^39-42).^39,40

Upadacitinib

Upadacitinib (Rinvoq) is an oral JAKi, recently FDA approved for use in patients 12 years and older with moderate to severe AD that is not adequately controlled with other systemic medications, or when such therapies are not advised.²⁶ The approval was based on the safety and efficacy data from the Measure Up 1, Measure Up 2, and AD Up trials that were multicenter, randomized, double-blind, placebo-controlled studies in patients with moderate to severe AD.^46,47 Co-primary end points of these trials included EASI-75 and validated IGA for AD (vIGA-AD) response (0 [clear] or 1 [almost clear] with ≥2-grade improvement from baseline).

In the Measure Up 1 and the Measure Up 2 trials, participants were randomized (1:1:1) to receive upadacitinib 15 mg, 30 mg, or placebo once daily for 16 weeks. After 16 weeks, a significantly increased percentage of participants in the upadacitinib-treated arms achieved co-primary end points versus placebo in both studies (Table 3^46-48). There was a similar incidence of serious AEs (2%-3%) in all groups across the studies. The most frequently reported treatment-emergent AEs (TEAEs [≥5% in the upadacitinib treatment groups]) were acne, upper respiratory infection, nasopharyngitis, headache, and creatine phosphokinase (CPK) increase. No deaths occurred during the studies, and AEs leading to drug discontinuation were similar among the groups. Serious infections occurred in less than or equal to 1% of all treatment groups. The incidence of herpes zoster infection was increased in the upadacitinib groups. Six cases of malignancy, not attributed to upadacitinib, occurred in participants 50 years and older in the upadacitinib treatment groups.⁴⁶

Participants in the AD Up study were randomized (1:1:1) to receive once-daily oral upadacitinib 15 mg, 30 mg, or placebo plus TCS. At week 16, a significantly increased proportion of participants in the upadacitinib plus TCS groups achieved EASI-75 and vIGA-AD response at week 16 than the placebo group (Table 4^45,49-51).TEAEs occurred in 67% of participants receiving upadacitinib 15 mg plus TCS, 72% receiving 30 mg plus TCS, and 63% of placebo. The most common (≥5%) TEAEs in the upadacitinib groups were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, increased CPK, AD, and headache. In the upadacitinib 30 mg plus TCS group, 2 malignancies (1 nonmelanoma skin cancer and 1 adenocarcinoma of the colon) occurred. No deaths occurred during the study.⁴⁷

Heads Up was a multicenter, double-blinded, double-dummy, active comparator trial. Participants aged 18 to 75 years with moderate to severe AD were randomized (1:1) to receive once-daily oral care upadacitinib 30 mg or dupilumab 300 mg subcutaneously every other week for 24 weeks. At week 16, a significantly increased percentage of participants achieved the primary end point of EASI-75 versus dupilumab (Table 4^45,49-51). The safety profile was consistent with the Measure Up, Measure Up 2, and AD trials. The incidence of anemia, neutropenia, and CPK elevations were increased in the upadacitinib-treated group compared with the dupilumab-treated group. The incidence of serious AEs was 2.9% for the upadacitinib group and 1.2% for the dupilumab group. The study reported 1 death due to influenza-associated bronchopneumonia in a 40-year-old patient treated with upadacitinib.⁴⁸

Emerging JAKi Phase 3 Trial Data for AD

Baricitinib

The BREEZE trials (-AD1, -AD2, -AD4, -AD5, and -AD7) were double-blind, randomized, multicenter studies that evaluated the safety and efficacy of baricitinib in adults 18 years and older with moderate to severe AD.^45,49-51 In the BREEZE-AD1 and BREEZE-AD2 studies, participants with an inadequate response to topical treatment were randomized (2:1:1:1) to receive once-daily placebo or baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks.⁴⁹ Both trials demonstrated a significantly greater percentage of participants receiving baricitinib monotherapy or baricitinib with TCS rescue achieved vIGA-AD of 0 (clear) or 1 (almost clear) and EASI-75 response in the baricitinib 2 mg and 4 mg arms after 16 weeks than placebo. The baricitinib 1 mg-treated groups had inconsistent treatment outcomes (Table 4^45,49-51). The incidence of TEAEs was similar across all groups. The most frequently reported AEs (>2% in any treatment group) were nasopharyngitis, upper respiratory infection, CPK elevations, and headaches. There were no reports of CV events, VTE, gastrointestinal perforation, significant hematological changes, or death in the baricitinib groups.⁴⁹

BREEZE-AD4 evaluated treatment with baricitinib and TCS in participants who were intolerant to, had a contraindication to, or in whom cyclosporine treatment failed. Participants were randomized to receive once-daily 1 mg, 2 mg, or 4 mg baricitinib or placebo in conjunction with TCS. Interim results demonstrated a statistically significant increase in the percentage of participants achieving EASI-75 and vIGA-AD response by week 16 in the 4 mg baricitinib group only compared with placebo (Table 3^46-48). The study reported no deaths or VTE, and the most common TEAEs were headache, influenza, and nasopharyngitis.⁵⁰

In the BREEZE-AD5 trial, participants with intolerance or inadequate response to topical therapy were randomized (1:1:1) to receive once-daily oral baricitinib 1 mg, 2 mg, or placebo. Topical and systemic AD therapies were not allowed during the trial, except as part of the rescue. At week 16, a greater percentage of participants in the 2 mg baricitinib group achieved a statistically significant EASI 75 and vIGA-AD response versus placebo (Table 3^46-48). Safety findings were similar to those observed in other BREEZE trials.⁴⁵

The BREEZE-AD7 trial assessed baricitinib plus TCS in participants with an inadequate response to TCS therapy. Participants were randomized (1:1:1) to receive daily oral baricitinib 4 mg, 2 mg, or placebo with low to moderate potencyTCS for 16 weeks. A significantly increased proportion of participants treated with baricitinib 4 mg achieved vIGA-AD and EASI-75 response than placebo, but not in the baricitinib 2 mg groups (Table 3^46-48). The incidence of TEAEs was similar in the baricitinib groups (58% in the 4 mg group, 56% in the 2 mg group) and was 38% in the placebo group. Participants reported serious AEs in 4% of the 4 mg group, 2% of the 2 mg group, and 4 % of the placebo group. Nasopharyngitis, upper respiratory tract infections, and folliculitis were most reported in the baricitinib groups.⁵¹

Emerging JAKi Phase 3 Trial Data for AA

Baricitinib

The BRAVE-AA1 (N = 598) and BRAVE-AA2 (N = 490) trials were two 36-week, double-blind, placebo-controlled, randomized trials that evaluated the safety and efficacy of baricitinib in patients 18 years and older with severe AA or at least 50% scalp hair loss (SALT score ≥50%). Patients were randomized (3:2:3) to receive once-daily oral baricitinib 4 mg, 2 mg, or placebo, and at baseline patients had a mean SALT score of 85.5. At 36 weeks, a significantly greater proportion of participants in the baricitinib-treated groups in the BRAVE-AA1 and BRAVE-AA2 trials, respectively, achieved the primary end point (SALT score ≤20; baricitinib 4 mg, 35.2% and 32.5%; baricitinib 2 mg, 21.7% and 17.3%) versus placebo (5.3% and 2.6%; all P <.0001). The safety profile was consistent with previous data, and most TEAEs were mild or moderate in severity. A small percentage (≤2.6% in both studies and treatment groups) stopped baricitinib due to AEs. In both studies, the most common AEs (≥5%) in any treatment group included upper respiratory infections, acne, headache, increases in CPK, and urinary tract infection.⁵²

Managed Care Considerations for JAKi

With all of the recent JAKi approvals, managed care organizations will be reviewing this class and making formulary and clinical management recommendations, including prior authorization (PA) decisions. Besides randomized controlled trials, managed care organizations will be looking at overall costs associated with AD as well as real-world evidence showing the value of treatment. Research has been conducted on these topics as well and the Institute for Clinical and Economic Review (ICER) has provided rationale for formulary decision making.

Cost of Disease and Treatment for AD

A conservative estimate of the annual costs of AD in the United States is $5.297 billion (in 2015 USD).⁸ A retrospective cohort study analyzed claims data of 31,164 adults with AD from 4 IBM MarketScan databases and calculated the 2018 direct and indirect costs compared with matched controls.⁵³ The average age of participants with AD was 45 years, and 64% were women. Participants with AD in the study had similar inpatient services utilization but greater all-cause healthcare resources utilization of outpatient services and outpatient pharmacy. Compared with the control cohort group, a significantly greater percentage of participants with AD had all-cause outpatient office visits (99.9% vs 84.2%), 1 or more all-cause emergency department (ED) visits (21.4% vs 17.6%), and outpatient prescriptions (97.1% vs 81.1%; all P <.0001). The unadjusted average total all-cause healthcare costs were greater in adults with AD, driven by outpatient services spending ($7566 vs $5344) and outpatient pharmacy claims ($4665 vs $1969 [both P <.001]). Spending was significantly more for outpatient office visits ($1033 vs $540) and radiology, laboratory, and phototherapy outpatient services ($6023 vs $4359 [both P <.001]) in participants with AD versus control. AD-related claims accounted for 16% of all-cause healthcare spending. After adjustment for baseline patient characteristics, the 2018 total all-cause healthcare costs were $13,999 for adults with prevalent AD versus $11,312 for the control group (P <.001). Total all-cause costs were also significantly greater in the adults with incident AD compared with control ($11,674 vs $11,312; P = .008). Adjusted all-cause prescription costs were greater for adults with prevalent AD ($7939 vs $2347)and incident AD ($3751 vs $2347) compared with control.⁵³

Another retrospective study analyzed claims between 2016 and 2018 for 4784 adults with AD to determine the economic burden by disease severity. Patients with severe AD had more use of dermatology office visits compared with patients with clear to mild disease (73.0% vs 58.5%). Medication usage was also higher for patients with severe AD compared with clear to mild disease (90.0% vs 64.3%). Annual all-cause total direct healthcare costs were largely driven by outpatient visit ($4546) and pharmacy ($3886) costs and varied by severity with $23,242, $11,755, and $8936 for patients with severe, moderate, and clear to mild AD, respectively.⁵⁴

Real-world Data and Treatment Patterns for AD

The QUEST-AD was a longitudinal, prospective, observational study using patient surveys and healthcare claims data (Optum Research Database) to assess real-world treatment patterns and unmet needs of adult patients with moderate to severe AD. The study included 801 participants who were diagnosed in the past 5 years and received IMM or phototherapy in the previous 6 months. Participants had a mean age of 45 years, 72% were women, and 74% had moderate AD severity. Participants reported using TCS (64%), OCS (11%), and IMM (5%) in the past month. Approximately 81% of participants reported at least 1 disease flare within the past month, with participants with severe AD experiencing more flares than those with moderate AD (2.4 vs 1.6; P <.001). About 58% of participants reported moderate to very severe symptoms, defined as Patient-Orientated Eczema Measure (POEM) scores 8 or greater over the past 7 days (Box 128-30). Participants experiencing a flare had worse mean POEM scores (13.5 vs 6.17), Peak Pruritus Numeric Rating Scale (NRS) scores (6.34 vs 3.52), Dermatology Life Quality Index (DLQI) scores (8.6 vs 3.67), Treatment Satisfaction Questionnaire for Medication (TQSM) scores for effectiveness, AEs, convenience, and global satisfaction, and Work Productivity and Activity Impairment (WPAI) for absenteeism, presenteeism, impairment in normal daily activities, and overall work impairment than those not experiencing a flare (all P <.001, except for absenteeism [P = .019]; [Box 128-30]). Similarly, participants with severe AD had significantly worse mean POEM scores (15.99 vs 8.24), pruritus NRS scores for worst itch (6.87 vs 4.46), DLQI (10.63 vs 4.95), TSQM scores for effectiveness, AEs, convenience, and global satisfaction, and WPAI for presenteeism, percent impairment with daily activities, and overall work impairment than those with moderate AD (all P <.001).⁵⁵

A retrospective cohort study examined the treatment patterns of participants 12 years and older with moderate to severe AD in the United States who recently initiated therapy with dupilumab, OCS, IMM (with methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine), and phototherapy between March 28, 2017 (approval date of dupilumab) and July 31, 2018. The study analyzed claims data (IQVIA Health Plan database) of 1980 participants with an average age of 41 years, 61% women, and 11% younger than 18 years. At baseline, about 65% of participants used TCS. Approximately 73% of participants started therapy on the index date with OCS, 13% with dupilumab, 5% with IMMs, and 8% with phototherapy. Participants in the dupilumab and IMM-treated groups were also more likely to have previously used high-potency TCS (40% and 41%, respectively), tacrolimus (12% and 7%), and crisaborole (8% and 5%). Participants commonly switched to a different advanced treatment or started combination therapy. About 20% of participants treated with dupilumab and 44% receiving IMM used an additional treatment. Significant decreases in treatment persistence were reported. At 6 and 12 months, respectively, 21% versus 25% discontinued dupilumab, 64% versus 72% discontinued IMM, and 97% versus 98% discontinued OCS. Based on the standard percentage of days covered of at least 0.8 or more defining adherence, about 69% of participants in the dupilumab-treated group, 32% in the IMM group, and 1% in the OCS group were adherent to treatment.⁵⁶

Cost of Disease and Treatment for AA

A retrospective, observational study also analyzed claims data to estimate the financial impact of AA in the United States.⁵⁷ During the first 12 months after AA diagnosis, researchers measured all-cause and AA-related healthcare resource utilization and costs for outpatient visits, ED visits, inpatient visits, and outpatient prescriptions. AA-specific use and costs included inpatient, outpatient, or ED claims with a primary diagnosis of AA or AA-related medications. The average total healthcare costs were $11,241.21 for all-causes, with $1175.20 in out-of-pocket (OOP) costs. The mean AA-related cost was $419.12, with $104.19 in OOP costs. The primary sources of AA-related expenses were outpatient visits (mean $226.17) and prescriptions (mean $190.39).⁵⁷

A total of 675 participants from the National Alopecia Areata Foundation (NAAF) Database completed a self-reported survey between June 1, 2018, and August 31, 2018, that assessed the self-reported impact of OOP costs on the financial burden of AA. About 93% of survey respondents had active AA, 67% had employer insurance, and 60% were employed full-time. The median annual reported OOP costs for participants were $1354 (interquartile range [IQR], $537-$3300). The OOP categories in the past year with the highest percentage of reporting included wigs, makeup, and/or hats (82%; median, $450; IQR, $50-$1500), vitamins/supplements (67.7%; median, $50; IQR, $0-$200), co-pays/deductibles for doctor visits (57.3%; median, $50; IQR, $0-$300), and hair appointments (56%; median, 50; IQR, $0-$300). The approximate median annual cost of lost income for patients who missed work was $500 (IQR, $200-$2250).⁵⁸

Real-world Data and Treatment Patterns for AA

Researchers analyzed data from an online survey of 216 US residents 18 years or older with AA recruited from the NAAF database from July 2018 to August 2018 to assess the burden of illness. Participants had a self-reported diagnosis of AA, with 77% reporting severe hair loss and 78% reporting the hair loss to involve greater than one-third of the scalp. Eighty-five percent reported at least 1 comorbidity. The most common comorbidities included anxiety and/or depression (47%), allergic rhinitis (35%), thyroid disease (30%), AD (19%), and asthma (13%). AA had a lasting negative effect on self-esteem in 71% of respondents, with concerns of unattractiveness to others (78%), social anxiety (69%), and anxiety about hair regrowth (56%). Survey respondents also reported difficulties in developing new relationships and maintaining existing relationships, with about one-third of romantic relationships ending because their partner could not accept their appearance. Sixty-two percent of respondents withdrew from activities, and 54% reduced interactions with friends upon first hair loss onset. Many survey respondents expressed that AA had adversely affected their education and career, with 51% reporting missed time from school and 45% reporting missed time from their job. Women reported initially and continually concealing their hair loss more than men (initial, 90% vs 84%; continual, 72% vs 38%). Additionally, over 50% of participants using a hairpiece/wig were unsatisfied with their comfort, expense, and appearance. Persistence with treatment declined, except with dietary/herbal supplements, due to perceived lack of effectiveness and adverse reactions, with participants describing treatment as highly unsatisfactory.¹⁸

A retrospective, observational study analyzed claims data from the IBM MarketScan Commercial Claims and Encounters Database and the Medicare Supplemental and Coordination of Benefits Database to understand AA comorbidity burden and treatment patterns. The study examined data of 68,121 participants with a diagnosis of AA between January 1, 2011, and December 31, 2018. The average age at diagnosis was 40 years, with nearly two-thirds being women. About 96% were newly diagnosed, with 15% mild disease, 35% moderate to severe disease, and 50% indeterminate severity. Participants with moderate to severe AA reported 26% prevalence of hypertension, 26% hyperlipidemia, 15% thyroid disorder, 13% contact dermatitis and eczema, and 11% depression. About 56% of participants received treatment for AA or other comorbid autoimmune diseases, with 15% overall receiving 2 or more treatment types. About one-fourth of all participants received treatment within 7 days of diagnosis, and 44% did not receive any treatment in the year following the diagnosis, including 44% newly diagnosed with AA. Most participants received initial treatment and follow-up treatment respectively with TCS (87% vs 80%), OCS (5% vs 30%), systemic antihistamines (2% vs 6%), topical nonsteroids (4% vs 6%), finasteride (4% vs 4%), and IMM (1% vs 4%).⁵⁷

Health Economics

The ICER published an evidence report with an analysis comparing the cost and effectiveness of abrocitinib, baricitinib, tralokinumab, and upadacitinib for the treatment of moderate to severe AD with topical emollients (standard of care) and dupilumab over 5 years.⁵⁹ After considering evidence of clinical benefits in short-term clinical trials, FDA safety concerns, and other contextual considerations, the New England Comparative Effectiveness Public Advisory Council (an ICER independent evidence appraisal committee) voted that there was adequate evidence to show the therapies demonstrated a net health benefit when compared with standard of care alone.⁶⁰ In adults: abrocitinib plus standard of care (8-5), baricitinib plus standard of care (7-6), upadacitinib plus standard of care (9-4), tralokinumab plus standard of care (11-2). In adolescents and adults with mild to moderate AD, compared with emollients alone, ruxolitinib received a vote in support of 12 to 1.

ICER also noted that indirect quantitative comparisons of JAKi with dupilumab and head-to-head comparison of upadacitinib and abrocitinib with dupilumab seem to indicate higher doses of upadacitinib and abrocitinib may be somewhat more effective than dupilumab.⁵⁹ In contrast, baricitinib (at the doses likely to be approved) and tralokinumab may be slightly less effective than dupilumab. Higher dose abrocitinib may also produce a resolution of itch quicker than dupilumab. It also notes these comparisons lack definitive certainty.⁶⁰

Health Benefit Price Benchmarks (HBPBs) are price ranges attaining incremental cost-effectiveness ratios of $100,000 to $150,000 per equal value of life-year or quality-adjusted life-year gained. The estimated HBPB annual cost of treatment or the JAKi and dupilumab when compared with standard of care alone ranged from⁵⁹:

• Abrocitinib: $30,600 to $41,800 (no discounts/placeholder price)
• Baricitinib: $24,400 to $33,300 (aligns with current wholesaler acquisition cost [WAC] price of $29,000)
• Tralokinumab: $25,700 to $35,000 (no discounts/placeholder price)
• Upadacitinib: $30,400 to $41,500 (discounts of 35%-53% from WAC of $64,300)
• Dupilumab from $29,000 to $39,500 (discounts of 6%-31% from WAC of $41,800)

The report also evaluated ruxolitinib cream.⁶⁰ Compared with topical emollients, the report determined the net health benefit for ruxolitinib cream to be comparable or better. Long-term safety data are lacking, but safety concerns are not likely to be as significant due to decreased systemic absorption.⁵⁹ Since clinical trials did not directly compare ruxolitinib cream with TCS, the ICER determined that the evidence for net health benefit compared with other topical medications to be insufficient.⁶⁰

Utilization Management and Formulary Considerations

Managed care organizations use utilization management strategies like PA, step-therapy edits, quantity limits, and work to ensure appropriate use of high-cost specialty pharmacies as part of the formulary benefit design.⁶¹ Appropriate utilization management criteria help reduce unnecessary drug use, cost, waste, and error while promoting optimal clinical outcomes.⁶² Pharmacy and therapeutics committees develop medication utilization criteria through evaluation of safety and efficacy evidence of clinical trials, consensus guidelines, and peer-reviewed literature and cost considerations of therapeutically similar comparators to determine formulary placement.⁶²

In the case of AD and AA, guidelines to inform decision making are lacking.^20,34,35 Currently, there are no FDA-approved medications to treat AA and sparse randomized controlled trial data to support the use of current treatment options.⁶³ Off-label treatment options have demonstrated variable results with high reoccurrence rates. The 2014 United States guideline for AD does not include recommendations about newer FDA-approved agents or information about investigational agents. Short-term JAKi trial data indicate safety and effectiveness, but long-term data are lacking. Additionally, trial evidence requiring labeling changes for JAKi complicates decision making.³⁷ Although there is an unmet treatment need, JAKi are unlikely to be first-line treatment agents for AA or AD until long-term safety and efficacy data become available.

The ICER issued final policy recommendations concerning JAKi and monoclonal antibodies for AD treatment.⁶⁴ For the oral JAKi, clinical experts agreed it was reasonable to:

• Restrict prescribing to specialists or prescribers with a specialist consult
• Limit availability to age in FDA label contingent upon pathways to seek coverage exceptions for patients near the age cutoff with critical unmet need
• Require step therapy with trial and failure with 1 less-expensive off-label systemic agent unless contraindicated
• Approve initial PA for 6 to 12 months to allow adequate time for titrating dose and assessing AEs and clinical response
• Include at least 1 oral JAKi and 1 biologic on the formulary within any step therapy policy (due to the difference between classes onset of action and risk profile)
• Accept prescriber attestation regarding disease severity or operationalize its definition using clinically relevant measures commonly used in clinical practice versus scoring systems used in clinical trials

For topical ruxolitinib cream, experts agreed on specialists prescribing and age restrictions (outlined above), confirming a mild to moderate AD diagnosis with prescriber attestation or clinically relevant definitions, and requiring step therapy with an adequate trial of TCS (strength requirement contingent on age) and/or TCI unless trials are not medically advisable.64 Other management strategies (outside of the ICER report) may include quantity limits, short approval periods, and restricting access to those patients not taking therapeutic biologics, other JAKi, or potent IMM to ensure safe and appropriate noncontinuous use by non-immunocompromised patients.

Specialty tier formulary designation of oral JAKi for AA and AD may be designated due to their high cost, safety concerns, and therapy complexity.⁶⁵ Specialty pharmacists can address cost concerns of the underinsured and uninsured through connection with patient assistance programs. They educate patients about their medications and treatment plan, identify and address treatment barriers, monitor labs and clinical outcomes, assist with PAs, offer medication therapy management services, identify medication-related issues, and manage treatment adherence. Timely outreach to prescribers concerning medication-related concerns may mitigate serious AEs and improve patient outcomes.

Conclusions

AA and AD are common inflammatory skin conditions that may coexist, associated with substantial physical, emotional, and financial burdens, and reduced QOL. The release of inflammatory cytokines involved in the pathogenesis of these autoimmune diseases is regulated by a common intracellular pathway involving JAKs. Despite the availability of treatment options, there is an urgent need for new treatment options with improved efficacy and AE profiles that oral and topical JAKi may fill. Short-term phase 3 clinical trial data have shown improvement with limited serious AEs. However, serious safety concerns with trial data from tofacitinib, which is used to treat rheumatoid arthritis, involving the increased risk of serious heart-related events, cancer, blood clots, and death surfaced, prompting the FDA to mandate a black box warning on baricitinib, tofacitinib, upadacitinib, abrocitinib, and ruxolitinib. Long-term safety and efficacy data for JAKi are needed to establish their proper place in therapy in treating AA and AD. Managed healthcare professionals can play an integral role in ensuring the effective use of these agents to improve clinical outcomes significantly.

Author affiliation: Dana McCormick, PharmD, is pharmacy director, Blue Cross Blue Shield of Texas, Richardson, TX.

Funding source: This activity is supported by an educational grant from Incyte Corporation.

Author disclosure: Dr McCormick has no relevant financial relationships with commercial interests to disclose.

Authorship information: Concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content.

Address correspondence to: Dana_Mccormick@bcbstx.com

Medical writing and editorial support provided by: Lori Uildriks, PharmD, BCPS, BCGP

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