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Executive Summary : A Disease That Extends Beyond Physical Manifestations

Approximately 700,000 people in the United States (US) are The High Costs of AA for Patients diagnosed or affected by alopecia areata (AA), with just under half of these patients estimated to have complete scalp or total Beyond the physical and mental health impact of AA, patients body baldness.1 AA is a serious, recurring with AA face significant out-of-pocket costs. These costs are from that affects all ages, both sexes, and all skin types.2 Although cost-sharing associated with medically covered services for AA symptoms range from bald patches to total loss, this is not and comorbid conditions as well as other interventions not simply a cosmetic issue. The converging physical and mental covered by insurance. For example, many AA patients reported impact of AA often carries a lifetime burden and has a use of non-medical interventions such as wigs or camouflage (71%) 8 substantial cost for payers and patients. and/or dietary changes or supplements (64%). All of this is potentially compounded by work productivity and activity Unmet Medical Need—Recognizing impairment due to AA.9 Mitigating the high out-of-pocket costs faced by patients with AA is key to improving access to treatment. This Is an Autoimmune Condition There are currently no Food and Drug Administration (FDA)- Coverage Policies Must Ensure Access to approved treatments available for patients with AA—just several FDA-Approved Treatments for AA therapies used off-label to manage the condition. With the current lack of formal treatment guidelines, patients are prescribed a AA should not be overlooked as a cosmetic condition. There is variety of therapeutics for AA.3 This makes it difficult for providers to an unmet need for an efficacious long-term treatment option. serve patients with AA effectively. As a result, nearly 8 in 10 patients AA is unpredictable, with spontaneous regrowth of sections of with AA are unsatisfied with the current treatment options.4 hair occurring in 80% of patients within the first year followed by sudden relapse. The Mental Health Impact of AA Over the next two years, US payers and policymakers need to AA is not just the loss of one’s hair, the disease can also have a drive coverage policies for new FDA-approved therapies devastating emotional impact. Patients with AA often experience currently in development to ensure appropriate patient access a variety of mental health issues related to their , such as and affordability when innovation becomes available. Coverage anxiety and depression.5 About 70% of patients reported that AA of future FDA-approved treatments will bring patients with AA had a marked impact on their self-esteem, an impact that did not stability and improved quality of life. 6 abate over time. Mortality risk associated with intentional Currently, a group of dermatologic conditions (, psoriasis, self-harm and psychiatric diseases is shown to be increased in and ) are specifically listed as non-cosmetic by the 7 patients with AA compared to individuals without AA. Centers for Medicare & Medicaid Services for the purposes of Transitioning the view of AA is vital; thinking of AA as simply “hair Medicare Part D coverage. As a result, FDA-approved loss” diminishes the suffering of many with the disease and lessens treatments for these conditions are covered by Medicare. With the importance of providing coverage for treatment. Much of the several shared characteristics between AA and these non- public continues to incorrectly regard AA as a cosmetic or cosmetic, Medicare-covered dermatologic conditions, there is communicable disease. Many patients with AA experience no question that future FDA-approved treatments for AA should diminished health-related quality of life, but patients with AA often be covered by payers. report feeling that their concerns are dismissed.6 01 AmerisourceBergen I Xcenda

Changing the Path Forward for AA Patients Innovative FDA-approved treatments for AA should be covered and deemed “medically necessary” by payers. There are actions payers and policymakers can take to change the trajectory of this condition by improving access to effective treatment, reducing costs, and managing this major life impact:

01 Update the Medicare Part D Drug manual to include 05 Ensure that cost-sharing is affordable for patients any future FDA-approved AA treatments as covered on a monthly and annual basis Part D drugs

06 Capture the medical and therapeutic advances for 02 Establish access and reimbursement for FDA-approved AA in physician-developed treatment guidelines treatments for AA as medically necessary once they become available 07 Support people with mental illness associated with AA in achieving access to affordable therapy to help 03 Avoid utilization management tools such as step manage the psychological impact of AA therapy and prior authorization that restrict patients’ access to preferred FDA-approved treatments 08 Identify any health disparities based on race or ethnicity and ensure health equality by delivering 04 Recognize the long-term nature of AA (hair grows personalized care through coverage and access to minimally every 2 months) and the potential for relapse treatments for AA when developing coverage and access guidelines

09 Involve a diverse range of participants in AA clinical trials

References

1. Benigno M, Anastassopoulos KP, Mostaghimi A, et al. A large cross-sectional survey study of the prevalence of alopecia areata in the United States. Clin Cosmet Investig Dermatol. 2020;13:259-266. 2. Korta D, Christiano A, Bergfeld W, et al. Alopecia areata is a medical disease. Commentary. J Am Acad Dermatol. 2018;78(4):832-834. 3. Meah N, Wall D, York K, et al. The Alopecia Areata Consensus of Experts (ACE) study: Results of an international expert opinion on treatments for alopecia areata. J Am Acad Dermatol. 2020 Jul;83(1):123-130. 4. Hussain ST, Mostaghimi A, Barr PJ, Brown JR, Joyce C, Huang KP. Utilization of mental health resources and complementary and alternative therapies for alopecia areata: a U.S. survey. Int J Trichology. 2017;9(4):160-164. 5. Conic R, Miller B, Piliang M, Bergfeld W, Atanaskova Mesinkovska N. Comorbidities in patients with alopecia areata. Research letter. J Am Acad Dermatol. 2017;76(4):755-757. 6. Mesinkovska N, King B, Mirmirani P, Ko J, Cassella J. Burden of illness in alopecia areata: a cross-sectional online survey study. J Investig Dermatol Symp Proc. 2020;(20) S62-S68. 7. Burns LJ, Mesinkovska N, Kranz D, Ellison A, Senna MM. Cumulative life course impairment of alopecia areata. Int J Trichology. 2020;12(5):197-204. 8. National Alopecia Areata Foundation data on file [not yet published]. NAAF Survey: 2020. 9. Burge R, Anderson P, Austin J, et al. The patient-reported burden of alopecia areata by current severity: a real-world study in US. [unpublished abstract]. 2021. 10. Villasante Fricke AC, Miteva M. Epidemiology and burden of alopecia areata: a systematic review. Clin Cosmet Investig Dermatol. 2015;8:397-403. 11. Centers for Medicare & Medicaid Services (CMS). Medicare Prescription Drug Benefit Manual: Chapter 6 – Part D drugs and formulary requirements. January 15, 2016. Accessed April 28, 2021. https://www.cms.gov/Medicare/Prescription-Drug-Coverage/PrescriptionDrugCovContra/Downloads/Part-D-Benefits-Manual-Chapter-6.pdf

© 2021 AmerisourceBergen This work was done through support of Eli Lilly; editorial control was maintained by the authors. 02 AmerisourceBergen I Xcenda

Alopecia Areata: A Disease That Extends Beyond Physical Manifestations

Alopecia areata (AA) is a serious recurring autoimmune disease that affects all ages, both sexes, and all skin types.1 This is not simply a cosmetic issue. AA can also have a devastating physical and emotional impact. The converging physical and mental impact of AA often carries a lifetime burden, and when left untreated or undertreated, has a substantial cost for payers and patients. A significant unmet need exists to improve treatment strategies and the Alopecia areata is a recurring options available to people with AA. There are currently no Food and Drug autoimmune disease; it is not Administration (FDA)-approved treatments available for patients with AA— just several therapies used off-label to manage the condition. This makes it simply a cosmetic issue. difficult for healthcare providers to treat patients with AA effectively. The converging physical and Nearly 8 in 10 patients with AA report being unsatisfied with the current treatment options.2 Patients are commonly prescribed off-label treatments mental impact of AA often carries with limited effectiveness and often face relapse after treatment. a lifetime burden, and when left Additionally, despite advanced understanding of the autoimmune nature of the disease and the low quality of life (QoL) for patients, many insurers do untreated or undertreated, has a not consider treatment for AA to be medically necessary.1 As a result, substantial cost for payers and patients’ annual and lifetime out-of-pocket costs can be significant. patients. Expanding policymakers’ and payers’ view of AA is vital; thinking of AA as simply “hair loss” diminishes the suffering of many patients living with this disease and minimizes the importance of providing coverage for treatment. In fact, the FDA recognizes AA as a chronic autoimmune disease with a “debilitating emotional and psychological impact on patients which goes beyond the loss of hair.”3 However, there are actions payers and policymakers can take to change the trajectory of this disease by improving access to effective treatment, reducing costs, and managing the major life impact AA has on patients. 03 AmerisourceBergen I Xcenda

Solutions to improve access to effective treatment: 01 Updating the Medicare Part D Drug manual to include any future FDA-approved AA treatments as covered Part D drugs

02 Establishing access and reimbursement for FDA-approved treatments for AA as medically necessary once they become available

03 Avoiding utilization management tools, such as step therapy and prior authorization, which restrict patients’ access to preferred FDA-approved treatments

04 Recognizing the long-term nature of AA (hair grows minimally every 2 months) and the potential for relapse when developing coverage and access guidelines

05 Ensuring that cost-sharing is affordable for patients on a monthly and annual basis

06 Capturing the medical and therapeutic advances for AA in physician-developed treatment guidelines

07 Supporting people with AA in accessing affordable treatment to help manage the psychological impact associated with the disease

08 Identifying any health disparities based on race or ethnicity and ensuring health equality by delivering personalized care through coverage and access to treatments for AA

09 Involving a diverse range of participants in AA clinical trials

This paper will make clear the need to treat AA as a serious autoimmune condition and to appreciate the impact of this disease on patients by highlighting significant data to support payer coverage. • We begin by describing the characteristics of AA that make it a serious autoimmune disease. • The paper then discusses the demographics of the AA patient population and reviews the types of AA. Using patients’ own words, the next section explains the mental and physical impact of AA, including out-of-pocket costs and current treatments. • Finally, the paper concludes by highlighting policy and payer changes that could shift the access paradigm and put patients with AA front and center. Given the burden of the illness and the FDA’s support for better treatment options, it is imperative that payers recognize and cover any FDA-approved treatment option(s). 04 AmerisourceBergen I Xcenda

There Is Pattern Baldness and Then There Is AA; One Is an Autoimmune Disease

AA is a serious autoimmune disease.4 Approximately 700,000 people in the United States (US) are diagnosed or affected by AA with just under half of AA Can Occur at Any Age these patients estimated to have complete scalp or total body baldness.5 to Anyone This makes AA the second most common type of hair loss in the US, just behind pattern baldness, or a receding hair line.6 However, AA is distinctive AA can occur at any age and from pattern baldness and age-related hair thinning. For example, unlike presents at similar rates in males 4 androgenetic alopecia (male pattern baldness), which is caused by and females. Onset before the hormones, AA occurs when the immune system attacks the hair follicles. age of 40 occurs in the majority 13 Like other autoimmune conditions, there is no pattern or predictability to (70%–80%) of patients. Almost AA, and it can occur with other autoimmune conditions or after infections half of patients with AA show and/or . clinical signs before the age of 20, with the condition It is important to understand that AA is a chronic disease that can be predominately severe when it treated, but not cured. The disease has a strong association with several appears in children.13 Cases of AA 7 genes with immune functions. The entry of inflammatory cells into the hair in children tend to lead into 8 follicle’s immune privilege zone is thought to result in hair loss. Like other adulthood and are more severe autoimmune diseases, AA can be treated if the immune signaling pathways than adult-onset cases.14 are inhibited. While the conventional view is AA is believed to be multifactorial, which means that there are a variety of that AA does not differ by race, genetic and environmental factors that contribute to the development and there are gaps in the findings that 7 progress of the disease. For example, studies have observed the impact of require further research.15 The environmental factors, such as nutrient deficiencies (vitamin D, zinc, folate, limited research that exists 9 etc). AA can also be inherited, with nearly 20% of patients with AA having a identified African Americans as 10 family history. having slightly increased odds of While autoimmune diseases can manifest differently across patients, AA diagnosis (odds ratio: 1.77) in 15 common autoimmune diseases tend to cluster in the same individual.11 the US. The authors of the study Unfortunately, patients with AA have a high comorbidity burden.12 A discussed the interplay between multi-year analysis of patients diagnosed with AA identified the most genetic and environmental factors common comorbidities associated with AA as hyperlipidemia (22.4%), as accounting for the racial hypertension (21.8%), thyroid disorders (13.1%), contact or eczema differences, but did not reach a 15 (10.8%), depression (9.5%), and anxiety (8.4%).12 Comorbid autoimmune conclusion. A separate cross- diseases linked to AA included (2.8%), psoriasis (2.1%), sectional analysis found higher chronic urticaria (1.5%), and rheumatoid (1.1%).12 incidence of AA in African American and Hispanic women The linking of these comorbid conditions can be devastating for patients, compared to White women.16 as they often have multiple serious conditions impacting their QoL. In addition, comorbid conditions can drive significant healthcare expenditures for patients and payers. 05 AmerisourceBergen I Xcenda

The Types of AA

There are several subtypes of AA based upon the location and extent of hair loss. AA most commonly causes scalp hair loss, but can also involve the face, including , , and . The clinical spectrum of AA ranges from patchy hair loss on the scalp to complete baldness across the entire body.17 AA is often classified into 3 broad categories based on the amount of hair loss: patchy alopecia areata, , and .18

Patchy alopecia areata:

Patchy alopecia areata is the most common type of AA.6 This type is 1+ characterized by 1 or more patches of hair loss on the scalp.6 The patches of hair loss on the patchy subtype may remit quickly, be persistent over time, or progress scalp to total scalp or loss.6 As many as half of patchy AA patients spontaneously regrow hair.19 Relapse may occur at any time.19

Alopecia totalis (loss of all hair on the scalp):

Alopecia totalis occurs when the patient has 100% or near total hair loss on the scalp.6 It is estimated that 5% of patients with AA develop 100% alopecia totalis.20 The median time between the presentation of AA and or near total hair loss on the 21 scalp the development of alopecia totalis is thought to be 1 year. Spontaneous recovery occurs in less than 10%, and long-term complete recovery is about 9%.22 The totalis variant generally has a worse prognosis than patchy, up to nearly a quarter of alopecia totalis patients do not respond to therapy.23

Alopecia universalis (loss of hair across the body):

Approximately 9% of patients with AA have loss of all scalp and body hair, classified as alopecia universalis.2 Universalis means losing nasal ~9% hair, eyebrows, and eyelashes, which leads to physical challenges later of patients with AA have loss of all scalp and body (discussed herein).24 Alopecia universalis is more advanced than other hair types and is the most severe.25 Similar to alopecia totalis, only 9% of universalis patients achieve complete recovery.22

Up to 25% of patients with AA progress to alopecia totalis or alopecia universalis, at which point, full recovery is rare.26 According to one study, without treatment, 55% of individuals with chronic AA, lasting over 12 months,27 will have persistent multifocal relapsing and remitting disease.27 Around 30% will develop alopecia totalis, and 15% will develop alopecia universalis.27 The clinical course of AA may be characterized by complete remission, progression to alopecia totalis or alopecia universalis, or recurring over a long period of time.28 Patients may have several incidents of hair loss and subsequent regrowth throughout their lives.8 Hair loss may naturally remit, although the time frame for regrowth may be months to years.8 06 AmerisourceBergen I Xcenda

A Significant Unmet Medical Need Exists for Patients With AA

Imagine being a teenager or a professional who has a new job and has an occurrence of AA. While hair can be changed and adopted into all sorts of styles, the absence of hair is not the same. Patients report a range of physical and psychological implications, as well as comorbidities associated with their AA. And, to add to the anxiety, AA is a relapsing-remitting disorder, so patients can feel like they are always waiting for their hair loss to potentially get worse. Coping with AA is a daily To enhance the likelihood of hair regrowth, the first-line and most common treatment for AA is steroids.29 An assessment of treatment patterns and challenge, one for which there healthcare costs and utilization among patients with AA found that of are currently no FDA-approved patients receiving treatment, 80.3% received topical steroids and 30% treatments. received oral steroids for AA.12 Any sign of hair regrowth may be helpful for the psyche of patients with AA, although the reaction to steroids can be The FDA has publicly different for every patient. Like all current non-FDA-approved treatments for AA, steroids do not prevent new hair loss from developing. acknowledged the need for safe 3 Coping with AA is a daily challenge, one for which there are currently and effective treatments for AA. no FDA-approved treatments. Instead, patients with AA assume the cost of unsuccessful medical therapies and camouflage, such as wigs or microblading, often with limited to no coverage from insurance and lost income. The FDA has publicly acknowledged the need for safe and effective treatments for AA.3 AA is one of only 24 disease-specific meetings hosted by the FDA, known as Patient-Focused Drug Development (PFDD) meetings. During the 2017 PFDD meeting, patients living with AA shared the day-to-day impact of the disease and described the ineffectiveness of current treatment options.3 Hundreds of patients with AA participated either in person, live webcast, or through written comments.3 After engaging with patients, the FDA recognized the “significant unmet medical need for treatments for patients with AA.”3 07 AmerisourceBergen I Xcenda

The Physical Implications of AA

Hair—both on the head and on the body—serves as protection from the elements.30 The hair loss associated with AA leaves patients susceptible to sunburn, eye irritation, allergies, poor thermoregulation, and harmful airborne particles.31 A recent population-based study investigated the atopic comorbidities among patients with AA. The data revealed a higher prevalence of asthma (7.8%–6.5%), allergic rhinitis (16%–12.8%), and allergic conjunctivitis (23.5%–19.6%) as a result of hair loss.32 These are all considered The hair loss associated with AA long-standing respiratory conditions that impact QoL and productivity and leaves patients susceptible to can require pharmacologic treatment. sunburn, eye irritation, allergies, Dermatological Issues poor thermoregulation, and Several dermatologic disorders are linked to AA. First, patients with AA harmful airborne particles.31 have a significantly increased risk for atopic dermatitis (eczema), a chronic inflammatory skin disease that causes the skin to become Data also indicates a higher inflamed and irritated, making it extremely itchy.33 A systematic review and meta-analysis found 9.4% of patients with AA had a previous and/or prevalence of asthma (7.8%–6.5%), current history of atopic dermatitis compared to 1.9% of patients without allergic rhinitis (16%–12.8%), and AA.33 Alopecia totalis or universalis patients were associated with higher allergic conjunctivitis (23.5% to odds of atopic dermatitis.33 19.6%) as a result of hair loss.32 In addition, there has long been a higher incidence of vitiligo in patients with AA. It is estimated that as high as 8% of patients with AA develop Several dermatologic disorders vitiligo.34 Vitiligo is a disease that causes loss of skin color in patches.35 The discolored areas usually get bigger with time.35 Vitiligo usually appears are also linked to AA. before age 20 and may affect nearly all skin surfaces.36 Patients with vitiligo are more likely to develop extensive AA.37 Vitiligo is among a group of dermatologic conditions (acne, psoriasis, and rosacea) specifically listed as non-cosmetic by the Centers for Medicare & Medicaid Services (CMS) for the purposes of Medicare Part D coverage.38 As a result, FDA-approved treatments for these conditions are covered by Medicare. With several shared characteristics between AA and these non-cosmetic Medicare-covered dermatologic conditions, there is no question that future FDA-approved treatments for AA should be covered by payers.

Beyond the Physical, the Hair is an important component Mental Health Impact of AA of identity and self-image.39 Hair is an important component of identity and self-image.39 Patients with AA often experience a variety of mental health issues related to their hair Patients with AA describe loss, such as anxiety and depression.40 feeling ashamed, humiliated, Given the unpredictable clinical course of AA and the impact on and profoundly depressed as appearance, it is not surprising that the disease carries a significant mental a result of hair loss.41 and emotional burden.4 Several systematic reviews connect the extent of the disease with the amount of psychological distress.23 08 AmerisourceBergen I Xcenda

Patients with AA who participated at the FDA’s 2017 PFDD meeting candidly Relationships (Romantic) described their loss of hair as “traumatic.”3 Several patients referenced the emotional toll AA took on their life, which was oftentimes severe.3 Many said Having AA continues to be an impediment to their hair was a core part of their identity while one patient remarked that developing new relationships. In a recent study, she would, “give anything to get my hair back.” This patient made the participants with AA found dating difficult or avoided remark after she was mistaken for a boy and asked if she was in the correct it entirely due to low confidence and fear of bathroom. judgment or rejection due to their AA.41 Patients reported not knowing how to speak to new partners The effects of AA are far-reaching, not only for the patient, but for the about AA and worried that potential partners would 3 patient’s family, coworkers, and friends. Patients with AA describe find them unattractive.41 Individuals affected by AA feeling ashamed, humiliated, and profoundly depressed as a result of hair have also reported problems within their existing 41 loss. About 70% of patients reported that AA had a marked impact on romantic relationships, citing feelings of insecurity 42 their self-esteem an impact that did not abate over time. The course of about appearance, which was often related to AA is unpredictable, with spontaneous regrowth of sections of hair decreased intimacy.46 This anxiety can further occurring in 80% of patients within the first year, followed by sudden increase feelings of isolation and depression.41 relapse.37 The risk of relapse introduces a higher likelihood of paranoia and obsessive-compulsive traits.4 This social impact to relationships is similar for conditions like vitiligo or acne—both of which have Social Stigmatization reimbursed covered treatments. An assessment of the psychological impact of vitiligo found the Patients with AA are often misunderstood and mischaracterized. condition negatively affected personal relationships Much of the public continues to incorrectly regard AA as a cosmetic or and even marriage potential for over half of patients communicable disease. Stigmatization and cultural perception of hair loss with the condition.47 The stigmatization of acne had drive cumulative life course impairment for patients with AA.43 This stigma been found to impact romantic relationships for acne leads to a significant reduction in patients’ QoL. patients as well.45 Non-sufferers commonly perceived The diagnosis of AA has been described as “emotionally devastating.”41 The those with acne as unattractive.45 stigmatization associated with AA often presents in the form of bullying or being misunderstood by coworkers and the public.3 Patients with AA at the FDA’s 2017 PFDD meeting described being bullied at school, having wigs and hats snatched off, and being insulted or mocked by classmates.3 The bullying was described as carrying a lifelong burden of anxiety and depression.3 One woman at the FDA meeting stated she lived in constant fear of “being discovered as a bald woman, fearing being thought of as sick, bizarre, ugly, or worse.”3 Others avoided social gatherings altogether.3 A group of patients remarked that the depression and emotional toll of AA brought suicidal ideation, while some stated that they had already previously attempted suicide.3 Patients with AA have similar stories to patients with psoriasis or acne. Like AA, psoriasis, which has 20+ FDA-approved and covered drugs, is a highly stigmatized autoimmune dermatologic condition. It is perceived as a contagious disease and a result of poor personal hygiene.44 As a result, patients with psoriasis are more likely to experience depression and lower QoL.4 Similarly, acne, recognized by CMS as non-cosmetic, is associated The course of AA is unpredictable, with greater stigmatization.45 In many instances, acne sufferers, like patients with AA reported bullying, teasing, and social exclusion.45 with spontaneous regrowth of sections of hair occurring in 80% of patients within the first year, followed by sudden relapse.37 Patients with AA reported significantly higher disease burden, both emotionally and physically. 09 AmerisourceBergen I Xcenda

Depression/Anxiety/Impact on Overall QoL Risk of Death Associated With AA A recent study showed a higher likelihood of depression for patients with AA. Mortality risk associated with intentional self-harm The incidence of major depression in patients with AA was reported as 8.8% and psychiatric diseases is shown to be increased in compared with 1.3% to 1.5% in the general population.48 A connection exists patients with AA compared to individuals without between AA and depression regardless of which disease occurs first.49 For AA.52 Participants at the FDA meeting described the example, patients with a major depressive disorder were at a 90% increased connection between their depression from AA and risk of developing AA.49 Patients with AA had a 34% increased risk of thoughts and attempts of suicide.3 Patients with developing a major depressive disorder.49 alopecia totalis or universalis saw their risk associated with self-harm significantly increase.15 AA Patients with AA often exhibit considerable anxiety from the general tends to be associated with more self-isolation, and uncertainty surrounding disease progression; many patients endure an inability to describe the feeling of hair loss to emotional and psychological distress on a daily basis.10,50 A generalized others—known as alexithymia. The prevalence of anxiety disorder has been reported in 18.2% of patients with AA compared alexithymia was reported to be 23% to 50% in with 2.5% of the general population.48 patients with AA,48 compared to 5% to 14% for the Analysis of cross-sectional patient survey data indicated that with general public.53 Relatedly, an increased risk of increasing severity, patients with AA reported significantly higher disease mortality due to any cause has been found in burden, both emotionally and physically: emotions (mild 39.6±26.3 vs patients with similar dermatologic conditions atopic moderate 56.6±29.8 vs severe 63.1±31.9, P<0.0001), symptoms (10.1±17.9 vs dermatitis and psoriasis—both of which have 18.2±22.5 vs 20.8±26.2, P=0.0265) and functioning (17.0±23.7 vs 28.8±29.3 vs covered treatments.54,55 36.4±33.1, P=0.0018).51 Work and activity impairment due to AA also increased with disease severity: overall work impairment (4.9%±11.7% in mild AA vs 12.5%±17.2% in moderate AA and 18.4%±20.2% in severe AA, P=0.0013) and activity impairment (7.1%±14.0% in mild AA vs 12.3%±16.0% in moderate AA and 19.7%±23.5% in severe AA, P=0.0007), as measured by the Work Productivity and Activity Impairment questionnaire.51 Accordingly, patients with AA report impaired health-related quality of life Patients with AA had a 34% (HRQoL).4 In studies of HRQoL in AA, patients responded to validated questionnaires about how AA impacts their life (eg, symptoms and feelings, increased risk of developing a daily activities, relationships, physical functioning, social functioning, and major depressive disorder.49 bodily pain).4 The most frequently used measures were the Life Quality Index (DLQI) and Short Form-36 (SF-36) for general health; and the Patients with AA often report feeling Alopecia Areata Symptom Impact Scale, the Alopecia Areata Quality of Life Index, and the Alopecia Areata Quality of Life for hair-specific QoL measures. that their concerns related to the psychological and social impact of A summary of multiple studies of patients completing the DLQI found that 42 almost 80% of patients with AA reported impaired HRQoL.4 Studies that the disease are dismissed. included SF-36 scores for patients, as well as a matched control group for the purpose of comparison, showed patients with AA had lower HRQoL in Almost 80% of patients with AA mental health, vitality, and role-emotional domain, suggesting diminished reported impaired health-related energy levels and reduced social functioning.50 Studies implementing 4 hair-specific QoL measures indicated that HRQoL can be affected by many quality of life. factors, including more severe hair loss and concomitant depression. A lower HRQoL was observed in the pediatric population as well, based on the Pediatric Quality of Life Inventory compared with controls. The overall HRQoL for parents of children with AA was also found to be poor. Additionally, children with AA may have a higher incidence of anxiety and depression, further reducing their QoL.4 Many patients with AA experience diminished QoL, but patients with AA often report feeling that their concerns related to the psychological and social impact of the disease are dismissed.42 The poor HRQoL in patients with AA may play a role in the development of psychiatric comorbidities such as depression, anxiety, and obsessive-compulsive disorder.50 10 AmerisourceBergen I Xcenda

The High Costs of AA for Patients

Beyond the physical and mental health impact of AA, patients with AA Beyond the physical and mental face significant out-of-pocket costs. These costs are from cost-sharing associated with medically covered services for AA and comorbid health impact of AA, patients with conditions, as well as other interventions not covered by insurance. For AA face significant out-of-pocket example, many AA patients reported using non-medical interventions, costs. such as wigs, other types of camouflage (71%), and/or dietary changes or supplements (64%).56 The out-of-pocket costs are potentially compounded by work and productivity losses. AA Treatment Patterns

Mitigating the high out-of-pocket costs faced by patients with AA is key A claims analysis of the US managed care to improving access to treatment. Out-of-pocket costs were $1,175.20 for population found total average 12-month all-cause 12 all-causes and $104.19 for AA. AA-related expenses likely extend well costs for patients with AA were higher compared to beyond those reported in claims data because much of AA treatment non-AA patients ($8,853 vs $5,548). Higher average occurs outside of the health plan. costs among patients with AA were driven primarily Currently there are no FDA-approved treatments for AA; however, with the by differences in ambulatory ($4,138 vs $2,266) and current diversity in expert opinion and lack of formal treatment guidelines, pharmacy costs ($2,422 vs $1,372)—without an 57 patients are prescribed a variety of therapeutics for AA.29 This starts with FDA-approved treatment for AA. Not surprisingly, topical steroids.12 Based on recently released research, mean total among patients with AA, those with alopecia healthcare costs were $11,241.21 for all causes and $419.12 for treating AA.12 totalis and universalis forms have significantly higher costs.57 Treatments prescribed to patients with AA within 12 months As previously described, AA is often coupled with of diagnosis other autoimmune diseases. The onset of multiple autoimmune diseases may require significant Index treatmenta Follow-up treatment expenditures for diagnostics and treatment Treatment class (N=17,062) (N=37,995) management. Diagnosis of certain autoimmune Topical steroidal 14,804 (86.8%) 30,526 (80.3%) diseases may be challenging, as the symptoms and issues presented by the patient may resemble Oral steroids 801 (4.7%) 11,394 (30.0%) several autoimmune conditions.58 This can lead to a Systematic antihistamines 309 (1.8%) 2,346 (6.2%) delay in diagnosis or patients being misdiagnosed Topical nonsteroidalb 701 (4.1%) 2,172 (5.7%) entirely. Some autoimmune diseases are well known, and others are rare and difficult to diagnose.59 Finasteride 723 (4.2%) 1,432 (3.8%) Immunomodulatorc 116 (0.7%) 1,367 (3.6%) Many of the autoimmune conditions associated with AA are best treated through innovative Acupuncture 100 (0.6%) 630 (1.7%) systemic therapies that often have significant Phototherapy 129 (0.8%) 295 (0.8%) out-of-pocket costs for patients—and that is once Systemic nonsteroidal 37 (0.2%) 127 (0.3%) they get past any utilization management hurdles.60 On average, patients take 3 medications Intralesional triamcinolone 9 (0.1%) 32 (0.1%) to treat 1 autoimmune condition.61 Platelet-rich plasma 0 (0.0%) 6 (0.0%)

Some patients received ≥2 treatment types. a Index treatment: treatment prescribed to patients within 7 days of AA diagnosis. The index treatment group is a subset of the broader follow-up treatment group. b Includes pimecrolimus, tacrolimus, calcipotriene, calcipotriene and betamethasone dipropionate, minoxidil, anthralin or dithranol, and topical antihistamines. 11 AmerisourceBergen I Xcenda

Mental Health Treatment As might be expected, patients with AA utilize mental health treatments— outside of the contemporary AA treatments—to aid in management of their disease.2 A cross-sectional survey found patients with AA consulted many healthcare professionals to manage different aspects of their AA, including dermatologists (89%), primary care physicians (61%), psychological or behavioral health specialists (23%), hair loss specialists (22%), Women often rely on wigs and rheumatologists (13%), and pharmacists (12%).42 In one longitudinal cohort cosmetic devices which are often study, the ratio of patients visiting a psychiatric clinic was approximately 1.6 uncomfortable and expensive. times higher in patients with AA than the control group.62 The highest 42 average cost for patients was for counseling or therapy at $1,961 per year. The average estimated cost of A sample of US hospitalization data revealed that patients with AA had higher one human hair wig or hairpiece proportions of mental health diagnoses.63 These mental health diagnoses 42 included anxiety, mood, attention-deficit/hyperactivity and conduct, and is around $2,211 per year. psychotic disorders.63 The average primary hospitalization and cost for a mental health disorder in patients with AA was 6 days and $11,907.63 Even synthetic wigs, worn daily, Despite the high demand for mental health treatment, barriers to mental can cost several hundred dollars health coverage and access still exist. These perceived and actual and need to be replaced every barriers start with high out-of-pocket costs for patients due to lack of 71 access to in-network providers and lack of coverage by both public and few months. private payers for mental health services. Mental health providers have some of the lowest participation rates of all specialties, in both Beyond wigs, a variety of hair concealment options government-sponsored and private health plans. Only 62% of exist. Pigmented concealing powders can be used psychiatrists were found to accept Medicare or private insurance.64 As a to camouflage thinning hair. Women, more than result, patients in need of mental healthcare are left to navigate narrow men, are likely to draw or purchase eyebrows which networks to find a physician who will accept their plan or use out-of- is socially acceptable. For men, it is not socially network care, which leads to more out-of-pocket costs. acceptable. This is the same for eyelashes; women who lose them from AA can always purchase and In a recent study, enrollees with mental health conditions were found to use fake eyelashes, whereas men would not. have significantly higher out-of-pocket costs than those with chronic physical conditions.65 Specifically, individuals with mental health On top of these high costs, it is common for conditions had cost-sharing payments for out-of-network care $341 patients with AA to miss time from work due to their higher than those with diabetes and no mental health condition.65 AA, not to mention their comorbid conditions.42 The average time spent attending therapy was Concealment Not Covered reported by 23 patients to be 1.5 hours per week Society puts an inordinate amount of pressure on beauty and attractiveness. and almost 4 hours per week when their AA was at 42 While it may be more socially acceptable for a man to be bald, as some its worst. Some patients with AA may even resign choose to shave their head regardless of thinning or lost hair, there is limited from their positions entirely or pause from seeking societal acceptance of a bald woman. Women often rely on wigs and employment, citing stress from having to wear a 42 cosmetic devices which are often uncomfortable and expensive. wig at work or unsupportive coworkers. Even though a wig is critical to help with the emotional burden of AA, Given the high burden of illness for patients with Medicare does not consider wigs necessary and reasonable.66 In the AA, long-term access and coverage of FDA- commercial market, coverage for wigs is generally excluded unless approved treatments for AA is critical. Innovative specifically listed by the payer as a covered healthcare service. Medicare FDA-approved treatments for AA should be Advantage plans (Medicare Part C) may offer wigs as a supplemental covered and deemed “medically necessary” by benefit for hair loss that is a result of . However, wigs are payers. While the criteria used by payers to define not offered as a supplemental benefit for any other purpose, such as for “medically necessary” may slightly vary in any hair loss from AA.67 Meanwhile, a small number of states mandate payer instance, FDA-approved treatments should meet coverage for wigs that are worn for hair loss caused by AA.68,69 While a the requirement, as they are needed to treat the few additional states mandate coverage for wigs worn for hair loss burden associated with AA. In summary, medical caused by cancer treatment.70 Coverage is often subject to dollar or necessity should equate to payer coverage for frequency limits, as specified by the payer. FDA-approved treatments for AA. The average estimated cost of one human hair wig or hairpiece is around $2,211 per year.42 These types of wigs can last 3 to 4 years.71 But even synthetic wigs, worn daily, can cost several hundred dollars and need to be replaced every few months.71 This added financial burden is another source of stress for patients with AA. 12 AmerisourceBergen I Xcenda

Alleviating the Burden of AA on Patients

There is a clear need to rethink how AA is framed among payers and policymakers. Given the burden of the illness, and the FDA’s support for better treatment options, plans must recognize the need to cover treatment option(s) approved by the FDA. That is just one of the steps that is needed; other potential ways of alleviating the burden of AA through improved access to treatments include:

Officially classifying future FDA-approved treatments for AA as covered Medicare Part D drugs. Today, the CMS Part D prescription drug manual lists conditions, which, while often perceived as cosmetic, are typically treated as dermatology disorders and thus covered (eg, acne, psoriasis, rosacea, vitiligo).38 CMS specifically classified FDA-approved drugs for the treatment of these dermatology conditions as covered under the Part D benefit. This list should be updated to include AA so that any FDA-approved treatment option(s) are more accessible to patients living with the disease.

Ensuring payer coverage of FDA-approved treatments used for a medically accepted labeled indication, whether in addition to or in place of being medically necessary. This will minimize or eliminate the time between FDA-approval and CMS coverage determination based on medical necessity. This will also differentiate FDA-approved treatments from experimental and investigational off-label therapies currently available for AA. Coverage of FDA-approved treatments for AA would allow healthcare practitioners and dermatologists to prescribe the most effective long-term treatment option.

Recognizing the long-term nature of AA and the potential for relapse in benefit plan design; in addition to the burden of comorbid conditions and ensuring that cost-sharing is affordable for patients on a monthly and annual basis.

Removing access hurdles. Patients with AA are often managing multiple comorbidities, and access to treatment should not be another burden. Appropriate access would help with the downstream costs associated with the burden from the comorbid conditions faced by the AA population. Patients subjected to utilization management experience delays in treatment, increased out-of-pocket expenses, added stress, and poorer health outcomes. Furthermore, patients should have access to the formulation and dosage of any future, FDA-approved treatments as prescribed by a healthcare practitioner in accordance with the medically accepted label without additional payer restrictions, ensuring that cost- sharing is affordable for patients on a monthly and annual basis. Finally, in preparation for future FDA-approved treatments for AA, payers who currently have coverage policies prohibiting coverage for hair loss should rescind or modify those guidelines so that they do not present access challenges for patients.

Covering mental health treatment linked to the disease.

Recognizing the need to not exacerbate health disparities and to promote health equality by ensuring access to innovative treatments for patients—regardless of income.

Achieving diverse representation in clinical trials to ensure AA medicines are as effective as possible for patients who use them.

Serving all communities and patient populations with innovative, new treatments, regardless of income or geography.

Capturing future medical advances in formal treatment guidelines to improve patient access to effective care. Patient preference for an effective long-term treatment is clear, as evidenced by a willingness to endure high out-of-pocket costs for current ineffective therapies and wigs. 13 AmerisourceBergen I Xcenda Conclusion

AA is an autoimmune disease with a significant and costly burden of illness. The burden manifests as physical implications, as well as significant QoL and productivity impact-related issues from hair loss. AA should not be overlooked as cosmetic. There is an unmet need for an efficacious long-term treatment option. Coverage of future FDA-approved treatments will bring patients with AA stability and improved QoL. Over the next 2 years, US payers and policymakers need to develop coverage policies for new FDA-approved treatments currently in development to ensure appropriate patient access and affordability when innovation becomes available. Coverage and reimbursement policies for FDA-approved treatments should meet the high physical and emotional burden faced by patients with AA. These policies will play a pivotal role to help patients with AA avoid the long-term suffering and overwhelming burdens associated with this disease.

© 2021 AmerisourceBergen This work was done through support of Eli Lilly; editorial control was maintained by the authors. 14 References Amerisourcebergen I Xcenda

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