Cumulative Life Course Impairment of Alopecia Areata.

Alopecia areata (AA), an unpredictable, nonscarring hair loss, is commonly perceived as a cosmetic, rather than medical, concern. However, substantial evidence exists describing the negative impact on quality of life, as the disease affects patients personally, socially, financially, and physically. Over time, the cumulative disability may perpetuate poor confidence, social disconnection, negative coping strategies, and failure to achieve a full life potential. Here, we describe the cumulative life course impairment (CLCI) of AA by examining the complex interaction of (1) stigmatization, (2) physical and psychiatric comorbidities, and (3) coping strategies. The model aggregates existing cross-sectional data, which have previously captured disease burden only as snapshots in time. Thus, by examining cumulative effects, the CLCI model serves as a proxy for longitudinal data to better describe life course epidemiology of the disease. Copyright:

INTRODUCTION

Despite substantial evidence demonstrating the negative effects on quality of life (QoL), alopecia areata (AA) is commonly considered to be a cosmetic concern by insurers and physicians alike. The Cumulative Life Course Impairment (CLCI) concept aims to characterize the compounding effects of disease resulting in a failure to achieve “full life potential” in some patients. It serves as an alternative to longitudinal data and can aid physicians in identifying high-risk patients to promote early intervention and expand access to treatment.

Background

AA is an inflammatory, nonscarring hair loss, affecting all ages, sexes, and ethnicities. Among the US population, the cumulative lifetime incidence is 2%, with 0.1%–0.2% prevalence in the general population.[12] AA most commonly presents as sudden onset of well-demarcated, asymptomatic, patches of hair loss. Approximately 5% of AA cases will progress to alopecia totalis (AT), a loss of all scalp hair, or alopecia universalis (AU), a loss of all scalp and body hair.[3] Conventionally, patients under 40 years of age are affected, with nearly 50% seeking treatment before the age of 20 years.[4] The condition is notoriously unpredictable,[5] with age at presentation, AA subtype, and duration of hair loss all predictive of prognosis. To date, there is no definitive treatment available.[6]

AA is an autoimmune disease driven by the loss of immune privilege of the anagen hair follicle. Infiltration of autoreactive cytotoxic T-lymphocytes disrupts hair cycling, causing premature entry into the telogen phase. Notably, inflammation is targeted at the hair bulb, sparing the follicular stem cells, and allowing for potential re-growth.[78] Recently, upregulation of the Janus kinase (JAK) transcription pathway has been identified in the pathogenesis of AA, with targeted therapies showing promise for treatment.[9]

The physical discomfort of AA is limited, perhaps leading to the common perception that AA is purely a cosmetic condition. However, the negative effects of AA on health-related QoL have been well documented, which are comparable to patients with chronic skin disease such as psoriasis.[1011] In fact, the effects are far reaching, not only impacting QoL of individuals with AA, but also their families.[12] Patients' willingness to pay for a cure matches that of patients with vitiligo, with a median value of 13%–22% of monthly income.[13] Even still, the treatment for AA is not viewed as medically necessary by many insurers, and in some cases, physicians.[14] It also remains underfunded by government agencies relative to the estimated disability burden among cutaneous diseases.[151617]

CUMULATIVE LIFE COURSE IMPAIRMENT

Stigmatization and cultural perception of hair loss drive social, economic, and emotional burden. Previous studies have sought to evaluate these effects by producing cross-sectional data in the single domains of functioning. However, the full disease impact cannot be fully appreciated through these snapshots alone. Instead, a more complete assessment of disability accounts for the complex series of emotional and physical consequences over a lifetime.

This concept was first proposed by Kimball et al. as the “CLCI.”[18] Through this model, the collective effects of stigmatization, physical and psychological co-morbidities, and coping strategies are compiled. First developed to evaluate psoriasis, the concept has since been applied to several other dermatologic conditions, including vitiligo, atopic dermatitis, epidermolysis bullosa, chronic wounds, acne, hidradenitis suppurativa, melanoma, and nonmelanoma skin cancers.[192021222324] It proves a powerful tool to evaluate the conditions causing functional impairment, prominent subjective symptoms, and/or profound psychosocial impairment.[23]

Personal patient accounts serve as compelling narratives but cannot capture implications for the broader patient population. Instead, life course epidemiology would best be assessed with longitudinal data. However, it is rendered largely infeasible by the complexity of required statistical techniques.[25] Alternatively, CLCI serves as a proxy. Here, we apply the core components of the CLCI concept to AA, as outlined in Table 1, by identifying cross-sectional data within each category of the established model. Thus, we propose a unique view of the cumulative impact of AA and its alterations of life trajectory.

Table 1

Intrapersonal components of the cumulative life course impairment model applied to alopecia areata

Stigma	Psychological comorbidities	Social/financial impact	Negative coping	Positive coping
Illness/cancer patient (perception)	Depression	Avoidance of activities/socializing	Wigs/make-up	Wigs/make-up
Not “life threatening” (perception)	Anxiety	Worry about wig being “found out”	Evolution of poor coping mechanisms	Support groups
Loss of self-identity	Suicidal ideation	Altered career course	Not worthy of support or treatment	Family/friends
Victim of bullying	Social avoidance	Inauthenticity of relationships	Lack of empathy from providers	Sense of part of larger AA community
Loss of femininity	Stress as a trigger for AA onset or recurrence	Restrictions on romantic/sexual relationships	Delayed referral to counseling	Self-acceptance
Pressure to conceal hair loss	Persistent worry about future loss	Cost of concealment and treatment	Minimization/expected to “come to terms with it”	Hope for future

AA – Alopecia areata

METHODS

A search of the PubMed database was conducted in October 2019 using a combination of free text keywords and medical subject headings for the concepts of AA and the way the condition may impact the individual based on the CLCI model. Numerous synonyms for the outcomes of interest were used and can be found in accompanying [Appendix S1]. The results were limited to the English language citations. Publications specific to AA that supported one of the CLCI concepts were included as evidence.

PHYSICAL CO-MORBIDITIES

Physiologically, hair serves as protection from the elements, including sun and air-borne particles. Thus, loss associated with AA leave patients susceptible to sunburn, eye irritation, and allergies.[26] However, the biological function of hair is only a small piece of the larger impact on physical health, as AA is associated with many systemic diseases.[27] The most prevalent association is nail abnormalities, with 46% of pediatric patients and 14%–19% of adults presenting with nail findings such as pitting or trachyonychia.[2829]

Intuitively, AA is strongly associated with other autoimmune conditions. The most common is thyroid disease, which is found in 19% of patients;[3031] however, AA is also reported to be associated with diabetes mellitus, psoriasis, vitiligo, lupus, multiple sclerosis, and rheumatoid arthritis.[32] In addition, patients with AA have an increased risk for atopic diseases, such as atopic dermatitis, allergic rhinitis, and asthma.[3334] Interestingly, nutritional deficiencies, including Vitamin D and iron are also more common in AA patients[3335] as are sleep disorders.[36]

STIGMA

Hair is more than “just hair,” as it serves as a symbol of gender, age, beauty, status, values, health, and group membership.[37] In a qualitative survey study conducted by Davey et al., patients report feeling “monstrous or alien,” noting the fact that villains and evil characters, such as Voldemort, Gollum, Nosferatu, are portrayed as bald.[38] They frequently encounter misconceptions of sickness or chemotherapy treatment, with public ostracizing or pity as a result.[39] Patients are even accused of belonging to extremist cults. The stigmatization is compounded by the high visibility and difficulty of concealing the condition. Thus, men and women alike, feel obligated to wear hats, scarves, wigs and make-up or fear being seen in public. The evolving effect is profound, as individuals with AA were found to have higher rates of self-stigmatization than mental health patients.[40]

PSYCHOLOGICAL CO-MORBIDITIES

Several mechanisms have been proposed linking stress to the development of AA. For instance, increased corticotropic releasing hormone secretion has been shown to stimulate neurogenic inflammation leading to the collapse of follicular immune privilege.[41] This is demonstrated clinically, as up to 58%–77% of patients report a stressful life event preceding the onset of AA.[424344] However, the role of stress in the development of AA remains controversial.

While the reciprocal relationship of stress and hair loss remains unclear, data evaluating psychiatric comorbidities associated with AA have been generated by cross-sectional, retrospective, case-controlled, epidemiologic, and survey studies [Tables 2-4]. The results demonstrate the higher rates of depression and anxiety, adjustment disorder, obsessive-compulsive disorder, and alexithymia.[545556575859606162] Patients with AA were found to be at an elevated risk of suicide and intentional self-inflicted injury (odds ratio: 2.84).[54] Mortality risk associated with intentional self-harm is significantly higher in AA patients, with a 2-fold higher risk for young adults with AT or universalis.[58] Disease severity appears to be an important factor, as the number of psychiatric visits in AA patients was increased according to the number of intralesional injection treatments received.[59]

Table 2

Social and financial-related evidence for cumulative life course impairment

Reference	Study type	Patients	Assessment Tool	Evidence
Social and financial
Aghaei et al. (2014)[45]	Case-control study	40 AA patients40 age-and sex-matched controls	Beck Depression InventoryBeck Anxiety InventoryEysenck Personality Questionnaire	There was a significant difference in educational level between AA patients and controls (P=0.001), revealing that AA group had a lower level of education
Li et al. (2018)[46]	Cross-sectional survey study	81 patients with AA	Online survey distributed to NAAF patient database	Women had a decreased sexual QOL with mean Sexual QOL-Female score of 51.3±22.9Men had a decreased sexual quality of life with mean Sexual QOL-male score of 62.7±33.9 (higher scores indicate greater sexual quality of life)
Christensen et al. (2017)[47]	Cross-sectional questionnaire study	69 patients with AA and their parents	Frequency and type of bullying reported	18% elementary school children had been bullied at least once, while 13% middle school-aged children and 40% of high school and college-aged adolescents were bulliedBoys experienced more frequent bullying, including physical bullying (P=0.04)
Díaz-Atienza and Gurpegui (2011)[48]	Case-controlled interview and questionnaire study	31 AA patients (7-19 y/o)23 children with epilepsy25 healthy sibling controls	Interview on childhood development (with parent), personality questionnaires, family climate questionnaires, blood and urine analysis	29% of AA patients had perceived financial difficulties as compared to 9% epilepsy42% of AA patients from single-parent family as compared to 9% epilepsy (P=0.007)
Kacar et al. (2016)[40]	Cross-sectional survey study	40 patients with AA42 patients with MD	28-items modified stigmatization questionnaire	Probability of reported “anticipation of rejection” (P=0.02) “sensitivity to the opinions of others” (P<0.001) “feeling of being flawed” (P<0.01) were significantly greater in AA patients than patients with a mental disorder

QOL – Quality of life; NAAF – National Alopecia Areata Foundation; AA – Alopecia areata

Table 4

Psychiatric co-morbidity related evidence for Cumulative Life Course Impairment

Reference	Study type	Patients	Assessment tool	Evidence
Psychiatric
Singam et al. (2019)[54]	Retrospective cross-sectional study	87,053,155 adults and children with AAReference group included all patients without AA	20% sample of US hospitalizations (2002-2012)	Inpatients with versus without AA had higher proportions of any and primary mental health diagnosis (P<0.0001)The mean length and cost of primary hospitalization for a mental health disorder in patients with AA were 6.0 days and $11,907Patients with AA were at an elevated risk of suicide and intentional self-inflicted injury (adjusted OR: 2.77, 95% CI: 1.66-4.63)
Chu et al. (2012)[55]	Case-controlled study	5117 outpatients diagnosed with AA by dermatologist	Data from the National Health Insurance Database of Taiwan	An increased risk of depression (OR: 2.23; CI: 1.09-4.54) was found in patients with AA aged<20 yearsAn increased rate of anxiety (OR: 1.43; CI: 1.15-1.77) was observed with AA onset between ages of 20-39 yearsThe highest odds of OCD (OR: 3.00; CI: 1.11-8.12) and anxiety (OR: 2.05; CI: 1.56-2.68) were observed in patients with AA aged 40-59 years
Dehghani et al. (2017)[56]	Cross-sectional survey study	30 patients with mild-moderate AA30 patients with psoriasis, 30 vitiligo, 30 acne, 30 controls	Toronto Alexithymia Scale-20	50% of AA patients were found to be alexithymic, as compared to 37% for vitiligo and 40% for psoriasis
Sellami et al. (2014)[57]	Case-controlled study	50 patients with new-onset AA50 healthy controls	Hospital Anxiety and Depression ScaleToronto Alexithymia Scale-20Severity of Alopecia Tool	Rates of depression (P=0.047) and anxiety (P=0.005) were increased in AA patients as compared by controls
Lee et al. (2019)[58]	Nationwide population-based cohort study	Patients with at least 3 documented visits with ICD-10 code for AAControl patients 18+years and alive at the end of 2006	Cause of death and mortalities	Mortality risk associated with intentional self-harm/psychiatric diseases was significantly increased in AA patientsYoung adult patients and those with AT/AU had approximately 2-fold higher riskPatients with AA had higher mortality from smoking-associated cancers (lung and pancreatic)
Hwang et al. (2019)[59]	Longitudinal cohort study	4707 patients with newly onset AA370,019 controls	Number of visits to psychiatric clinic	The ratio of patients visiting a psychiatric clinic was approximately 1.6 × higher in AA patients than controlsAdjusted hazard ratios for psychiatric visits were significantly increased according to the number of intralesional injection treatments
Karia et al. (2015)[60]	Case-control study	50 patients with AA50 with psoriasis50 controls	Clinical interviewingSeverity of Alopecia ToolWHO-QoL ScaleHamilton rating scale for anxiety and depression	22% of AA patients suffered from psychiatric disorder, depression present in 18%, anxiety present in 4%. Control group had only 6% of psychiatric comorbidities
Bilgiç et al. (2014)[61]	Case-control study	74 children with AA65 matched controls	Severity of Alopecia ToolChild Depression InventoryState-Trait Anxiety Inventories for ChildrenPediatric QoL Inventory	For children ages 8-12: mean-state anxiety (P=0.003) and trait-anxiety (P=0.004) scores were significantly higher, parent-rated psychosocial QoL (P=0.001) and HRQL (P=0.009) were significantly lower than for controls
Baghestani et al. (2015)[62]	Case-control study	68 AA patients68 controls	Hamilton rating scale for anxiety and depression	The means of anxiety scores in cases and control group were 12.76±7.21 versus 8.54±6.37, P=0.003. Similarly, the means of depression scores for the groups were 12.84±4.03 versus 6.22±4.95, P=0.001

HRQL – Health-related quality of life; CI – Confidence interval; OR – Odds ratio; QOL – Quality of life; AA – Alopecia areata; ICD – International classification disease; AT - Alopecia totalis; AU - Alopecia universalis

SOCIAL AND ECONOMIC IMPACT

Perception of stigmatization or overt social rejection has significant effects on self-confidence and self-worth, particularly important given the frequent onset of AA in pediatric patients. Adolescence is a time of internal conflict and pressure to conform. Visible disfigurement at this transitional period can be devastating, leading to social withdrawal. As such, affected children are common targets of bullying, limiting their participation in activities and formation of friendships.[4763] With time, the consequences compound, leading to learned social avoidance and fears of rejection. Patients struggle with a restricted life, avoiding activities such as sports, swimming, shopping, and social events. Many make alterations to career and education trajectory,[45] choosing roles with less public visibility.[3863] Romantic relationships are broadly affected, with sexual QoL affected in men and women alike, regardless of marital status.[46]

As with many chronic medical conditions, the financial burden to patients and their families can become substantial. Wigs, although helpful tools for concealment, can cost patients several thousands of dollars, with 65% of patients reporting worry about affording replacements.[49] Medical costs, associated with treatment of AA, as well as comorbid conditions, are often a source of stress for patients and families, with 29% reporting perceived financial difficulties.[48] JAK inhibitors, although demonstrating efficacy in AU and AT, are currently prescribed off label and rarely covered by insurance or pharmaceutical financial assistance programs. Out-of-pocket costs near $5000 per month.

COPING

Coping is a key moderating component of CLCI caused by physical, psychological, social, financial, and stigmatizing factors. Even a small disease burden can result in significant impairment when ineffective coping strategies are coupled with limited social support. Personality traits can also combat disease burden. However, like coping techniques, these are shaped throughout development, often during or after AA onset.

Maladaptive coping strategies can further perpetuate the CLCI. It is not uncommon for patients first experiencing an episode of AA to blame themselves or fate. Intropunitive measures are taken, such as stopping social occasions, wearing fashionable clothes, or looking in the mirror.[52] Intuitively, avoidant coping and less active emotional coping were associated with high rates of QoL impairment.[53] Some coping mechanisms, while beneficial in the short term, may have delayed detrimental consequences. Patients with first onset of AA were found to feel less burdened when adopting an attitude of regrowth.[50] However, with time, 43% of patients report their treatments as ineffective,[42] leading to a sense of less personal control and stronger illness identity, both found to be predictive of greater QoL impairment.[53]

Conversely, some patients cultivate adaptive coping mechanisms, such as humor, support-seeking, or acceptance.[64] Practical coping, such as with scarves and wigs, can improve self-esteem and adaptability.[51] One study reports 87% of patients using a wig to socialize.[49] Unfortunately, this too can be a source of anxiety, as 43% felt that wigs could negatively affect their confidence in social situations, due to fears of being “found out.”[49] Perhaps, one of the strongest coping mechanisms reported by AA patients is acceptance,[385064] often developed only after many years of AA and attempting multiple treatment modalities.

Adopting the abstract concept of a “coping reservoir,” one can imagine a steady depletion from the daily struggles of AA.[39] This is true even in the absence of active disease, as the patients often live with worry given the unpredictable relapsing nature of the condition. As such, their ability to navigate social, familial, or personal problems is impaired compared to the general population. Fortunately, resources exist for patients, including relaxation techniques, yoga, and mindfulness, which have recently gained traction.[5265] Support groups and social media can be powerful resources for patients and their family members.[6667] The National Alopecia Areata Foundation serves to educate, advocate, and connect patients, offering tools to overcome the physical and emotional challenges.

DISCUSSION

The negative effects of dermatologic disease on QoL have been well recognized, as is the case for AA.[10] However, QoL, by nature, is cross-sectional, representing the symptomatic, emotional, and social impact of AA only at a given snapshot in time. By comparison, the concept of life course impairment, characterizes the consequences of chronic diseases accumulated over a lifetime. It captures the impact on life milestones, relationships, health, and finances – assessing how a disease can limit the possibility of patients living life to their full potential.

Demonstrated here, AA affects patients in nearly every facet of life. Patient specific life-trajectory is variable; however, the CLCI concept can support physicians in better understanding and identifying patients at increased vulnerability. This information can inform early intervention to prevent the progression of life course impairment, by screening for physical comorbidities (i.e., thyroid function testing[31] and Vitamin levels), connecting patients to behavioral/psychiatric health resources, or establishing contact with support groups. In addition, the CLCI model further combats the belief that AA is a cosmetic, rather than medical, concern. This tool demonstrates the multifactorial dimensions of the disease and highlights the importance of improved treatment options and standardized insurance coverage. It also further characterizes the global burden of disease for improved prioritization of health care resources.

Further, longitudinal research is required to better establish how to define and measure the cumulative life course impact. CLCI instruments and surveys are being developed, with hopes of standardization across institutions and cultures.[2468] Regardless of how it is defined, the overarching goal of the CLCI and other epidemiologic studies is the same: to identify the patients at risk and promote early assistance from health-care providers, payment agencies, and social support groups to minimize long-term impact.

Financial support and sponsorship

This project was in part funded by a National Alopecia Areata Foundation medical student research award.

Conflicts of interest

There are no conflicts of interest.

Table 3

Coping related evidence for cumulative life course impairment

Reference	Study type	Patients	Assessment tool	Evidence
Coping
Firooz et al. (2005)[42]	Survey of patients attending a skin clinic	80 patients with AA	Illness Perception Questionnaire	76.9% of the patients believed that the role of stress was the cause of disease >50% of patients believed that their illness had major consequences on their lives40% of patients believed that their illness would likely be permanent58% of patients considered treatments to be effective
Montgomery et al. (2017)[49]	Cross-sectional email survey to Alopecia UK mailing list	279 patients with alopecia areata >13 year/old	Validated measures of social anxiety, depression, anxiety and questions on wig usage	87% of participants reported wearing a wig to socialize66% of respondents reported they would not feelconfident leaving the house without a wig43% of participants reported that wearing a wig could negatively impact confidence during social situations
Matzer et al. (2011)[50]	Questionnaire survey and qualitative study	45 patients with AA	Interview with 5 standardized topics combined with stress and coping process questionnaire	Patients with first onset of AA felt less burdened when they had an attitude of waiting for regrowth (P=0.038)The coping competencecorrelated with the number of coping behaviors (P=0.033) and acceptance (P=0.030)
Inui et al. (2013)[51]	Prospective exploratory study	49 females with AA using a wig or hairpiece	Psychosocial Impact of Assistive Device Scale questionnaire	QoL indicators such as competence, adaptability and self‐esteem were significantly improved from zero (P<0.001) as the result of using a wig or hairpiece
Hussain et al. (2017)[52]	Electronic survey study	1083 patients with AA	13-item electronic survey distributed to NAAF database	31% pursued mental health therapy29% sought out support groups50% used yoga or relaxation techniques as an alternative treatment
Willemse et al. (2019)[53]	Online survey on QoL	243 patients with AA	Dermatology life quality index, brief-illness perception questionnaire, brief-coping orientation to problems experienced	QoL impairment was reported by 84% of participants, with 31% reporting very to extremely large impairmentMore QoL impairment was related to a stronger illness identity (P<0.001), more concern about AA (P<0.001), and experiencing less personal control (P=0.003)

QOL – Quality of life; NAAF – National Alopecia Areata Foundation; AA – Alopecia areata

Appendix S1

Keywords used in the literature search related to alopecia areata and the cumulative life course impairment concept

Stigma

Rejection

Concealment

Self-esteem

Self-confidence

Self-image

Embarrassment

Avoidance

Social and economic outcomes

Quality of life

Employment/Job

Financial burden

Earning capacity

Sick leave

Lost days from work

Cost of treatment

Education

Low income

Divorce rate

Sexual life

Relationships

Marital status

Psychological comorbidities

Depression

Anxiety

Stress

Mental health

Suicidal ideation

Substance use disorder

Alcoholism/alcohol consumption

Addiction

Mortality rate

Coping

Coping mechanisms

Coping strategies

Expression of emotion

Wig/hair prosthesis

Support group