Psychosocial and psychiatric comorbidities and health-related quality of life in alopecia areata: A systematic review.

METHODS
A systematic review was performed in the PubMed database according PubMed database according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for clinical studies to identify the psychosocial aspects of AA up to October 8, 2019 (Supplemental Table I, available at http://www.jaad.org). A combination of the following search terms was used: “alopecia areata,” or “alopecia totalis,” or “alopecia universalis” and “psychosocial” or “psychiatry” or “psychology” or “quality of life” or “social” or “stigma.” Studies were eligible for our systematic review if they met the following inclusion criteria: peer-reviewed, with available full texts in English, providing primary data on psychosocial effects, psychiatric effects, or quality of life in patients with any form of AA. There was no exclusion of studies focusing specifically on a certain age range. Studies that met the inclusion criteria were assessed for level of evidence on a modified Oxford Centre for Evidence-based Medicine scale of 1 to 5: (1) a systematic review of randomized clinical trials (RCTs) with homogeneity, individual RCT with homogeneity, and all-or-none case series; (2) a systematic review of cohort studies, individual cohort study (including low-quality RCT), and outcomes research or ecological studies; (3) a systematic review of case-control studies, individual case-control study; (4) a case series or cross-sectional study; and (5) a case report or opinion of respected authorities. A checklist is presented in Supplemental Table II (available at http://www.jaad.org). We excluded non–peer-reviewed studies without full texts available and studies that focused solely on pathophysiology or pharmacologic treatments.

RESULTS

Study selection and characteristics
The initial search strategy resulted in 377 unique studies with human subjects. The articles were screened by title and abstracts to identify 308 articles in English. Seventy-three original publications met the inclusion criteria. Of these, we identified 24 cohort studies, 12 case-control studies, 30 cross-sectional studies, 3 case series, and 4 case reports. In total, all identified studies involved approximately 414,330 unique participants. A total of 28 studies addressed the psychosocial aspects of adults with AA, and 10 studies were pediatric-specific psychosocial studies. Seventeen articles discussed adult health-related quality of life, and 3 articles addressed pediatric health-related quality of life. Fifteen articles focused on nonpharmacologic treatments that target psychosocial well-being in patients with AA.

Psychosocial and psychiatric comorbidities are associated with AA in adults
Our review identified 28 articles addressing the psychological and psychiatric dimensions of AA in adults (Table I). The strongest level of evidence was 2b (for definition, see Methods).
Twelve of 28 studies involving 32,461 patients discussed the relationship between psychiatric disorders and AA. Nine of these 12 studies including 31,766 total participants demonstrated or suggested a higher incidence of mental health disorders, such as anxiety, depression, attention deficit hyperactivity disorder, and certain psychotic disorders in patients with AA compared with healthy controls.5,11,12,25,28,30,32 Level of evidence for these studies ranged from 2b to 3b. Of importance, patients with AA were found to have higher rates of psychiatric hospitalizations.5,11,12,25,28,30,32
Personality differences between patients with AA and healthy controls are less clear, as some studies denoted minimal differences,21,31 whereas others noted a higher prevalence of harm-avoidant and reward-dependent personalities in AA patients. Patients with AA might also exhibit a higher level of alexithymia, which is the inability to express emotions.14,18,24,33,34 Finally, AA relapse can pose a risk of developing paranoia and obsessive-compulsive traits.6 Some studies demonstrated impaired coping with stress in AA patients, whereas others found no differences.9,15,17 Lastly, similar to patients with psoriasis and atopic dermatitis, patients with AA have higher levels of family dysfunction than controls.14
Frequently, stressful life events preceded diagnosis (n = 17 articles).19,20,23,29 Specifically, emotional stress and neglect were implicated.10,16 The remaining 11 of 28 studies, however, found no significant difference between patients’ experiences versus those of healthy controls,24 even immediately preceding hair loss.22,27

Psychosocial and psychiatric comorbidities are associated with AA in children
We identified 10 articles focusing exclusively on the psychiatric comorbidities and psychological aspects of AA within pediatric patients (Table II). The strongest level of evidence is 2b. Pediatric patients with AA have, on average, a higher psychiatric burden than age-matched controls, with higher prevalence of anxiety, depression, and psychiatry appointments.35,41,42 The prevalence of major depressive disorder or obsessive-compulsive disorder is as high as 50% or 30%, respectively, among others such as anxiety disorders, mood disorders, and disruptive behavioral disorders.39
One study investigated the social ramifications of AA in children. Healthy children can perceive children with AA as sick or dying,37 emphasizing the need for counseling patients, families, and peers to help avoid social isolation caused by AA. In addition, like their adult counterparts, pediatric patients with AA experience more stressful lifetime events than their healthy siblings do.38,40,44

Suicide risk in AA
The link between suicidality and AA is not clear. Although one report concluded that patients with AA do not show suicidal ideation,26 another study found that 12.8% of patients with AA are at risk of committing suicide.4 In further support for possible increased risk of suicide in patients with AA is a case series of suicides in 4 AA-affected boys between the ages of 14 and 17 years within 1 year of diagnosis.36

Health-related quality of life is reduced in AA
Our review revealed 17 studies focused on adult-specific, health-related quality-of-life measures, with the highest level of evidence at 2b (Table III). The most frequently used and validated questionnaires were dermatology-specific instruments, the Dermatology Life Quality Index (DLQI) and Skindex (61-item questionnaire), and a generic measure, the Short-Form (SF) Health Survey.46,50,55 Hair-specific measures included the Hairdex,47 the Alopecia Areata Symptom Impact Scale (AASIS), the Alopecia Areata Quality of Life Index, and the Alopecia Areata Quality of Life (Table III).57,59,61,62
Nearly 80% of AA patients report impaired health-related quality of life based on DLQI survey results,48 particularly those with severe AA.13 Areas predominantly affected are embarrassment and social interaction, with the severity of the effects being related to percent hair loss and concomitant depression.46,50 Skindex survey results indicate that worse scores are more prevalent in older patients with AA; these results can be influenced by educational level, social class, and family history.46,54 SF Health Survey results demonstrate that mental health and vitality are the most affected dimensions in AA, whereas physical functioning and pain are the least affected.66 Notably, scores do not correlate with severity of disease, and unmarried individuals score lower than their married counterparts.
Hair-specific quality-of-life measures depict a lower quality of life in patients with AA compared with that in healthy adults. Specifically, decreased quality of life is more prevalent in those younger than 50 years, in female patients, in those with ongoing hair loss, in those with concurrent family stress, and in those with recent job changes.51 Nail involvement does not contribute to lower quality of life.60 In addition, patients with higher AASIS scores are willing to pay more to control their disease, and overall willingness-to-pay levels in AA are similar to those in vitiligo, atopic dermatitis, and psoriasis.58
As expected, the presence of psychosocial and psychiatric comorbidities influences quality of life in AA patients. For example, anxiety and anxiety-related personality traits within the context of AA contribute to lower health-related quality-of-life scores, regardless of severity.5,8,45 In comparison with other dermatologic diseases, patients with AA report better overall quality of life than psoriasis patients do.67

Quality of life is impacted in children with AA, but measures are lacking
Our review identified 3 articles that discussed pediatric-specific, health-related quality of life (Table III). The quality-of-life measures discussed were the Quality of Life in a Child’s Chronic Disease Questionnaire (QLCCDQ), the Family Dermatology Life Quality Index (FDLQI), and the Pediatric Quality of Life Inventory.
Overall, quality of life decreases in proportion to disease severity and age of the affected child. This finding applies to caretakers of affected children as well. One prospective study of AA-affected children found a negative correlation between symptom severity and parent quality of life, as measured with the QLCCDQ and the FDLQI.63
Likewise, the Pediatric Quality of Life Inventory, among other psychology-oriented questionnaires, revealed that children with AA have higher anxiety, depression, and maladaptive coping habits, which negatively affect their quality of life.17,65 Adolescents with AA have higher rates of anxiety but not depression. Both children and adolescents have a lower parent-rated quality of life.65

Therapies targeting psychosocial impact and quality of life
Our review identified 15 articles discussing nonpharmacologic therapies targeting quality of life in AA patients (Table IV). The highest level of evidence was 2b. The most commonly cited effective treatment was psychotherapy (n = 6), followed by hypnotherapy (n = 4). Other techniques included wigs and pharmacotherapy to increase quality of life, with evidence lacking to support the adopted use of any one specific technique.74
Willemsen et al34,56,68,69 studied hypnosis from 2006 to 2011, testing it in conjunction with conventional therapies and alone. In these studies, hypnosis improved alexithymia, anxiety, and depression, with these results being sustained over 6 months, as quantified by quality-of-life measures such as the Symptom Checklist-90, SF Health Survey, and Skindex.34,56,68,69 Psychiatric medications have also been shown to improve well-being. A cohort of patients with AA and depression who received citalopram in addition to triamcinolone injections saw a reduction in diameter of their patchy hair loss compared with those who received treatment with triamcinolone injections alone.78 Conventional therapies aiming at improved hair growth can also improve quality of life. Patients treated with standard or emerging therapies, such as tofacitinib, have demonstrated an improvement in quality of life when experiencing hair growth.53
Family, group, and individual psychotherapy are often-cited tools that help patients and families cope with AA.33,70 Less rigorous are case reports detailing behavioral modification such as hair massage, relaxation, and monetary rewards for the patient as nonpharmacologic treatment options.72 A case-control study comparing psychotherapy and relaxation training in addition to immunosuppressants versus immunosuppressants alone demonstrated greater hair regrowth in those undergoing psychoimmunotherapy.73 Similarly, mindfulness-based stress reduction programs in conjunction with conventional therapy improved quality of life in patients with AA, with results lasting 6 months after cessation of the program.71 Wigs and hairpieces improve quality of life through enhanced confidence and perceived competence.76 Although wearing wigs increases social confidence, it can also contribute to maintaining anxiety.75

DISCUSSION
This systematic review highlights the psychosocial effects of AA. The highest level of evidence in all categories, 2b, supports the following ideas: (1) psychiatric comorbidities, including anxiety and depression, are more prevalent in patients with AA; (2) stressful life events typically precede diagnosis; and (3) health-related quality of life is reduced with AA. Although psychiatric differences are evident between AA patients and healthy controls, personality differences, such as variation in coping strategies, are less clearly correlated to AA.
AA patients experience depression and anxiety at a rate higher than that in controls and at rates similar to other chronic skin conditions. For example, approximately 5%−21% of patients with hidradenitis suppurativa experience depression79; they experience anxiety nearly twice as much as healthy controls (odds ratio, 1.7).80 Patients with psoriasis are 1.5-fold more likely to experience depression than healthy controls, with depression as the third leading comorbidity in this population (nearly 18%).81 Prevalence of anxiety typically matches that of depression in patients with psoriasis.81 Patients with atopic dermatitis also experience depression at a rate of 20% versus 14% in healthy controls, with higher accompanying rates of suicidality.82 Although all conditions place patients at risk for depression, patients with hidradenitis suppurativa seem to have the highest levels of anxiety. Regarding psychiatric comorbidities, it seems that results are generalizable between AA and other chronic skin diseases.
AA patients typically experience stressful events, and they doso at a rate nearly twice as high as that of healthy controls. This finding is similar to that found in other dermatologic and cutaneous disorders, such as psoriasis and atopic dermatitis, in which 30%−70% of patients, respectively, have experienced stressful lifetime events.83 Stress and related oxidative stress can be particularly important for the pathogenesis of AA. In one study, patients with AA who demonstrated elevated psychosocial stress compared with controls had a corresponding novel polymorphism in their adrenocorticotropin receptor resulting in an insufficient hormonal response to stress; this was true in both patients with AA and controls with severe stress.84 Other studies have more directly illustrated the association between stress and AA. When exposed to reactive oxygen species (ROS), cellular membranes create byproducts (eg, malondialdehyde) that can negatively regulate cellular function.85 Multiple studies have demonstrated elevated levels of these byproducts in the plasma, red blood cells, and scalps of patients with AA.85
Health-related quality of life is reduced in patients with AA, and psychiatric comorbidities reduce it further. Although hair-specific quality-of-life measures have been incorporated into the field, future studies are necessary to evaluate the validity of general health-related quality-of-life questionnaires, such as the DLQI in AA. Further study is also needed to clarify the relationship between alopecia severity and health-related quality of life, as our results were contradictory but similar to the results reported by Rencz et al.3 Greater quality-of-life measures specific to pediatric patients with alopecia are also needed to fully understand the nuances of the disease’s effects on children and their caretakers. This is important, as some studies suggest a strong link between AA and suicidality in children.
Within this context, we suggest that interventions targeting the complex psychosocial dimension of AA should accompany conventional therapies to reduce morbidity and mortality, particularly in children. Practically speaking, patients and their families should be counseled at each visit to anticipate psychosocial comorbidity. Given that stressful lifetime events precede diagnosis and are thought to possibly exacerbate disease, it is imperative that resources be available to reduce and manage stress. These resources include individual therapy, family support groups, and peer support groups. The National Alopecia Areata Foundation provides similar resources for affected patients. National Alopecia Areata Foundation resources vary from support groups and youth mentorship programs to cosmetic guides, treatment overviews, and parent support packs. The affiliated peer support groups are a topic of discussion within the literature, as authors speak to their therapeutic effect through reduced isolation and the experience of catharsis.86
As demonstrated here, stress and psychosocial comorbidities are associated with AA, thereby affecting health-related quality of life in both adults and children with AA. As a result, interventions aimed at improving psychosocial well-being are an important part of managing patients with AA.

CONCLUSION
Our systematic review demonstrates a relationship among psychiatric comorbidities, stressful life events, and AA. Although health-related quality of life is affected, pediatric quality-of-life measures are lacking. Adjuvant psychotherapy and support groups should be considered in addition to systemic medications to reduce morbidity and mortality.

Supplementary Material
Supp.Table1Supp.Table2