
==== Front
JAMA Dermatol
JAMA Dermatol
JAMA Dermatology
2168-6068
2168-6084
American Medical Association

39083282
10.1001/jamadermatol.2024.2404
doi240025
Research
Research
Original Investigation
Featured
Online First
Comments
Immune-Mediated and Psychiatric Comorbidities Among Patients Newly Diagnosed With Alopecia Areata
Immune-Mediated and Psychiatric Comorbidities Among Patients Newly Diagnosed With Alopecia Areata
Immune-Mediated and Psychiatric Comorbidities Among Patients Newly Diagnosed With Alopecia Areata
Mostaghimi Arash MD MPA MPH 1
Soliman Ahmed M. PhD 2
Li Chao PhD 2
Barqawi Yazan K. PhD 3
Grada Ayman MD 2
1 Brigham and Women’s Hospital, Harvard University, Boston, Massachusetts
2 AbbVie Inc, North Chicago, Illinois
3 AstraZeneca, Gaithersburg, Maryland
Article Information

Accepted for Publication: May 30, 2024.

Published Online: July 31, 2024. doi:10.1001/jamadermatol.2024.2404

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2024 Mostaghimi A et al. JAMA Dermatology.

Corresponding Author: Arash Mostaghimi, MD, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 (amostaghimi@bwh.harvard.edu).
Author Contributions: Dr Mostaghimi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Mostaghimi, Soliman, Barqawi, Grada.

Acquisition, analysis, or interpretation of data: Mostaghimi, Soliman, Li, Grada.

Drafting of the manuscript: Grada.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Li, Grada.

Obtained funding: Soliman, Grada.

Administrative, technical, or material support: Mostaghimi, Soliman, Barqawi, Grada.

Supervision: Soliman, Grada.

Conflict of Interest Disclosures: Dr Mostaghimi reported receiving personal fees from Hims & Hers Health, Inc, AbbVie Inc, Sun Pharma, Pfizer, Digital Diagnostics, Lilly, Equillium, ASLAN Pharmaceuticals, Boehringer Ingelheim, Figure 1, Acom Healthcare, Olaplex, and Legacy Healthcare outside the submitted work. Dr Soliman reported being an employee of, having stock or stock options in AbbVie Inc, and being a coinventor of AbbVie Inc patents during the conduct of the study. Dr Li reported being an employee of and having stocks or stock options in AbbVie Inc during the conduct of the study. Dr Barqawi reported being a former employee of AbbVie Inc during the conduct of the study and may hold AbbVie Inc stock and/or stock options. Dr Grada reported being an employee of and having stocks or stock options in AbbVie Inc during the conduct of the study.

Funding/Support: This study was funded by AbbVie Inc.

Role of the Funder/Sponsor: AbbVie funded the study (including paying for access to the MarketScan databases and all publication-related charges) and, via the study’s AbbVie-employed authors, was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. No honoraria or payments were made for authorship.

Data Sharing Statement: See Supplement 2.

Additional Contributions: Medical writing support was provided by Nakeirah Christie, PhD, and Samantha D. Francis Stuart, PhD, of Fishawack Facilitate Ltd, part of Avalere Health, and was funded by AbbVie. We thank the participating patients and their families, clinicians, and study investigators.

31 7 2024
9 2024
31 7 2024
160 9 945952
12 3 2024
30 5 2024
Copyright 2024 Mostaghimi A et al. JAMA Dermatology.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the CC-BY-NC-ND License.
jamadermatol-e242404.pdf

Key Points

Question

What are the risks of developing new-onset psychiatric or autoimmune diseases after diagnosis of alopecia areata?

Findings

This cohort study of 3 372 491 patients found that those newly diagnosed with alopecia areata had a higher prevalence and incidence of psychiatric and autoimmune comorbidities. Patients with alopecia areata had a significantly higher risk of developing a new-onset psychiatric or other autoimmune disease than patients without alopecia areata.

Meaning

These findings suggest that individuals with vs without alopecia areata have higher risks of developing psychiatric and/or autoimmune comorbidities after diagnosis; early treatment with effective therapies may reduce these risks and thereby reduce the burden of disease for patients.

This cohort study evaluates the prevalence, incidence, and risk of new-onset autoimmune and psychiatric comorbidities after alopecia areata diagnosis in adolescent and adult patients.

Importance

Alopecia areata (AA) has been associated with multiple comorbidities, yet information regarding the timing of comorbidity development after AA diagnosis is limited.

Objective

To evaluate the prevalence and new-onset incidence of psychiatric and autoimmune comorbidities in patients with AA in the US.

Design, Setting, and Participants

This retrospective cohort analysis used data collected from January 1, 2007, to April 30, 2023, from the Merative MarketScan Research Databases, which contains medical and drug claims data from more than 46 million patients in the US. Data from adolescent and adult patients (aged 12-64 years) diagnosed with AA and patients without AA (ie, controls) were evaluated. For some analyses, patients with AA were matched (1:4) to controls based on sex, age, and geographic region.

Main Outcomes and Measures

Prevalence (at the time of AA diagnosis) and incidence (new onset after AA diagnosis) of psychiatric and autoimmune diseases were reported as percentage of patients. Risk of developing a new-onset psychiatric or autoimmune disease after AA diagnosis was calculated as adjusted hazard ratios (AHRs) with 95% CIs.

Results

At baseline, 63 384 patients with AA and 3 309 107 without AA were identified. After matching, there were 16 512 and 66 048 patients in the AA and control groups, respectively, with a mean (SD) age of 36.9 (13.4) years and 50.6% of whom were female. Compared with the unmatched controls, patients with AA had higher prevalence of psychiatric (30.9% vs 26.8%; P < .001) and autoimmune (16.1% vs 8.9%; P < .0001) comorbidities at AA diagnosis; incidence was also higher in patients with AA (without history of these comorbidities) vs the matched control group. Patients with AA vs controls had a significantly higher risk of developing a psychiatric (AHR, 1.3; 95% CI, 1.3-1.4) or autoimmune (AHR, 2.7; 95% CI, 2.5-2.8) comorbidity.

Conclusions and Relevance

In this cohort study, patients with AA had a higher prevalence of autoimmune and psychiatric comorbidities at AA diagnosis and demonstrated an elevated risk of new-onset autoimmune and psychiatric comorbidities after their diagnosis. These data highlight the most common comorbidities among patients with AA and may help physicians counsel and monitor patients newly diagnosed with AA.
==== Body
pmcIntroduction

Alopecia areata (AA) is a chronic, immune-mediated disorder characterized by sudden, inflammatory, nonscarring hair loss that can be limited or extensive, involving the entire scalp and body hair.1,2,3 Both genetic4 and environmental factors5 play a role in AA, with reports suggesting that an upregulation of inflammatory cytokines (eg, interferon-γ and interleukin 15) that signal through Janus kinases and other pathways may be involved.6 These inflammatory pathways, however, are not unique to AA but are known to play roles in several autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis.7,8 Alopecia areata itself has been associated with many other systemic disorders, including atopic dermatitis, inflammatory bowel disease, and rheumatoid arthritis.9 Studies have shown that patients with AA have increased rates of psychiatric conditions,10 including depression and posttraumatic stress disorder.11,12 A meta-analysis conducted by Toussi et al13 found higher incidences of mental health disorders, including anxiety, attention-deficit/hyperactivity disorder, and depression, in patients with AA.

Altogether, the potential comorbidity burden of patients with AA may contribute to a reduced health-related quality of life,14,15,16,17,18 yet most studies that have assessed comorbidities associated with AA are limited.19 Although some studies examine a correlation between AA and psychiatric or autoimmune disorders, none have assessed the risks of developing psychiatric and autoimmune comorbidities in patients with newly diagnosed AA. Thus, there remains a lack of evidence of the comorbidity burden among those with AA in the US, particularly that of new-onset comorbidities after AA diagnosis. Therefore, the objective of this study was to evaluate the prevalence of autoimmune and psychiatric comorbidities at the time of AA diagnosis, as well as the incidence and risk of developing new-onset autoimmune and psychiatric comorbidities after AA diagnosis in patients in the US.

Methods

Study Design and Patient Selection

This cohort study used data from the Merative MarketScan Research Databases collected between January 1, 2007, and April 30, 2023. As a retrospective study that used anonymized data, this work is classified as non–human participant research as defined by 45 CFR 46.104(d) and therefore exempt from institutional review board approval and informed consent. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

For this study, the index date was defined as the earliest date of confirmed diagnosis of AA, determined by inpatient and outpatient claims. For controls, the index date was randomly assigned based on the index distribution among patients with AA. The study baseline period was defined as 12 months or more before the index date, and the study follow-up period was defined as 12 months or more after the index date (eFigure 1 in Supplement 1).

For the control group, patients included in the analysis met the following criteria: aged 12 to 64 years, maintained continuous enrollment (medical) for 12 months or more before and after the index date (ie, baseline and follow-up periods), and not diagnosed with AA during the study period. Likewise, patients in the AA group were aged 12 to 64 years, maintained continuous enrollment for 12 months or more before and after the index date, and had either 1 or more qualifying AA inpatient encounters or 2 or more outpatient claims with a diagnosis code for AA (International Statistical Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] code L63.x or International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 704.01) during index identification period, and without any AA diagnosis during the baseline period using previously validated methods.20

To limit our analysis to new-onset comorbidities, for the analyses on incidence and risk of autoimmune and psychiatric comorbidities, we excluded patients if they had recorded diagnoses of other immune-mediated inflammatory skin disorders (eg, atopic dermatitis, eczema, or other pigmentation disorders), autoimmune diseases (eg, type 1 diabetes, celiac disease, or systemic lupus erythematosus), or psychiatric diseases (eg, depression or anxiety) (eTable 1 in Supplement 1) during the baseline period (ie, ≥12 months to the start of baseline continuous enrollment). Individuals’ race and ethnicity could not be reported because that information is not captured in the Merative MarketScan database.

Outcomes

Prevalence of psychiatric or autoimmune comorbidities, reported as percentage of patients, was assessed among those diagnosed with AA and the control group at baseline. The incidence of new-onset psychiatric and autoimmune diseases during the first 12-month follow-up was analyzed among patients who did not have any comorbidities of interest at baseline and was reported as a percentage of patients. The risk of developing a psychiatric or autoimmune disease during the total available follow-up period, reported as adjusted hazard ratios (AHRs) and 95% CIs, was also determined.

Statistical Analysis

Patients diagnosed with AA were matched with the control group 1:4 based on sex, age, and geographic region. Prevalence in the prematched populations was calculated by dividing the total number of patients who had a confirmed diagnosis of a psychiatric or autoimmune disease by the total number of patients included in the study for each group. Incidence of these comorbidities in the matched populations was calculated by dividing the number of new diagnoses of conditions by the total number of eligible cohort patients. Fisher exact tests or χ2 tests were used to assess statistical significance of prevalence and incidence of psychiatric and autoimmune comorbidities. The risks of developing psychiatric and autoimmune comorbidities, reported as AHRs and 95% CIs, were estimated by Cox proportional hazards regressions, controlling for age, sex, geographic region, obesity, and Charlson Comorbidity Index. A 2-sided P < .05 was considered statistically significant.

Results

Prevalence

At baseline, 63 384 patients with AA (62.4% female and 37.6% male), and 3 309 107 non-AA control patients (52.1% female and 47.9% male) were identified (eTable 2 in Supplement 1). The mean (SD) age at index in the AA and control groups was 39.3 (14.0) years and 39.8 (15.3) years, respectively. For any psychiatric disease, the overall prevalence was 30.9% in patients with AA compared with 26.8% in the control group (P < .001) (Table 1). Patients with AA vs the control group had significantly higher rates of anxiety (15.5% vs 12.3%), sleep disturbance (10.4% vs 8.9%), and depression (9.3% vs 7.6%) (P < .001). For any autoimmune or immune-mediated disease, the overall prevalence was 16.1% in patients with AA compared with 8.9% in the control group (P < .001). Patients with AA vs the control group had significantly higher rates of atopic dermatitis (5.1% vs 2.0%), psoriasis (2.4% vs 1.2%), and rheumatoid arthritis (2.3% vs 1.3%) (P < .001).

Table 1. Prevalence of Comorbidities Associated With Alopecia Areata (Before Matching)

Comorbidity	Patients with alopecia areata, No. (%) (n = 63 384)	Controls, No. (%) (n = 3 309 107)	P valuea	
Any psychiatric disease	19 596 (30.9)	885 835 (26.8)	<.001	
Anxiety	9816 (15.5)	406 384 (12.3)	<.001	
Sleep disturbance	6619 (10.4)	293 232 (8.9)	<.001	
Depression	5896 (9.3)	251 824 (7.6)	<.001	
Substance misuse or dependence	3648 (5.8)	19 6751 (5.9)	.046	
Adjustment disorder	2838 (4.5)	113 199 (3.4)	<.001	
Dysthymic disorder	1852 (2.9)	78 170 (2.4)	<.001	
Panic disorder	979 (1.5)	39 781 (1.2)	<.001	
Bipolar disorder	942 (1.5)	43 923 (1.3)	<.001	
Alcohol misuse or dependence	861 (1.4)	43 393 (1.3)	.31	
Suicidal ideation and attempts	449 (0.7)	23 894 (0.7)	.70	
Sexual dysfunction	390 (0.6)	21 165 (0.6)	.46	
Eating disorder	253 (0.4)	10 241 (0.3)	<.001	
Personality disorder	169 (0.3)	6916 (0.2)	.002	
Social phobia	143 (0.2)	7253 (0.2)	.76	
Schizophrenia	136 (0.2)	5464 (0.2)	.003	
Agoraphobia	117 (0.2)	5183 (0.2)	.09	
Any autoimmune or immune-mediated disease	10 172 (16.0)	292 995 (8.9)	<.001	
Atopic dermatitis	3224 (5.1)	65 451 (2.0)	<.001	
Psoriasis	1550 (2.4)	40 379 (1.2)	<.001	
Rheumatoid arthritis	1434 (2.3)	43 190 (1.3)	<.001	
Vitiligo	908 (1.4)	16 770 (0.5)	<.001	
Systemic lupus erythematosus	858 (1.4)	14 757 (0.4)	<.001	
Inflammatory bowel disease	795 (1.3)	29 443 (0.9)	<.001	
Type 1 diabetes	774 (1.2)	42 858 (1.3)	.11	
Ulcerative colitis	497 (0.8)	18 450 (0.6)	<.001	
Uveitis	470 (0.7)	15 943 (0.5)	<.001	
Crohn disease	433 (0.7)	15 052 (0.5)	<.001	
Graves disease	394 (0.6)	12 710 (0.4)	<.001	
Pernicious anemia	350 (0.6)	11 841 (0.4)	<.001	
Sjogren disease	339 (0.5)	7028 (0.2)	<.001	
Multiple sclerosis	307 (0.5)	10 977 (0.3)	<.001	
Celiac disease	288 (0.5)	8868 (0.3)	<.001	
Linear morphea	243 (0.4)	4497 (0.1)	<.001	
Scleroderma	144 (0.2)	3907 (0.1)	<.001	
Addison disease	107 (0.2)	3800 (0.1)	<.001	
Dermatomyositis	80 (0.1)	2884 (0.1)	.001	
Idiopathic thrombocytopenic purpura	71 (0.1)	2654 (0.1)	.007	
Myasthenia gravis	62 (0.1)	1936 (0.1)	<.001	
Rheumatic fever	35 (0.1)	970 (0.03)	<.001	
Guillain-Barré syndrome	24 (0.04)	804 (0.02)	.04	
Pemphigus vulgaris	13 (0.02)	299 (<0.01)	.006	
a χ2 Tests were used to obtain P values.

Incidence

After matching, there were 16 512 and 66 048 patients in the AA and control groups, respectively (Table 2). The overall mean (SD) age was 36.9 (13.4) years, 50.6% were female, and 49.4% were male. The mean (SD) Charlson Comorbidity Index score was 0.1 (0.5) for patients with AA and 0.1 (0.4) for the control group. Within the first 12 months after AA diagnosis, the overall incidence for any psychiatric disease was 10.2% for patients with AA and 6.8% for the control group (P < .001). Psychiatric diseases with the highest incidence for patients with AA compared with the control group were anxiety (4.0% vs 2.6%), sleep disturbance (2.6% vs 1.7%), and depression (1.9% vs 1.2%) (P < .001) (Table 3). Likewise, overall incidence for any autoimmune or immune-mediated disease within the first 12 months after AA diagnosis was 6.2% for patients with AA and 1.5% for the control group (P < .001). Autoimmune and immune-mediated disorders with the highest incidence for patients with AA vs the control group were atopic dermatitis (2.2% vs 0.3%), vitiligo (1.0% vs 0.1%), and psoriasis (0.9% vs 0.2%) (P < .001).

Table 2. Demographics of Incidence Analysis Cohort (After Matching)a

Characteristic	Patients with alopecia areata (n = 16 512)	Controls (n = 66 048)	
Age at index date, y			
Mean (SD)	36.9 (13.4)	36.9 (13.4)	
Median (range)	37 (12-64)	37 (12-64)	
Age group, y			
12-17	1514 (9.2)	6056 (9.2)	
18-29	3635 (22.0)	14 540 (22.0)	
30-39	4300 (26.0)	17 200 (26.0)	
40-49	3638 (22.0)	14 552 (22.0)	
50-64	3425 (20.7)	13 700 (20.7)	
Sex			
Female	8350 (50.6)	33 400 (50.6)	
Male	8162 (49.4)	32 648 (49.4)	
Health care plan			
Encounter	2601 (15.8)	9637 (14.6)	
Fee for service	13 911 (84.3)	56 411 (85.4)	
Charlson Comorbidity Index score			
Mean (SD)	0.1 (0.5)	0.07 (0.4)	
Median (range)	0 (0-10)	0 (0-10)	
Region			
Midwest	3048 (18.5)	12 192 (18.5)	
Northeast	3987 (24.1)	15 948 (24.2)	
South	6204 (37.6)	24 816 (37.6)	
West	3273 (19.8)	13 092 (19.8)	
Health care plan			
CDHP	1182 (7.4)	4551 (7.2)	
Comprehensive	314 (2.0)	1194 (1.9)	
EPO	292 (1.8)	957 (1.5)	
HDHP	914 (5.7)	3604 (5.7)	
HMO	2481 (15.4)	9295 (14.6)	
POS	1546 (9.6)	5596 (8.8)	
POS with capitation	128 (0.8)	376 (0.6)	
PPO	9213 (57.3)	38 085 (59.8)	
Obesityb	395 (2.4)	1244 (1.9)	
Abbreviations: CDHP, consumer-directed health plan; EPO, exclusive provider organization; HDHP, high-deductible health plan; HMO, health maintenance organization; POS, point of service; PPO, preferred provider organization.

a Data are presented as number (percentage) of participants unless otherwise indicated.

b Including International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes E66.0x, E66.1, E66.2, E66.8, E66.9, Z68.3x, and Z68.4x.

Table 3. Incidence of Comorbidities Associated With Alopecia Areata for the 1-Year Follow-Up (After Matching)

Comorbidity	Patients with alopecia areata, No. (%) (n = 16 512)	Controls, No. (%) (n = 66 048)	P valuea	
Any psychiatric disease	1679 (10.2)	4503 (6.8)	<.001	
Anxiety	668 (4.0)	1749 (2.6)	<.001	
Sleep disturbance	432 (2.6)	1123 (1.7)	<.001	
Depression	318 (1.9)	816 (1.2)	<.001	
Substance misuse or dependence	292 (1.8)	940 (1.4)	.03	
Adjustment disorder	157 (1.0)	419 (0.6)	<.001	
Dysthymic disorder	74 (0.5)	212 (0.3)	.006	
Panic disorder	50 (0.3)	128 (0.2)	.04	
Bipolar	29 (0.2)	77 (0.1)	<.001	
Alcohol misuse or dependence	60 (0.4)	201 (0.3)	.06	
Suicidal ideation and attempts	38 (0.2)	92 (0.1)	.27	
Sexual dysfunction	44 (0.3)	53 (0.1)	.003	
Eating disorder	40 (0.2)	138 (0.2)	.46	
Personality disorder	4 (0.02)	10 (0.02)	.50b	
Social phobia	5 (0.03)	12 (0.02)	.36b	
Schizophrenia	3 (0.02)	16 (0.02)	.78b	
Agoraphobia	2 (0.02)	14 (0.02)	.75b	
Any autoimmune or immune-mediated disease	1025 (6.2)	962 (1.5)	<.001	
Atopic dermatitis	358 (2.2)	184 (0.3)	<.001	
Vitiligo	159 (1.0)	70 (0.1)	<.001	
Psoriasis	155 (0.9)	109 (0.2)	<.001	
Systemic lupus erythematosus	97 (0.6)	39 (0.1)	<.001	
Rheumatoid arthritis	32 (0.2)	63 (0.1)	.001	
Inflammatory bowel disease	31 (0.2)	73 (0.1)	.02	
Type 1 diabetes	31 (0.2)	119 (0.2)	.92	
Sjogren disease	30 (0.2)	6 (0.01)	<.001	
Celiac disease	28 (0.2)	42 (0.1)	<.001	
Graves disease	26 (0.2)	39 (0.1)	<.001	
Ulcerative colitis	23 (0.1)	49 (0.07)	.02	
Uveitis	21 (0.1)	70 (0.1)	.55	
Pernicious anemia	18 (0.1)	49 (0.1)	.21	
Linear morphea	16 (0.1)	19 (0.03)	<.001	
Addison disease	11 (0.1)	7 (0.01)	<.001	
Crohn disease	10 (0.06)	28 (0.04)	.44	
Multiple sclerosis	7 (0.04)	27 (0.04)	>.99	
Idiopathic thrombocytopenic purpura	7 (0.04)	13 (0.02)	.10	
Scleroderma	6 (0.04)	12 (0.02)	.23b	
Myasthenia gravis	5 (0.03)	2 (<0.01)	.005b	
Dermatomyositis	1 (0.01)	7 (0.01)	>.99b	
Pemphigus vulgaris	1 (0.01)	1 (<0.01)	.36b	
Guillain-Barré syndrome	0	0	NA	
Rheumatic fever	0	1 (<0.01)	NA	
Abbreviation: NA, not applicable.

a χ2 Tests were used to obtain P values unless otherwise noted.

b Fisher exact tests were used to obtain P values.

Patients with AA vs controls had a significantly higher risk of developing a psychiatric (AHR, 1.3; 95% CI, 1.3-1.4) or autoimmune comorbidity (AHR, 2.7; 95% CI, 2.5-2.8). Psychiatric disorders with the highest risk included adjustment disorder (AHR, 1.5; 95% CI, 1.3-1.6; P < .001), panic disorder (AHR, 1.4; 95% CI, 1.2-1.7; P < .001), and sexual dysfunction (95% CI, 1.4; 95% CI, 1.1-1.8; P = .003) (Figure, A). Autoimmune and immune-mediated disorders with the highest risk included systemic lupus erythematosus (AHR, 5.7; 95% CI, 4.6-7.2; P < .001), atopic dermatitis (AHR, 4.3; 95% CI, 3.9-4.8; P < .001), and vitiligo (AHR, 3.8; 95% CI, 3.2-4.4; P < .001) (Figure, B).

Figure. Adjusted Hazard Ratios (AHRs) for Development of Psychiatric or Autoimmune and Immune-Mediated Comorbidities in Patients With Alopecia Areata (AA) vs Controls

Patients with AA had a significantly higher risk of developing psychiatric and autoimmune comorbidities compared with the control population.

aUnivariate analysis.

Discussion

This study found that patients who were diagnosed with AA were more likely to be diagnosed with a new-onset psychiatric or autoimmune disorder within the first year after AA diagnosis. This study builds on prior evaluations that demonstrated that patients with AA often have comorbid autoimmune, immune-mediated, and psychiatric disorders.9,18 Prior research has shown that compared with healthy controls, patients with AA had a significantly higher likelihood of having several comorbidities, including systemic lupus erythematosus, metabolic syndrome, and Hashimoto thyroiditis,8 as well as an increased likelihood of comorbid anxiety and depression.21 A systematic literature review12 of 37 studies examining patient perspectives reported consistently negative mental health outcomes in those with AA, including emotional distress, reduced social functioning, and increased stress. However, unlike those studies, which have demonstrated an association between AA and existing comorbidities, our analysis is one of the first studies, to our knowledge, to examine the risk of developing these comorbidities after AA diagnosis.

Despite the well-known associations with autoimmune and psychiatric disorders, the causes of these comorbidities in AA remain unknown.22 Stress, in addition to genetics and the microbiome, has been identified as a factor that exacerbates certain diseases by upregulating and activating inflammatory signaling cascades.23 A recent systematic review found that patients often reported stressful life events, such as emotional stress and neglect, occurring before their AA diagnosis.13 Furthermore, a previous study found that in patients with AA, there is a marked increase in proinflammatory signaling molecules, including interferon-γ, tumor necrosis factor α, and various interleukins, which were all elevated in the sera of patients with AA.24 Additionally, studies24,25,26 have shown that proinflammatory factors, such as apoptotic neuropeptide substance P, and inflammatory cortisol-releasing hormone receptors are increased locally in the affected areas in patients with AA. In line with these findings, a year-long observational study among patients with AA showed high rates of depression and anxiety among patients with AA.15 Although the association between the severity of AA and the severity of depression and anxiety did not reach statistical significance (likely due to small sample size), the findings highlight the potential synergistic nature of AA and depression.15

Therefore, it is perhaps unsurprising that AA has been consistently linked to high prevalences of psychiatric and autoimmune disorders and worse scores in health-related quality-of-life measures.8,12,13,15,21,27,28 Moreover, the high prevalence of comorbidities is also associated with a high economic burden. A previous study published in 2022 assessing patients in the US showed that those with vs without AA have nearly $2000 more in all-cause medical costs annually.29 The elevated cost is thought to be at least partially due to comorbidities associated with AA, including hyperlipidemia, hypertension, thyroid disorders, depression, and anxiety.30 Another study, published in 2023, reported that patients with AA who had at least 1 Charlson Comorbidity Index comorbidity, vs those who did not, had 104.4% higher medical costs.31

Overall, our study emphasizes the persistent unmet needs of patients with AA and the importance of studying the collective burden of AA and its comorbidities because their combination may have a worse impact than any one disease alone. Because AA and many of these comorbidities share underlying signaling pathways,18 it is not unreasonable to think effective and tolerable treatment could address multiple disorders—that is, AA and various comorbidities—simultaneously. Indeed, the Janus kinase inhibitor baricitinib is approved by the US Food and Drug Administration for treatment of AA and rheumatoid arthritis32 and by the European Medicines Agency for the treatment of atopic dermatitis and juvenile idiopathic arthritis. Additionally, there is some evidence of interplay between depressive and dermatologic disorders and that treating the latter with advanced therapies can likewise reduce the impact of the former.33

Longer-term studies are needed to determine the most effective treatment that can maximize patient health and minimize patient cost. Future studies should assess whether, for patients with AA who have psychological or autoimmune comorbidities, the use of a single therapy can treat both indications more cost-effectively than multiple therapies. Likewise, further research is needed to understand whether earlier and/or more aggressive treatment of AA may limit the development of comorbidities.

Strengths and Limitations

The strengths of this study include that it is, to our knowledge, the first study to determine new-onset psychiatric and autoimmune comorbidity incidence in patients with AA compared with a non-AA population. Likewise, this study analyzed data from a large, diverse population of patients with AA. The limitations of this study include that, as with all retrospective studies, causality cannot be inferred. Moreover, diagnosis of comorbidity states was based on diagnostic codes, and we did not have access to characteristics, such as laboratory values (eg, antibodies), that may have indicated underlying comorbidity before AA diagnosis but that did not result in official diagnosis of a comorbidity. Likewise, it is possible that, after an AA diagnosis, patients may be more closely monitored compared with controls, which may also contribute to overestimated rates of new-onset comorbidity. Results may not be generalizable to those outside commercial health coverage. Lastly, because this study did not account for varying levels of disease severity, disease burden and risk of comorbidities associated with the disease may be underestimated.

Conclusions

This cohort study found that patients with AA have a higher incidence of several new-onset psychiatric and autoimmune comorbidities within the first year of diagnosis, which could further exacerbate the disease burden and reduce quality of life of those affected. Routine monitoring of patients with AA, especially those at risk of developing comorbidities, may permit earlier and more effective intervention.

Supplement 1. eFigure. Study Design

eTable 1. Diagnostic Codes for Exclusion (Incidence Analysis Only)

eTable 2. Demographics of Prevalence Analysis Cohort (Unmatched)

Supplement 2. Data Sharing Statement
==== Refs
References

1 Darwin E, Hirt PA, Fertig R, Doliner B, Delcanto G, Jimenez JJ. Alopecia areata: review of epidemiology, clinical features, pathogenesis, and new treatment options. Int J Trichology. 2018;10 (2 ):51-60. doi:10.4103/ijt.ijt_99_17 29769777
2 Sibbald C. Alopecia areata: an updated review for 2023. J Cutan Med Surg. 2023;27 (3 ):241-259. doi:10.1177/12034754231168839 37340563
3 Benigno M, Anastassopoulos KP, Mostaghimi A, . A large cross-sectional survey study of the prevalence of alopecia areata in the United States. Clin Cosmet Investig Dermatol. 2020;13 :259-266. doi:10.2147/CCID.S245649 32280257
4 Pratt CH, King LE Jr, Messenger AG, Christiano AM, Sundberg JP. Alopecia areata. Nat Rev Dis Primers. 2017;3 :17011. doi:10.1038/nrdp.2017.11 28300084
5 Ito T, Tokura Y. The role of cytokines and chemokines in the T-cell-mediated autoimmune process in alopecia areata. Exp Dermatol. 2014;23 (11 ):787-791. doi:10.1111/exd.12489 25040075
6 King B, Ohyama M, Kwon O, ; BRAVE-AA Investigators. Two phase 3 trials of baricitinib for alopecia areata. N Engl J Med. 2022;386 (18 ):1687-1699. doi:10.1056/NEJMoa2110343 35334197
7 Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs. 2017;77 (5 ):521-546. doi:10.1007/s40265-017-0701-9 28255960
8 Ly S, Manjaly P, Kamal K, . Comorbid conditions associated with alopecia areata: a systematic review and meta-analysis. Am J Clin Dermatol. 2023;24 (6 ):875-893. doi:10.1007/s40257-023-00805-4 37464249
9 Huang KP, Mullangi S, Guo Y, Qureshi AA. Autoimmune, atopic, and mental health comorbid conditions associated with alopecia areata in the United States. JAMA Dermatol. 2013;149 (7 ):789-794. doi:10.1001/jamadermatol.2013.3049 23700152
10 Hunt N, McHale S. The psychological impact of alopecia. BMJ. 2005;331 (7522 ):951-953. doi:10.1136/bmj.331.7522.951 16239692
11 Drake L, Li SJ, Reyes-Hadsall S, Lee K, Huang K, Mostaghimi A. Post-traumatic stress disorder in patients with alopecia areata: a survey study in the USA. Skin Appendage Disord. 2023;9 (5 ):342-345. doi:10.1159/000530356 37900780
12 Mostaghimi A, Napatalung L, Sikirica V, . Patient perspectives of the social, emotional and functional impact of alopecia areata: a systematic literature review. Dermatol Ther (Heidelb). 2021;11 (3 ):867-883. doi:10.1007/s13555-021-00512-0 33770385
13 Toussi A, Barton VR, Le ST, Agbai ON, Kiuru M. Psychosocial and psychiatric comorbidities and health-related quality of life in alopecia areata: a systematic review. J Am Acad Dermatol. 2021;85 (1 ):162-175. doi:10.1016/j.jaad.2020.06.047 32561373
14 Villasante Fricke AC, Miteva M. Epidemiology and burden of alopecia areata: a systematic review. Clin Cosmet Investig Dermatol. 2015;8 :397-403.26244028
15 Marahatta S, Agrawal S, Adhikari BR. Psychological impact of alopecia areata. Dermatol Res Pract. 2020;2020 :8879343. doi:10.1155/2020/8879343 33424962
16 Sellami R, Masmoudi J, Ouali U, . The relationship between alopecia areata and alexithymia, anxiety and depression: a case-control study. Indian J Dermatol. 2014;59 (4 ):421. doi:10.4103/0019-5154.135525 25071275
17 Shi Q, Duvic M, Osei JS, . Health-related quality of life (HRQoL) in alopecia areata patients—a secondary analysis of the National Alopecia Areata Registry Data. J Investig Dermatol Symp Proc. 2013;16 (1 ):S49-S50. doi:10.1038/jidsymp.2013.18 24326555
18 Islam N, Leung PS, Huntley AC, Gershwin ME. The autoimmune basis of alopecia areata: a comprehensive review. Autoimmun Rev. 2015;14 (2 ):81-89. doi:10.1016/j.autrev.2014.10.014 25315746
19 Lee S, Lee H, Lee CH, Lee WS. Comorbidities in alopecia areata: a systematic review and meta-analysis. J Am Acad Dermatol. 2019;80 (2 ):466-477.e16. doi:10.1016/j.jaad.2018.07.013 30031145
20 Lavian J, Li SJ, Lee EY, . Validation of case identification for alopecia areata using International Classification of Diseases coding. Int J Trichology. 2020;12 (5 ):234-237. doi:10.4103/ijt.ijt_67_20 33531746
21 Okhovat JP, Marks DH, Manatis-Lornell A, Hagigeorges D, Locascio JJ, Senna MM. Association between alopecia areata, anxiety, and depression: a systematic review and meta-analysis. J Am Acad Dermatol. 2023;88 (5 ):1040-1050. doi:10.1016/j.jaad.2019.05.086 31163237
22 Euesden J, Danese A, Lewis CM, Maughan B. A bidirectional relationship between depression and the autoimmune disorders: new perspectives from the National Child Development Study. PLoS One. 2017;12 (3 ):e0173015. doi:10.1371/journal.pone.0173015 28264010
23 Jeppesen R, Benros ME. Autoimmune diseases and psychotic disorders. Front Psychiatry. 2019;10 :131. doi:10.3389/fpsyt.2019.00131 30949074
24 Teraki Y, Imanishi K, Shiohara T. Cytokines in alopecia areata: contrasting cytokine profiles in localized form and extensive form (alopecia universalis). Acta Derm Venereol. 1996;76 (6 ):421-423. doi:10.2340/0001555576421423 8982401
25 Ahn D, Kim H, Lee B, Hahm DH. Psychological stress-induced pathogenesis of alopecia areata: autoimmune and apoptotic pathways. Int J Mol Sci. 2023;24 (14 ):11711. doi:10.3390/ijms241411711 37511468
26 Simakou T, Butcher JP, Reid S, Henriquez FL. Alopecia areata: a multifactorial autoimmune condition. J Autoimmun. 2019;98 :74-85. doi:10.1016/j.jaut.2018.12.001 30558963
27 Hirani R, Grunfeld M, Khan U, Marmon S. Addressing the psychosocial burden of alopecia areata in clinical practice. JAAD Int. 2022;10 :84-85. doi:10.1016/j.jdin.2022.12.003 36655211
28 Chu SY, Chen YJ, Tseng WC, . Psychiatric comorbidities in patients with alopecia areata in Taiwan: a case-control study. Br J Dermatol. 2012;166 (3 ):525-531. doi:10.1111/j.1365-2133.2011.10714.x 22049923
29 Mostaghimi A, Xenakis J, Meche A, Smith TW, Gruben D, Sikirica V. Economic burden and healthcare resource use of alopecia areata in an insured population in the USA. Dermatol Ther (Heidelb). 2022;12 (4 ):1027-1040. doi:10.1007/s13555-022-00710-4 35381975
30 Senna M, Ko J, Tosti A, . Alopecia areata treatment patterns, healthcare resource utilization, and comorbidities in the US population using insurance claims. Adv Ther. 2021;38 (9 ):4646-4658. doi:10.1007/s12325-021-01845-0 34292518
31 Gao W, Mostaghimi A, Gandhi K, . Patient characteristics associated with all-cause healthcare costs of alopecia areata in the United States. J Med Econ. 2023;26 (1 ):441-444. doi:10.1080/13696998.2023.2188843 36896625
32 Eli Lily and Company. OLUMIANT Prescribing Information. Updated June 2022. Accessed June 12, 2024. https://uspl.lilly.com/olumiant/olumiant.html#pi
33 Mar K, Rivers JK. The mind body connection in dermatologic conditions: a literature review. J Cutan Med Surg. 2023;27 (6 ):628-640. doi:10.1177/12034754231204295 37898903
