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Burden of skin pain in atopic dermatitis
Ann Allergy Asthma Immunol 119 (2017) 548–552
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Burden of skin pain in atopic dermatitis Paras P. Vakharia, PharmD *; Rishi Chopra, MS *; Ryan Sacotte, BS *; Kevin R. Patel, BS *; Vivek Singam, BA *; Neha Patel, BS *; Supriya Immaneni, BS *; Takeshia White, CNA *; Robert Kantor, MD *; Derek Y. Hsu, MD *; Jonathan I. Silverberg, MD, PhD, MPH *,†,‡,§ * Department of Dermatology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois † Department of Preventive Medicine, Feinberg School of Medicine at Northwestern University, Chicago, Illinois ‡ Department of Medical Social Sciences, Feinberg School of Medicine at Northwestern University, Chicago, Illinois § Northwestern Medicine Multidisciplinary Eczema Center, Chicago, Illinois
A R T I C L E
I N F O
Article history: Received for publication August 5, 2017. Received in revised form September 25, 2017. Accepted for publication September 27, 2017.
A B S T R A C T
Background: Atopic dermatitis (AD) is associated with itch, skin inflammation and barrier disruption, and scratching, all of which may be associated with skin pain. Objective: To characterize the patient burden of skin pain in AD. Methods: We performed a prospective dermatology practice–based study using questionnaires and evaluation by a dermatologist. Results: Overall, 305 patients (age range, 13–97 years) were included in the study, with 564 encounters. The cohort included 195 females (63.9%) and 193 whites (63.7%). The mean (SD) age at enrollment was 42.3 (18.1) years, and the mean (SD) age of patient-reported AD onset was 29.6 (31.9) years. At baseline, 144 patients (42.7%) reported skin pain in the past week, with 42 (13.8%) reporting severe or very severe pain. Twentyfour (16.8%) thought the skin pain was part of their itch, 16 (11.2%) from scratching, and 77 (72.0%) from both. Patients with skin pain were more likely to describe their itch using terms that resembled neuropathic pain. Prevalence of skin pain was increased in patients with vs without excoriations (72.6% vs 57.6%; χ2 test P = .02) but not other morphologic characteristics. Skin pain severity was most strongly correlated with the Patient-Oriented Eczema Measure (Spearman ρ = 0.54), followed by ItchyQOL (ρ = 0.52), 5-dimensions of itch scale (ρ = 0.47), Dermatology Life Quality Index (ρ = 0.45), numeric rating scale for itch (ρ = 0.43) and sleep (ρ = 0.36), Patient Health Questionnaire 9 (ρ = 0.36), patient-reported global AD severity (ρ = 0.34), Eczema Area and Severity Index (ρ = 0.23), and objective Scoring AD index (ρ = 0.20) (P < .001 for all). Patients with both severe itch and pain vs those with only one or neither symptom being severe had significant increases in all these measures. Conclusion: Skin pain is a common and burdensome symptom in AD. Skin pain severity should be assessed with itch severity in AD patients and may be an important end point for monitoring treatment response. © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Atopic dermatitis (AD) is a chronic, inflammatory skin disease associated with a heterogeneous presentation and highly symptomatic clinical course. The hallmark symptom of AD is itch or pruritus. However, recent studies have found additional symptoms of AD, including increased sleep disturbance1,2 and mental health symptoms.3–5 These additional symptoms add to the patient burden of disease and significantly worsen patients’ quality of life (QOL).
Reprints: Jonathan I. Silverberg, MD, PhD, MPH, Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Ste 1600, Chicago, IL 60611; E-mail: [email protected]. Disclosures: Authors have nothing to disclose. Funding Sources: This publication was supported by grant K12 HS023011 from the Agency for Healthcare Research and Quality and the Dermatology Foundation.
Skin pain is yet another symptom that may play an important role in AD. Patients with AD and chronic itch may scratch their skin, resulting in skin barrier disruption and painful erosions. In addition, recent studies suggested that patients with AD have increased rates of skin pain and sensitivity to mechanical stimulation.6 Pain has been associated with profoundly harmful effects on patients’ mental health and all aspects of QOL in many disease states.7 In the present study, we sought to determine whether AD is associated with increased skin pain. Moreover, we sought to identify the predictors of skin pain and understand the effect of skin pain on patients’ mental health and QOL.
Methods Study Design We performed a prospective, dermatology practice–based, observational study to determine the effect of skin pain in AD.
https://doi.org/10.1016/j.anai.2017.09.076 1081-1206/© 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
P.P. Vakharia et al. / Ann Allergy Asthma Immunol 119 (2017) 548–552
Self-administered questionnaires were completed by patients of the eczema clinic before their encounter. Patients were then evaluated with a medical history and total body skin examination by a dermatologist (J.S.). Patients were enrolled between September 2014 and January 2017. The study was approved by the institutional review boards of Northwestern University, and informed consent was waived. Assessments for AD The diagnosis of AD was confirmed using the Hanifin and Rajka diagnostic criteria.8 The objective assessments of AD were the Eczema Area and Severity Index (EASI) (range, 0–72),9 objective Scoring AD (oSCORAD) (range, 0–83), and SCORAD (range, 0–103).10 The Harmonizing Outcome Measures in Eczema (HOME) group found that only oSCORAD and EASI were adequately validated and assessed the 4 essential signs of AD: erythema, induration/ papulation, lichenification, and excoriation.11 Between these 2 assessment tools, EASI was preferred over oSCORAD for the assessment of AD signs in clinical trials.12 Patients completed a questionnaire that included the following questions: “Over the past week, did you have any pain of your skin?” “How severe was the pain on a scale of 0–10?” and “Do you think the pain is part of the itch, from scratching, or both?” Additional patient-reported outcomes (PROs) related to AD included the following: numeric rating scale (NRS) for itch and sleep loss in the past 3 days (range, 0–10), Patient-Oriented Eczema Measure (POEM) (range, 0–28),13 Dermatology Life Quality Index (DLQI) (range, 0–30),14 mean ItchyQOL (range, 0–5),15,16 5 dimensions of itch (5-D itch) scale (range, 0–28),17 and Patient Health Questionnaire 9 (PHQ9) (range, 0–30).18 POEM measures the frequency of patient-reported signs and symptoms of AD and is the preferred assessment of AD symptoms in clinical trials.19 DLQI and ItchyQOL assess dermatologyand itch-specific QOL impairment, respectively. The 5-D itch scale is a composite measure that incorporates the different dimensions of itch and related QOL impairment. PHQ9 is a PRO for screening, diagnosing, and measuring the severity of depression. Data Processing and Statistical Analysis All data analyses and statistical processes were performed using SAS statistical software, version 9.4 (SAS Institute Inc, Cary, North Carolina). Complete data analysis was performed (ie, patients with missing data were excluded). Statistical significance was determined based on 2-sided P ≤ .05. Associations of any skin pain with personal history of AD and signs and symptoms of AD were tested using the χ2 or Fisher exact tests. Skin pain severity was not normally distributed. Therefore, nonparametric Spearman correlations were performed for comparisons of skin pain severity and NRS-itch, NRS-sleep, POEM, DLQI, ItchyQOL, 5-D itch scale, PHQ9, patient-reported global AD severity,20 EASI, and oSCORAD. Kruskal-Wallis tests were used to compare NRS-
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itch, NRS-sleep, POEM, DLQI, ItchyQOL, 5-D itch scale, PHQ9, EASI and oSCORAD scores for no, mild, moderate, severe, and very severe skin pain severity, as well between patients with or without severe itch and/or pain. The χ2 tests were used to compare individual items from the DLQI questionnaire between patients with any vs no skin pain, as well moderate-severe vs mild skin pain. The Fisher exact test was performed and κ coefficients were determined for comparisons of patient-reported global AD severity with skin pain severity and patients with or without severe itch and/or pain.
Results Patient Characteristics Overall, 305 patients (age range, 13–97 years) were included in the study, with 564 encounters. The cohort included 195 females (63.9%) and 193 whites (63.7%). The mean (SD) age at enrollment was 42.3 (18.1) years, and the mean (SD) age of patient-reported AD onset was 29.6 (31.9) years (eTable 1). At baseline, 144 patients (42.7%) reported any skin pain in the past week, with 42 (13.8%) reporting severe or very severe pain. Twenty-four (16.8%) thought their skin pain was part of their itch, 16 (11.2%) from scratching, and 77 (72.0%) from both. Patients with skin pain were more likely to describe their itch as painful (P < .0001), throbbing (P = .0007), biting (P = .01), stinging (P = .009), burning (P < .001), sharp (P = .05), tingling (P = .03), pinprick-like (P = .01), and a crawling sensation (P = .007) but not warm (P = .24), tight (P = .41), shooting (P = .18), or sensitive (P = .24) (Fig 1). In a sensitivity analysis of patients with no or only mild excoriations, the rates of use of the abovementioned pain-like descriptors were similarly increased in those reporting skin pain compared with those without skin pain (Fig 1).
Associations of Skin Pain in AD Any skin pain was associated with increased personal history of hay fever (P = .001) and higher rates of conjunctivitis or eyelid dermatitis (P = .05) and cheilitis (P = .002) but not race/ethnicity, sex, alcohol consumption habits, current smoking status, personal or family history of other AD, or other physical signs or symptoms of AD (P ≥ .11) (eTable 2). Prevalence of skin pain was also significantly increased in patients with vs without excoriations (72.6% vs 57.6%; χ2 test P = .02) but was not associated with other morphologic characteristics, such as lichenification (70.6% vs 66.7%, P = .57), erythema (80.4% vs 72.7%, P = .53), oozing or crusting (83.6% vs 79.0%, P = .43), edema or papulation (79.5% vs 80.6%, P = .83), or xerosis (78.6% vs 87.0%, P = .20). Skin Pain Severity and Other AD Assessments Skin pain severity was most strongly correlated with POEM (Spearman ρ = 0.54), followed by ItchyQOL (ρ = 0.52), 5-D itch scale
Figure 1. Pain-like descriptors of itch in atopic dermatitis (AD). Proportion of patients with AD who described their itch using pain-like descriptors. Results are stratified by those with vs without skin pain. Sensitivity analyses were performed in patients reporting skin pain who had either no or only mild excoriations on physical examination.
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A
F
B
G
C
H
D
I
E
Figure 2. Associations of skin pain severity with itch, atopic dermatitis signs and symptoms, and quality of life. Box-whisker plots and overlaid jitter plots of (A) numeric rating scale for itch (NRS-itch), (B) Patient-Oriented Eczema Measure (POEM), (C) mean ItchyQOL, (D) Dermatology Life Quality Index (DLQI), (E) 5 dimensions of itch (5-D itch), (F) numeric rating scale for sleep (NRS-sleep), (G) Patient Health Questionnaire 9 (PHQ9), (H) Eczema Area and Severity Index (EASI), and (I) objective Scoring AD (oSCORAD).
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(ρ = 0.47), DLQI (ρ = 0.45), NRS-itch in the past 3 days (ρ = 0.43), NRS-sleep in the past 3 days (ρ = 0.36), PHQ9 (ρ = 0.36), patientreported global AD severity (ρ = 0.34), EASI (ρ = 0.23), and oSCORAD (ρ = 0.20) (P < .001 for all). For each stepwise increase of skin pain from mild to very severe, there was a greater burden of disease with significant increases of skin symptoms (NRS-itch in the past 3 days, POEM) and poorer quality of life (ItchyQOL, DLQI, 5-D itch scale), as well as worsening sleep (NRS-sleep in the past 3 days), mental health symptoms (PHQ9), and greater AD severity (EASI and oSCORAD) (KruskalWallis test, P < .001 for all) (Fig 2). The correlations between skin pain and the abovementioned objective assessments and PRO were similar in both men and women, whites and nonwhites, and those younger than 40 years and 40 years or older (P < .01 for all; data not shown). Additive Burden of Itch and Pain in AD Skin symptoms (POEM), quality of life effect (ItchyQOL, DLQI, 5-D itch scale), sleep disturbance (NRS-sleep in the past 3 days), mental health symptoms (PHQ9), and AD severity (EASI and oSCORAD) were all increased in patients who rated both itch and pain as severe compared with those who rated one or neither of these measures as severe (Kruskal-Wallis test, P < .001 for all) (eFig 1). In particular, skin pain was associated with increased selfconsciousness and treatment burden and had a negative effect on ability to shop and perform other activities of daily living, to make clothing decisions, to socialize or pursue leisure activities, to play sports, to work or study, to have relationships with others, and to have normal sexual function (P ≤ .02 for all) (Table 2, eTable 3). Moreover, there was a significant dose-response effect with an even more harmful impact on the above aspects of QOL with increasing severity of skin pain (P < .001 for all) (eTable 4). Skin Pain and Patient-Reported Global AD Severity Among patients reporting skin pain, there was moderate concordance between skin pain and patient-reported global AD severity (mild, moderate, and severe) (weighted κ = 0.31) (χ2 test, P < .001) (Table 1). The presence of both severe itch and pain vs either alone or neither symptom being severe was associated with significant increases of patient-reported global AD severity (P < .001). Discussion The present study found high rates of skin pain in patients with AD. Most patients reported that the pain was attributable at least in part to scratching (83.2%), but a substantial proportion reported that their pain was related to their itch. Patients with skin pain were more likely to describe their itch with distinct terms that
Table 1 Concordance Between Skin Pain and Patient-Reported Global AD Severity Variable
Patient-reported global AD severity, no. (%) Mild
Skin pain Mild Moderate Severe or very severe Severe pain and/or itch None Either Both
Moderate
P valuea
Severe <.001
34 (34.0) 35 (28.5) 12 (10.3)
47 (47.0) 53 (43.1) 22 (19.0)
19 (19.0) 35 (28.5) 82 (70.7)
379 (53.1) 42 (19.7) 6 (8.8)
239 (33.5) 70 (32.9) 7 (10.3)
96 (13.4) 101 (47.4) 55 (80.9)
Abbreviation: AD, atopic dermatitis. aχ2 test.
<.001
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Table 2 Specific Aspects of Quality of Life Impairment Associated With Skin Pain, Particularly Severe Skin Pain Self-consciousness Ability to shop, take care of home, and garden Clothing decisions Socializing or leisure activities Sports Work or study in past week (yes/no) Work or study overall Relationship with partner, friend, or relative Sexual function Effect of treatment on quality of life
resembled neuropathic pain, even when no or only mild excoriations were present. Skin pain was associated with excoriations, eyelid dermatitis, and cheilitis but not other physical signs of AD. Skin pain, particularly severe pain, was associated with increased AD severity, poor sleep, depressive symptoms, and poorer QOL. Combined severe skin pain and itch were associated with even poorer outcomes. Together, these results indicate that AD is associated with a profound burden of skin pain in addition to itch. Interestingly, a substantial proportion of patients reporting skin pain thought their pain was unrelated (16.8%) or only partially related (72.0%) to scratching and had no demonstrable excoriations on physical examination. A substantial proportion of patients with AD described their itch using pain-related terms, with even higher rates in those with no or only mild excoriations. It may be that some patients experience the sensation of pain secondary to cutaneous inflammation and/or neurosensory dysfunction. A casecontrol study of 25 patients with AD and 25 controls found that the patients with AD had a mean pain visual analog score of 39.7, increased sensitivity to mechanically induced pain both lesionally and extralesionally, and hyperknesis.6 These findings suggest that sensitivity and pain may not be limited to sites of active skin lesions or excoriations. Another case-control study of 25 patients with AD, 9 patients with psoriasis, and 20 controls found that noxious and chemical stimuli primarily triggered itch in patients with AD, whereas pain was experienced in patients with psoriasis and controls.21 These findings suggest that the perception of pain may be aberrant and overlap with itch in patients with AD. Together, it appears that patients with AD commonly experience skin pain and pain-like itch sensations, which may result from increased sensitivity. The mechanisms of increased skin pain in AD are likely multifactorial. Two studies found increased density of dermal nerves in patients with AD compared with controls.22,23 In contrast, another study found that patients with AD had lower nerve density than controls but longer individual nerve fibers in lichenified and unlichenified lesions.24 Cutaneous nerve endings might be more vulnerable to exogenous stimuli secondary to impaired barrier function. There may also be increased and aberrant activation of cutaneous nerves to mechanical and other exogenous stimuli secondary to activation of transient receptor potential V1 and other receptors, which have been implicated in mouse models of AD.25–27 Future studies are needed to better understand these mechanisms, which may lead to improved treatments of itch and skin pain in AD. This study has several strengths, including being prospective and using validated objective assessments and PRO to assess the burden of skin pain. However, the study has limitations. In particular, the study was performed in an urban, academic, dermatologic setting and may not be generalizable to the entire US population. Future, larger-scale multicenter studies are needed to confirm the results of this study. In conclusion, AD appears to be associated with increased skin pain. For most patients, scratching appears to be the major driver of pain. However, a subset of patients with AD seem to
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experience pain-like itch that resembles neuropathic pain without evidence of scratching. Skin pain was associated with increased AD severity and affected all aspects of patients’ QOL. We recommend that skin pain severity be routinely assessed along with itch severity in all patients with AD. Moreover, skin pain severity may be an important end point for monitoring clinical response to treatment. Future studies are needed to determine the precise mechanisms and optimal treatment approaches for skin pain in AD. Supplementary Data Supplementary data related to this article can be found at https:// doi.org/10.1016/j.anai.2017.09.076. References [1] Silverberg JI, Garg NK, Paller AS, Fishbein AB, Zee PC. Sleep disturbances in adults with eczema are associated with impaired overall health: a US populationbased study. J Invest Dermatol. 2015;135:56–66. [2] Yu SH, Attarian H, Zee P, Silverberg JI. Burden of sleep and fatigue in US adults with atopic dermatitis. Dermatitis. 2016;27:50–58. [3] Yu SH, Silverberg JI. Association between atopic dermatitis and depression in US adults. J Invest Dermatol. 2015;135:3183–3186. [4] Garg N, Silverberg JI. Association between childhood allergic disease, psychological comorbidity, and injury requiring medical attention. Ann Allergy Asthma Immunol. 2014;112:525–532. [5] Strom MA, Fishbein AB, Paller AS, Silverberg JI. Association between atopic dermatitis and attention deficit hyperactivity disorder in U.S. children and adults. Br J Dermatol. 2016;175:920–929. [6] Andersen HH, Elberling J, Solvsten H, Yosipovitch G, Arendt-Nielsen L. Nonhistaminergic and mechanical itch sensitization in atopic dermatitis. Pain. 2017;158:1780–1791. [7] McCarberg BH, Nicholson BD, Todd KH, Palmer T, Penles L. The impact of pain on quality of life and the unmet needs of pain management: results from pain sufferers and physicians participating in an Internet survey. Am J Ther. 2008; 15:312–320. [8] Hanifin J, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh). 1980;92:44–47. [9] Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. EASI Evaluator Group. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. Exp Dermatol. 2001;10:11–18. [10] Severity scoring of atopic dermatitis: the SCORAD index: consensus report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186:23– 31.
[11] Schmitt J, Langan S, Deckert S, et al. Assessment of clinical signs of atopic dermatitis: a systematic review and recommendation. J Allergy Clin Immunol. 2013;132:1337–1347. [12] Chalmers JR, Schmitt J, Apfelbacher C, et al. Report from the third international consensus meeting to harmonise core outcome measures for atopic eczema/ dermatitis clinical trials (HOME). Br J Dermatol. 2014;171:1318–1325. [13] Charman CR, Venn AJ, Ravenscroft JC, Williams HC. Translating PatientOriented Eczema Measure (POEM) scores into clinical practice by suggesting severity strata derived using anchor-based methods. Br J Dermatol. 2013;169: 1326–1332. [14] Basra MK, Fenech R, Gatt RM, Salek MS, Finlay AY. The Dermatology Life Quality Index 1994–2007: a comprehensive review of validation data and clinical results. Br J Dermatol. 2008;159:997–1035. [15] Desai NS, Poindexter GB, Monthrope YM, Bendeck SE, Swerlick RA, Chen SC. A pilot quality-of-life instrument for pruritus. J Am Acad Dermatol. 2008;59: 234–244. [16] ItchyQol: A Pruritus-Specific Quality of Life Instrument, Vol. 2017. Atlanta, GA: Emory University; 2009. [17] Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus. Br J Dermatol. 2010;162:587–593. [18] Gilbody S, Richards D, Brealey S, Hewitt C. Screening for depression in medical settings with the Patient Health Questionnaire (PHQ): a diagnostic metaanalysis. J Gen Intern Med. 2007;22:1596–1602. [19] Spuls PI, Gerbens LA, Simpson E, et al. Patient-Oriented Eczema Measure (POEM), a core instrument to measure symptoms in clinical trials: a HOME statement. Br J Dermatol. 2017;176:979–984. [20] Vakharia PP, Chopra R, Sacotte R, et al. Validation of patient-reported global severity of atopic dermatitis in adults. Allergy. 2017;doi:10.1111/all.13309. [21] Ikoma A, Fartasch M, Heyer G, Miyachi Y, Handwerker H, Schmelz M. Painful stimuli evoke itch in patients with chronic pruritus: central sensitization for itch. Neurology. 2004;62:212–217. [22] Urashima R, Mihara M. Cutaneous nerves in atopic dermatitis: a histological, immunohistochemical and electron microscopic study. Virchows Arch. 1998; 432:363–370. [23] Sugiura H, Omoto M, Hirota Y, Danno K, Uehara M. Density and fine structure of peripheral nerves in various skin lesions of atopic dermatitis. Arch Dermatol Res. 1997;289:125–131. [24] Tsutsumi M, Kitahata H, Fukuda M, et al. Numerical and comparative threedimensional structural analysis of peripheral nerve fibres in epidermis of patients with atopic dermatitis. Br J Dermatol. 2016;174:191–194. [25] Shibata T, Takahashi K, Matsubara Y, Takahashi N, Mori Y, Uchida K. 15-deoxy?(12,14)-prostaglandin J2 as a potential TRPV1-dependent atopic dermatitis enhancer. Free Radic Biol Med. 2014;75(suppl 1):S49. [26] Mollanazar NK, Smith PK, Yosipovitch G. Mediators of chronic pruritus in atopic dermatitis: getting the itch out? Clin Rev Allergy Immunol. 2016;51:263–292. [27] Yun JW, Seo JA, Jeong YS, et al. TRPV1 antagonist can suppress the atopic dermatitis-like symptoms by accelerating skin barrier recovery. J Dermatol Sci. 2011;62:8–15.
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Supplementary Data
A
F
B
G
C
H
D
I
E
eFigure 1. Additive effects of severe itch and skin on atopic dermatitis signs and symptoms and quality of life. Box-whisker plots and overlaid jitter plots of (A) numeric rating scale for itch (NRSitch), (B) Patient-Oriented Eczema Measure (POEM), (C) mean ItchyQOL, (D) Dermatology Life Quality Index (DLQI), (E) 5 dimensions of itch (5-D itch), (F) numeric rating scale for sleep (NRS-sleep), (G) Patient Health Questionnaire 9 (PHQ9), (H) Eczema Area and Severity Index (EASI), and (I) objective Scoring AD (oSCORAD).
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eTable 2 Association of Skin Pain in Atopic Dermatitis
eTable 1 Demographic Characteristics of the 305 Patients in the Study Cohort Findinga
Characteristic Sex Male Female Race/ethnicity White, non-Hispanic Black Hispanic Asian Multiracial/other Age at enrollment, mean (SD), y Age at AD onset, mean (SD), y Skin pain severity Mean (SD) Frequency None Mild Moderate Severe Very severe
110 (36.1) 195 (63.9) 193 (63.7) 37 (12.2) 17 (5.6) 49 (17.0) 7 (2.3) 42.3 (18.1) 29.6 (31.9) 2.4 (3.1) 161 (52.8) 52 (17.1) 50 (16.4) 21 (6.9) 21 (6.9)
a
Data are presented as number (percentage) of patients unless otherwise indicated. Missing values were encountered for 0 patients for sex, race/ethnicity, age at enrollment, and skin pain severity and 23 (7.5%) for age at AD onset.
Variable
Any skin pain, no. (%)
Race/ethnicity White Black Hispanic Asian Multiracial/other Female sex Alcohol Current smoker Personal history Asthma Hay fever Food allergy Medication allergy Physical signs Facial dermatitis Conjunctivitis or eyelid dermatitis Cheilitis Hand dermatitis Foot dermatitis Nipple dermatitis Scalp Posterior auricular Nummular lesions White dermatographism Symptoms Clinical course worsened by environmental or emotional factors Pruritus when sweating Tendency toward cutaneous infections
P value
No (n = 161)
Yes (n = 144)
106 (65.8) 18 (11.2) 7 (4.3) 29 (18.0) 1 (0.6) 100 (62.1) 92 (63.4) 16 (10.9)
87 (61.3) 19 (13.4) 10 (7.0) 22 (15.5) 4 (2.8) 95 (66.0) 87 (65.9) 15 (11.2)
.48b .67b .93b
59 (38.6) 63 (41.2) 52 (34.4) 37 (24.7)
53 (40.2) 80 (60.6) 51 (38.9) 41 (31.5)
.78b .001b .43b .20b
59 (51.8) 48 (41.7) 29 (25.9) 52 (49.5)
55 (60.4) 51 (55.4) 43 (46.7) 52 (60.5)
.21b .05b .002b .13b
15 (13.5) 47 (40.5) 38 (33.6) 12 (10.3) 7 (6.0)
12 (13.2) 48 (51.6) 40 (43.5) 11 (11.3) 3 (3.1)
.95b .11b .15b .80b .32a
78 (86.7)
72 (83.7)
.58b
63 (70.8) 53 (32.9)
58 (67.4) 48 (33.3)
.63b .94b
.41a
aFisher bχ2
exact test. test.
eTable 3 Effect of Skin Pain on Individual Aspects of the DLQI in Atopic Dermatitis Any skin pain
DLQI response, no. (%) Not at all/Not relevant
1. Itching and/or burning of skin No Yes 2. Self-conscious No Yes 3. Ability to shop, take care of home, and garden No Yes 4. Clothing decisions No Yes 5. Socializing or leisure activities No Yes 6. Sports No Yes 7-1. Work or study in past week (yes/no) No Yes 7-2. Work or study overall No Yes 8. Relationship with partner, friend, or relative No Yes 9. Sexual function No Yes 10. Effect of treatment on quality of life No Yes Abbreviation: DLQI, Dermatology Life Quality Index.
P value A little
A lot
Very much
22 (10.5) 7 (2.3)
109 (52.2) 97 (31.9)
50 (23.9) 111 (36.5)
28 (13.4) 89 (29.3)
<.001
64 (30.6) 67 (22.0)
91 (43.5) 99 (32.6)
27 (12.9) 53 (17.4)
27 (12.9) 85 (28.0)
<.001
32 (15.3%) 65 (21.4%)
15 (7.2%) 44 (14.5%)
4 (1.9%) 38 (12.5%)
<.001
84 (40.2) 67 (22.2)
67 (32.1) 86 (28.5)
35 (16.8) 72 (23.8)
23 (11.0) 77 (25.5)
<.001
120 (57.4) 120 (39.5)
56 (26.8) 82 (27.0)
23 (11.0) 61 (20.1)
10 (4.8) 41 (13.5)
<.001
148 (70.8) 161 (53.1%)
37 (17.7) 54 (17.8%)
16 (7.7) 40 (13.2%)
8 (3.8) 48 (15.8%)
<.001
193 (92.8) 231 (76.2)
15 (7.2) 72 (23.8)
139 (70.2) 157 (57.9)
51 (25.8) 83 (30.6)
7 (3.5) 25 (9.2)
1 (0.5) 6 (2.2)
.009
153 (73.2) 170 (56.1)
39 (18.7) 85 (28.1)
9 (4.3) 24 (7.9)
8 (3.8) 24 (7.9)
.001
179 (85.7) 235 (77.6)
12 (5.7) 36 (11.9)
12 (5.7) 12 (4.0)
6 (2.9) 20 (6.6)
.02
105 (50.2) 101 (33.3)
68 (32.5) 108 (35.6)
30 (14.4) 53 (17.5)
6 (2.9) 41 (13.5)
158 (75.6%) 157 (51.6%)
<.001
<.001
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552.e3
eTable 4 Effect of Skin Pain Severity on Individual Aspects of the DLQI in Atopic Dermatitis Any skin pain
DLQI response, no. (%) Not at all/Not relevant
1. Itching and/or burning of skin No Mild Moderate Severe Very severe 2. Self-conscious about lesions No Mild Moderate Severe Very severe 3. Ability to shop, take care of home, and garden No Mild Moderate Severe Very severe 4. Clothing decisions No Mild Moderate Severe Very severe 5. Socializing or leisure activities No Mild Moderate Severe Very severe 6. Sports No Mild Moderate Severe Very severe 7-1. Work or study in past week (yes/no) No Mild Moderate Severe Very severe 7-2. Work or study overall No Mild Moderate Severe Very severe 8. Relationship with partner, friend, or relative No Mild Moderate Severe Very severe 9. Sexual function No Mild Moderate Severe Very severe 10. Effect of treatment on quality of life No Mild Moderate Severe Very severe Abbreviation: DLQI, Dermatology Life Quality Index.
P value A little
A lot
Very much
22 (10.5) 6 (6.3) 0 (0.0) 0 (0.0) 1 (2.2)
109 (52.2) 51 (53.1) 39 (38.2) 4 (6.6) 3 (6.7)
50 (23.9) 29 (30.2) 44 (43.1) 28 (45.9) 10 (22.2)
28 (13.4) 10 (10.4) 19 (18.6) 29 (47.5) 31 (968.9)
<.001
64 (30.6) 35 (36.5) 25 (24.5) 4 (6.6) 3 (6.7)
91 (43.5) 36 (37.5) 35 (34.3) 19 (31.2) 9 (20.0)
27 (12.9) 13 (13.5) 18 (17.7) 16 (26.2) 6 (13.3)
27 (12.9) 12 (12.5) 24 (23.5) 22 (36.1) 27 (60.0)
<.001
158 (75.6) 74 (77.1) 53 (52.0) 22 (26.1) 8 (17.8)
32 (15.3) 14 (14.6) 26 (25.5) 13 (21.3) 12 (26.7)
15 (7.2) 6 (6.3) 18 (17.7) 14 (23.0) 6 (13.3)
4 (1.9) 2 (2.1) 5 (4.9) 12 (19.7) 19 (42.2)
<.001
84 (40.2) 31 (32.6) 21 (20.6) 10 (16.7) 5 (11.1)
67 (32.1) 34 (35.8) 32 (31.4) 13 (21.7) 7 (15.6)
35 (16.8) 18 (19.0) 21 (20.6) 21 (35.0) 12 (26.7)
23 (11.0) 12 (12.6) 28 (27.5) 16 (26.7) 21 (46.7)
<.001
120 (57.4) 57 (59.4) 43 (42.2) 14 (23.0) 6 (13.3%)
56 (26.8) 27 (28.1) 28 (27.5) 13 (21.3) 14 (31.1%)
23 (11.0) 7 (7.3) 22 (21.6) 22 (36.1) 10 (22.2%)
10 (4.8) 5 (5.2) 9 (8.8) 12 (19.7) 15 (33.3%)
<.001
148 (70.8) 64 (66.7) 59 (58.4) 21 (34.4) 17 (37.8)
37 (17.7) 20 (20.8) 15 (14.9) 14 (23.0) 4 (11.1)
16 (7.7) 5 (5.2) 20 (19.8) 11 (18.0) 4 (8.9)
8 (3.8) 7 (7.3) 7 (6.9) 15 (24.6) 19 (42.2)
<.001
193 (92.8) 91 (95.8) 79 (77.5) 37 (60.7) 24 (53.3)
15 (7.2) 4 (4.2) 23 (22.6) 24 (39.3) 21 (46.7)
139 (70.2) 66 (69.5) 56 (60.9) 19 (39.6) 16 (44.4)
51 (25.8) 24 (25.3) 26 (28.3) 21 (43.8) 12 (33.3)
7 (3.5) 5 (5.3) 9 (9.8) 5 (10.4) 6 (16.7)
1 (0.5) 0 (0.0) 1 (1.1) 3 (6.3) 2 (5.6)
.001
153 (73.2) 73 (76.0) 55 (53.9) 27 (45.0) 15 (33.3)
39 (18.7) 23 (24.0) 36 (5.3) 13 (21.7) 13 (28.9)
9 (4.3) 0 (0.0) 6 (5.9) 11 (18.3) 7 (15.6%
8 (3.8) 0 (0.0) 5 (4.9) 9 (15.0) 10 (22.2)
<.001
179 (85.7) 87 (90.6) 76 (74.5) 46 (76.7) 26 (57.8)
12 (5.7) 7 (7.3) 17 (16.7) 7 (11.7) 5 (11.1)
12 (5.7) 1 (1.0) 5 (4.9) 4 (6.7) 2 (4.4)
6 (2.9) 1 (1.0) 4 (3.9) 3 (5.0) 12 (26.7)
<.001
105 (50.2) 49 (51.0) 30 (29.4) 14 (23.3) 8 (17.8)
68 (32.5) 32 (33.3) 44 (43.1) 14 (23.3) 18 (40.0)
30 (14.4) 12 (12.5) 20 (19.6) 16 (26.7) 5 (11.1)
6 (2.9) 3 (3.1) 8 (7.8) 16 (26.7) 14 (31.1)
<.001
<.001
Contents lists available at ScienceDirect
Burden of skin pain in atopic dermatitis Paras P. Vakharia, PharmD *; Rishi Chopra, MS *; Ryan Sacotte, BS *; Kevin R. Patel, BS *; Vivek Singam, BA *; Neha Patel, BS *; Supriya Immaneni, BS *; Takeshia White, CNA *; Robert Kantor, MD *; Derek Y. Hsu, MD *; Jonathan I. Silverberg, MD, PhD, MPH *,†,‡,§ * Department of Dermatology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois † Department of Preventive Medicine, Feinberg School of Medicine at Northwestern University, Chicago, Illinois ‡ Department of Medical Social Sciences, Feinberg School of Medicine at Northwestern University, Chicago, Illinois § Northwestern Medicine Multidisciplinary Eczema Center, Chicago, Illinois
A R T I C L E
I N F O
Article history: Received for publication August 5, 2017. Received in revised form September 25, 2017. Accepted for publication September 27, 2017.
A B S T R A C T
Background: Atopic dermatitis (AD) is associated with itch, skin inflammation and barrier disruption, and scratching, all of which may be associated with skin pain. Objective: To characterize the patient burden of skin pain in AD. Methods: We performed a prospective dermatology practice–based study using questionnaires and evaluation by a dermatologist. Results: Overall, 305 patients (age range, 13–97 years) were included in the study, with 564 encounters. The cohort included 195 females (63.9%) and 193 whites (63.7%). The mean (SD) age at enrollment was 42.3 (18.1) years, and the mean (SD) age of patient-reported AD onset was 29.6 (31.9) years. At baseline, 144 patients (42.7%) reported skin pain in the past week, with 42 (13.8%) reporting severe or very severe pain. Twentyfour (16.8%) thought the skin pain was part of their itch, 16 (11.2%) from scratching, and 77 (72.0%) from both. Patients with skin pain were more likely to describe their itch using terms that resembled neuropathic pain. Prevalence of skin pain was increased in patients with vs without excoriations (72.6% vs 57.6%; χ2 test P = .02) but not other morphologic characteristics. Skin pain severity was most strongly correlated with the Patient-Oriented Eczema Measure (Spearman ρ = 0.54), followed by ItchyQOL (ρ = 0.52), 5-dimensions of itch scale (ρ = 0.47), Dermatology Life Quality Index (ρ = 0.45), numeric rating scale for itch (ρ = 0.43) and sleep (ρ = 0.36), Patient Health Questionnaire 9 (ρ = 0.36), patient-reported global AD severity (ρ = 0.34), Eczema Area and Severity Index (ρ = 0.23), and objective Scoring AD index (ρ = 0.20) (P < .001 for all). Patients with both severe itch and pain vs those with only one or neither symptom being severe had significant increases in all these measures. Conclusion: Skin pain is a common and burdensome symptom in AD. Skin pain severity should be assessed with itch severity in AD patients and may be an important end point for monitoring treatment response. © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Atopic dermatitis (AD) is a chronic, inflammatory skin disease associated with a heterogeneous presentation and highly symptomatic clinical course. The hallmark symptom of AD is itch or pruritus. However, recent studies have found additional symptoms of AD, including increased sleep disturbance1,2 and mental health symptoms.3–5 These additional symptoms add to the patient burden of disease and significantly worsen patients’ quality of life (QOL).
Reprints: Jonathan I. Silverberg, MD, PhD, MPH, Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Ste 1600, Chicago, IL 60611; E-mail: [email protected]. Disclosures: Authors have nothing to disclose. Funding Sources: This publication was supported by grant K12 HS023011 from the Agency for Healthcare Research and Quality and the Dermatology Foundation.
Skin pain is yet another symptom that may play an important role in AD. Patients with AD and chronic itch may scratch their skin, resulting in skin barrier disruption and painful erosions. In addition, recent studies suggested that patients with AD have increased rates of skin pain and sensitivity to mechanical stimulation.6 Pain has been associated with profoundly harmful effects on patients’ mental health and all aspects of QOL in many disease states.7 In the present study, we sought to determine whether AD is associated with increased skin pain. Moreover, we sought to identify the predictors of skin pain and understand the effect of skin pain on patients’ mental health and QOL.
Methods Study Design We performed a prospective, dermatology practice–based, observational study to determine the effect of skin pain in AD.
https://doi.org/10.1016/j.anai.2017.09.076 1081-1206/© 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
P.P. Vakharia et al. / Ann Allergy Asthma Immunol 119 (2017) 548–552
Self-administered questionnaires were completed by patients of the eczema clinic before their encounter. Patients were then evaluated with a medical history and total body skin examination by a dermatologist (J.S.). Patients were enrolled between September 2014 and January 2017. The study was approved by the institutional review boards of Northwestern University, and informed consent was waived. Assessments for AD The diagnosis of AD was confirmed using the Hanifin and Rajka diagnostic criteria.8 The objective assessments of AD were the Eczema Area and Severity Index (EASI) (range, 0–72),9 objective Scoring AD (oSCORAD) (range, 0–83), and SCORAD (range, 0–103).10 The Harmonizing Outcome Measures in Eczema (HOME) group found that only oSCORAD and EASI were adequately validated and assessed the 4 essential signs of AD: erythema, induration/ papulation, lichenification, and excoriation.11 Between these 2 assessment tools, EASI was preferred over oSCORAD for the assessment of AD signs in clinical trials.12 Patients completed a questionnaire that included the following questions: “Over the past week, did you have any pain of your skin?” “How severe was the pain on a scale of 0–10?” and “Do you think the pain is part of the itch, from scratching, or both?” Additional patient-reported outcomes (PROs) related to AD included the following: numeric rating scale (NRS) for itch and sleep loss in the past 3 days (range, 0–10), Patient-Oriented Eczema Measure (POEM) (range, 0–28),13 Dermatology Life Quality Index (DLQI) (range, 0–30),14 mean ItchyQOL (range, 0–5),15,16 5 dimensions of itch (5-D itch) scale (range, 0–28),17 and Patient Health Questionnaire 9 (PHQ9) (range, 0–30).18 POEM measures the frequency of patient-reported signs and symptoms of AD and is the preferred assessment of AD symptoms in clinical trials.19 DLQI and ItchyQOL assess dermatologyand itch-specific QOL impairment, respectively. The 5-D itch scale is a composite measure that incorporates the different dimensions of itch and related QOL impairment. PHQ9 is a PRO for screening, diagnosing, and measuring the severity of depression. Data Processing and Statistical Analysis All data analyses and statistical processes were performed using SAS statistical software, version 9.4 (SAS Institute Inc, Cary, North Carolina). Complete data analysis was performed (ie, patients with missing data were excluded). Statistical significance was determined based on 2-sided P ≤ .05. Associations of any skin pain with personal history of AD and signs and symptoms of AD were tested using the χ2 or Fisher exact tests. Skin pain severity was not normally distributed. Therefore, nonparametric Spearman correlations were performed for comparisons of skin pain severity and NRS-itch, NRS-sleep, POEM, DLQI, ItchyQOL, 5-D itch scale, PHQ9, patient-reported global AD severity,20 EASI, and oSCORAD. Kruskal-Wallis tests were used to compare NRS-
549
itch, NRS-sleep, POEM, DLQI, ItchyQOL, 5-D itch scale, PHQ9, EASI and oSCORAD scores for no, mild, moderate, severe, and very severe skin pain severity, as well between patients with or without severe itch and/or pain. The χ2 tests were used to compare individual items from the DLQI questionnaire between patients with any vs no skin pain, as well moderate-severe vs mild skin pain. The Fisher exact test was performed and κ coefficients were determined for comparisons of patient-reported global AD severity with skin pain severity and patients with or without severe itch and/or pain.
Results Patient Characteristics Overall, 305 patients (age range, 13–97 years) were included in the study, with 564 encounters. The cohort included 195 females (63.9%) and 193 whites (63.7%). The mean (SD) age at enrollment was 42.3 (18.1) years, and the mean (SD) age of patient-reported AD onset was 29.6 (31.9) years (eTable 1). At baseline, 144 patients (42.7%) reported any skin pain in the past week, with 42 (13.8%) reporting severe or very severe pain. Twenty-four (16.8%) thought their skin pain was part of their itch, 16 (11.2%) from scratching, and 77 (72.0%) from both. Patients with skin pain were more likely to describe their itch as painful (P < .0001), throbbing (P = .0007), biting (P = .01), stinging (P = .009), burning (P < .001), sharp (P = .05), tingling (P = .03), pinprick-like (P = .01), and a crawling sensation (P = .007) but not warm (P = .24), tight (P = .41), shooting (P = .18), or sensitive (P = .24) (Fig 1). In a sensitivity analysis of patients with no or only mild excoriations, the rates of use of the abovementioned pain-like descriptors were similarly increased in those reporting skin pain compared with those without skin pain (Fig 1).
Associations of Skin Pain in AD Any skin pain was associated with increased personal history of hay fever (P = .001) and higher rates of conjunctivitis or eyelid dermatitis (P = .05) and cheilitis (P = .002) but not race/ethnicity, sex, alcohol consumption habits, current smoking status, personal or family history of other AD, or other physical signs or symptoms of AD (P ≥ .11) (eTable 2). Prevalence of skin pain was also significantly increased in patients with vs without excoriations (72.6% vs 57.6%; χ2 test P = .02) but was not associated with other morphologic characteristics, such as lichenification (70.6% vs 66.7%, P = .57), erythema (80.4% vs 72.7%, P = .53), oozing or crusting (83.6% vs 79.0%, P = .43), edema or papulation (79.5% vs 80.6%, P = .83), or xerosis (78.6% vs 87.0%, P = .20). Skin Pain Severity and Other AD Assessments Skin pain severity was most strongly correlated with POEM (Spearman ρ = 0.54), followed by ItchyQOL (ρ = 0.52), 5-D itch scale
Figure 1. Pain-like descriptors of itch in atopic dermatitis (AD). Proportion of patients with AD who described their itch using pain-like descriptors. Results are stratified by those with vs without skin pain. Sensitivity analyses were performed in patients reporting skin pain who had either no or only mild excoriations on physical examination.
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A
F
B
G
C
H
D
I
E
Figure 2. Associations of skin pain severity with itch, atopic dermatitis signs and symptoms, and quality of life. Box-whisker plots and overlaid jitter plots of (A) numeric rating scale for itch (NRS-itch), (B) Patient-Oriented Eczema Measure (POEM), (C) mean ItchyQOL, (D) Dermatology Life Quality Index (DLQI), (E) 5 dimensions of itch (5-D itch), (F) numeric rating scale for sleep (NRS-sleep), (G) Patient Health Questionnaire 9 (PHQ9), (H) Eczema Area and Severity Index (EASI), and (I) objective Scoring AD (oSCORAD).
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(ρ = 0.47), DLQI (ρ = 0.45), NRS-itch in the past 3 days (ρ = 0.43), NRS-sleep in the past 3 days (ρ = 0.36), PHQ9 (ρ = 0.36), patientreported global AD severity (ρ = 0.34), EASI (ρ = 0.23), and oSCORAD (ρ = 0.20) (P < .001 for all). For each stepwise increase of skin pain from mild to very severe, there was a greater burden of disease with significant increases of skin symptoms (NRS-itch in the past 3 days, POEM) and poorer quality of life (ItchyQOL, DLQI, 5-D itch scale), as well as worsening sleep (NRS-sleep in the past 3 days), mental health symptoms (PHQ9), and greater AD severity (EASI and oSCORAD) (KruskalWallis test, P < .001 for all) (Fig 2). The correlations between skin pain and the abovementioned objective assessments and PRO were similar in both men and women, whites and nonwhites, and those younger than 40 years and 40 years or older (P < .01 for all; data not shown). Additive Burden of Itch and Pain in AD Skin symptoms (POEM), quality of life effect (ItchyQOL, DLQI, 5-D itch scale), sleep disturbance (NRS-sleep in the past 3 days), mental health symptoms (PHQ9), and AD severity (EASI and oSCORAD) were all increased in patients who rated both itch and pain as severe compared with those who rated one or neither of these measures as severe (Kruskal-Wallis test, P < .001 for all) (eFig 1). In particular, skin pain was associated with increased selfconsciousness and treatment burden and had a negative effect on ability to shop and perform other activities of daily living, to make clothing decisions, to socialize or pursue leisure activities, to play sports, to work or study, to have relationships with others, and to have normal sexual function (P ≤ .02 for all) (Table 2, eTable 3). Moreover, there was a significant dose-response effect with an even more harmful impact on the above aspects of QOL with increasing severity of skin pain (P < .001 for all) (eTable 4). Skin Pain and Patient-Reported Global AD Severity Among patients reporting skin pain, there was moderate concordance between skin pain and patient-reported global AD severity (mild, moderate, and severe) (weighted κ = 0.31) (χ2 test, P < .001) (Table 1). The presence of both severe itch and pain vs either alone or neither symptom being severe was associated with significant increases of patient-reported global AD severity (P < .001). Discussion The present study found high rates of skin pain in patients with AD. Most patients reported that the pain was attributable at least in part to scratching (83.2%), but a substantial proportion reported that their pain was related to their itch. Patients with skin pain were more likely to describe their itch with distinct terms that
Table 1 Concordance Between Skin Pain and Patient-Reported Global AD Severity Variable
Patient-reported global AD severity, no. (%) Mild
Skin pain Mild Moderate Severe or very severe Severe pain and/or itch None Either Both
Moderate
P valuea
Severe <.001
34 (34.0) 35 (28.5) 12 (10.3)
47 (47.0) 53 (43.1) 22 (19.0)
19 (19.0) 35 (28.5) 82 (70.7)
379 (53.1) 42 (19.7) 6 (8.8)
239 (33.5) 70 (32.9) 7 (10.3)
96 (13.4) 101 (47.4) 55 (80.9)
Abbreviation: AD, atopic dermatitis. aχ2 test.
<.001
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Table 2 Specific Aspects of Quality of Life Impairment Associated With Skin Pain, Particularly Severe Skin Pain Self-consciousness Ability to shop, take care of home, and garden Clothing decisions Socializing or leisure activities Sports Work or study in past week (yes/no) Work or study overall Relationship with partner, friend, or relative Sexual function Effect of treatment on quality of life
resembled neuropathic pain, even when no or only mild excoriations were present. Skin pain was associated with excoriations, eyelid dermatitis, and cheilitis but not other physical signs of AD. Skin pain, particularly severe pain, was associated with increased AD severity, poor sleep, depressive symptoms, and poorer QOL. Combined severe skin pain and itch were associated with even poorer outcomes. Together, these results indicate that AD is associated with a profound burden of skin pain in addition to itch. Interestingly, a substantial proportion of patients reporting skin pain thought their pain was unrelated (16.8%) or only partially related (72.0%) to scratching and had no demonstrable excoriations on physical examination. A substantial proportion of patients with AD described their itch using pain-related terms, with even higher rates in those with no or only mild excoriations. It may be that some patients experience the sensation of pain secondary to cutaneous inflammation and/or neurosensory dysfunction. A casecontrol study of 25 patients with AD and 25 controls found that the patients with AD had a mean pain visual analog score of 39.7, increased sensitivity to mechanically induced pain both lesionally and extralesionally, and hyperknesis.6 These findings suggest that sensitivity and pain may not be limited to sites of active skin lesions or excoriations. Another case-control study of 25 patients with AD, 9 patients with psoriasis, and 20 controls found that noxious and chemical stimuli primarily triggered itch in patients with AD, whereas pain was experienced in patients with psoriasis and controls.21 These findings suggest that the perception of pain may be aberrant and overlap with itch in patients with AD. Together, it appears that patients with AD commonly experience skin pain and pain-like itch sensations, which may result from increased sensitivity. The mechanisms of increased skin pain in AD are likely multifactorial. Two studies found increased density of dermal nerves in patients with AD compared with controls.22,23 In contrast, another study found that patients with AD had lower nerve density than controls but longer individual nerve fibers in lichenified and unlichenified lesions.24 Cutaneous nerve endings might be more vulnerable to exogenous stimuli secondary to impaired barrier function. There may also be increased and aberrant activation of cutaneous nerves to mechanical and other exogenous stimuli secondary to activation of transient receptor potential V1 and other receptors, which have been implicated in mouse models of AD.25–27 Future studies are needed to better understand these mechanisms, which may lead to improved treatments of itch and skin pain in AD. This study has several strengths, including being prospective and using validated objective assessments and PRO to assess the burden of skin pain. However, the study has limitations. In particular, the study was performed in an urban, academic, dermatologic setting and may not be generalizable to the entire US population. Future, larger-scale multicenter studies are needed to confirm the results of this study. In conclusion, AD appears to be associated with increased skin pain. For most patients, scratching appears to be the major driver of pain. However, a subset of patients with AD seem to
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experience pain-like itch that resembles neuropathic pain without evidence of scratching. Skin pain was associated with increased AD severity and affected all aspects of patients’ QOL. We recommend that skin pain severity be routinely assessed along with itch severity in all patients with AD. Moreover, skin pain severity may be an important end point for monitoring clinical response to treatment. Future studies are needed to determine the precise mechanisms and optimal treatment approaches for skin pain in AD. Supplementary Data Supplementary data related to this article can be found at https:// doi.org/10.1016/j.anai.2017.09.076. References [1] Silverberg JI, Garg NK, Paller AS, Fishbein AB, Zee PC. Sleep disturbances in adults with eczema are associated with impaired overall health: a US populationbased study. J Invest Dermatol. 2015;135:56–66. [2] Yu SH, Attarian H, Zee P, Silverberg JI. Burden of sleep and fatigue in US adults with atopic dermatitis. Dermatitis. 2016;27:50–58. [3] Yu SH, Silverberg JI. Association between atopic dermatitis and depression in US adults. J Invest Dermatol. 2015;135:3183–3186. [4] Garg N, Silverberg JI. Association between childhood allergic disease, psychological comorbidity, and injury requiring medical attention. Ann Allergy Asthma Immunol. 2014;112:525–532. [5] Strom MA, Fishbein AB, Paller AS, Silverberg JI. Association between atopic dermatitis and attention deficit hyperactivity disorder in U.S. children and adults. Br J Dermatol. 2016;175:920–929. [6] Andersen HH, Elberling J, Solvsten H, Yosipovitch G, Arendt-Nielsen L. Nonhistaminergic and mechanical itch sensitization in atopic dermatitis. Pain. 2017;158:1780–1791. [7] McCarberg BH, Nicholson BD, Todd KH, Palmer T, Penles L. The impact of pain on quality of life and the unmet needs of pain management: results from pain sufferers and physicians participating in an Internet survey. Am J Ther. 2008; 15:312–320. [8] Hanifin J, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh). 1980;92:44–47. [9] Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. EASI Evaluator Group. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. Exp Dermatol. 2001;10:11–18. [10] Severity scoring of atopic dermatitis: the SCORAD index: consensus report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186:23– 31.
[11] Schmitt J, Langan S, Deckert S, et al. Assessment of clinical signs of atopic dermatitis: a systematic review and recommendation. J Allergy Clin Immunol. 2013;132:1337–1347. [12] Chalmers JR, Schmitt J, Apfelbacher C, et al. Report from the third international consensus meeting to harmonise core outcome measures for atopic eczema/ dermatitis clinical trials (HOME). Br J Dermatol. 2014;171:1318–1325. [13] Charman CR, Venn AJ, Ravenscroft JC, Williams HC. Translating PatientOriented Eczema Measure (POEM) scores into clinical practice by suggesting severity strata derived using anchor-based methods. Br J Dermatol. 2013;169: 1326–1332. [14] Basra MK, Fenech R, Gatt RM, Salek MS, Finlay AY. The Dermatology Life Quality Index 1994–2007: a comprehensive review of validation data and clinical results. Br J Dermatol. 2008;159:997–1035. [15] Desai NS, Poindexter GB, Monthrope YM, Bendeck SE, Swerlick RA, Chen SC. A pilot quality-of-life instrument for pruritus. J Am Acad Dermatol. 2008;59: 234–244. [16] ItchyQol: A Pruritus-Specific Quality of Life Instrument, Vol. 2017. Atlanta, GA: Emory University; 2009. [17] Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus. Br J Dermatol. 2010;162:587–593. [18] Gilbody S, Richards D, Brealey S, Hewitt C. Screening for depression in medical settings with the Patient Health Questionnaire (PHQ): a diagnostic metaanalysis. J Gen Intern Med. 2007;22:1596–1602. [19] Spuls PI, Gerbens LA, Simpson E, et al. Patient-Oriented Eczema Measure (POEM), a core instrument to measure symptoms in clinical trials: a HOME statement. Br J Dermatol. 2017;176:979–984. [20] Vakharia PP, Chopra R, Sacotte R, et al. Validation of patient-reported global severity of atopic dermatitis in adults. Allergy. 2017;doi:10.1111/all.13309. [21] Ikoma A, Fartasch M, Heyer G, Miyachi Y, Handwerker H, Schmelz M. Painful stimuli evoke itch in patients with chronic pruritus: central sensitization for itch. Neurology. 2004;62:212–217. [22] Urashima R, Mihara M. Cutaneous nerves in atopic dermatitis: a histological, immunohistochemical and electron microscopic study. Virchows Arch. 1998; 432:363–370. [23] Sugiura H, Omoto M, Hirota Y, Danno K, Uehara M. Density and fine structure of peripheral nerves in various skin lesions of atopic dermatitis. Arch Dermatol Res. 1997;289:125–131. [24] Tsutsumi M, Kitahata H, Fukuda M, et al. Numerical and comparative threedimensional structural analysis of peripheral nerve fibres in epidermis of patients with atopic dermatitis. Br J Dermatol. 2016;174:191–194. [25] Shibata T, Takahashi K, Matsubara Y, Takahashi N, Mori Y, Uchida K. 15-deoxy?(12,14)-prostaglandin J2 as a potential TRPV1-dependent atopic dermatitis enhancer. Free Radic Biol Med. 2014;75(suppl 1):S49. [26] Mollanazar NK, Smith PK, Yosipovitch G. Mediators of chronic pruritus in atopic dermatitis: getting the itch out? Clin Rev Allergy Immunol. 2016;51:263–292. [27] Yun JW, Seo JA, Jeong YS, et al. TRPV1 antagonist can suppress the atopic dermatitis-like symptoms by accelerating skin barrier recovery. J Dermatol Sci. 2011;62:8–15.
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Supplementary Data
A
F
B
G
C
H
D
I
E
eFigure 1. Additive effects of severe itch and skin on atopic dermatitis signs and symptoms and quality of life. Box-whisker plots and overlaid jitter plots of (A) numeric rating scale for itch (NRSitch), (B) Patient-Oriented Eczema Measure (POEM), (C) mean ItchyQOL, (D) Dermatology Life Quality Index (DLQI), (E) 5 dimensions of itch (5-D itch), (F) numeric rating scale for sleep (NRS-sleep), (G) Patient Health Questionnaire 9 (PHQ9), (H) Eczema Area and Severity Index (EASI), and (I) objective Scoring AD (oSCORAD).
552.e1
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eTable 2 Association of Skin Pain in Atopic Dermatitis
eTable 1 Demographic Characteristics of the 305 Patients in the Study Cohort Findinga
Characteristic Sex Male Female Race/ethnicity White, non-Hispanic Black Hispanic Asian Multiracial/other Age at enrollment, mean (SD), y Age at AD onset, mean (SD), y Skin pain severity Mean (SD) Frequency None Mild Moderate Severe Very severe
110 (36.1) 195 (63.9) 193 (63.7) 37 (12.2) 17 (5.6) 49 (17.0) 7 (2.3) 42.3 (18.1) 29.6 (31.9) 2.4 (3.1) 161 (52.8) 52 (17.1) 50 (16.4) 21 (6.9) 21 (6.9)
a
Data are presented as number (percentage) of patients unless otherwise indicated. Missing values were encountered for 0 patients for sex, race/ethnicity, age at enrollment, and skin pain severity and 23 (7.5%) for age at AD onset.
Variable
Any skin pain, no. (%)
Race/ethnicity White Black Hispanic Asian Multiracial/other Female sex Alcohol Current smoker Personal history Asthma Hay fever Food allergy Medication allergy Physical signs Facial dermatitis Conjunctivitis or eyelid dermatitis Cheilitis Hand dermatitis Foot dermatitis Nipple dermatitis Scalp Posterior auricular Nummular lesions White dermatographism Symptoms Clinical course worsened by environmental or emotional factors Pruritus when sweating Tendency toward cutaneous infections
P value
No (n = 161)
Yes (n = 144)
106 (65.8) 18 (11.2) 7 (4.3) 29 (18.0) 1 (0.6) 100 (62.1) 92 (63.4) 16 (10.9)
87 (61.3) 19 (13.4) 10 (7.0) 22 (15.5) 4 (2.8) 95 (66.0) 87 (65.9) 15 (11.2)
.48b .67b .93b
59 (38.6) 63 (41.2) 52 (34.4) 37 (24.7)
53 (40.2) 80 (60.6) 51 (38.9) 41 (31.5)
.78b .001b .43b .20b
59 (51.8) 48 (41.7) 29 (25.9) 52 (49.5)
55 (60.4) 51 (55.4) 43 (46.7) 52 (60.5)
.21b .05b .002b .13b
15 (13.5) 47 (40.5) 38 (33.6) 12 (10.3) 7 (6.0)
12 (13.2) 48 (51.6) 40 (43.5) 11 (11.3) 3 (3.1)
.95b .11b .15b .80b .32a
78 (86.7)
72 (83.7)
.58b
63 (70.8) 53 (32.9)
58 (67.4) 48 (33.3)
.63b .94b
.41a
aFisher bχ2
exact test. test.
eTable 3 Effect of Skin Pain on Individual Aspects of the DLQI in Atopic Dermatitis Any skin pain
DLQI response, no. (%) Not at all/Not relevant
1. Itching and/or burning of skin No Yes 2. Self-conscious No Yes 3. Ability to shop, take care of home, and garden No Yes 4. Clothing decisions No Yes 5. Socializing or leisure activities No Yes 6. Sports No Yes 7-1. Work or study in past week (yes/no) No Yes 7-2. Work or study overall No Yes 8. Relationship with partner, friend, or relative No Yes 9. Sexual function No Yes 10. Effect of treatment on quality of life No Yes Abbreviation: DLQI, Dermatology Life Quality Index.
P value A little
A lot
Very much
22 (10.5) 7 (2.3)
109 (52.2) 97 (31.9)
50 (23.9) 111 (36.5)
28 (13.4) 89 (29.3)
<.001
64 (30.6) 67 (22.0)
91 (43.5) 99 (32.6)
27 (12.9) 53 (17.4)
27 (12.9) 85 (28.0)
<.001
32 (15.3%) 65 (21.4%)
15 (7.2%) 44 (14.5%)
4 (1.9%) 38 (12.5%)
<.001
84 (40.2) 67 (22.2)
67 (32.1) 86 (28.5)
35 (16.8) 72 (23.8)
23 (11.0) 77 (25.5)
<.001
120 (57.4) 120 (39.5)
56 (26.8) 82 (27.0)
23 (11.0) 61 (20.1)
10 (4.8) 41 (13.5)
<.001
148 (70.8) 161 (53.1%)
37 (17.7) 54 (17.8%)
16 (7.7) 40 (13.2%)
8 (3.8) 48 (15.8%)
<.001
193 (92.8) 231 (76.2)
15 (7.2) 72 (23.8)
139 (70.2) 157 (57.9)
51 (25.8) 83 (30.6)
7 (3.5) 25 (9.2)
1 (0.5) 6 (2.2)
.009
153 (73.2) 170 (56.1)
39 (18.7) 85 (28.1)
9 (4.3) 24 (7.9)
8 (3.8) 24 (7.9)
.001
179 (85.7) 235 (77.6)
12 (5.7) 36 (11.9)
12 (5.7) 12 (4.0)
6 (2.9) 20 (6.6)
.02
105 (50.2) 101 (33.3)
68 (32.5) 108 (35.6)
30 (14.4) 53 (17.5)
6 (2.9) 41 (13.5)
158 (75.6%) 157 (51.6%)
<.001
<.001
P.P. Vakharia et al. / Ann Allergy Asthma Immunol 119 (2017) 548–552
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eTable 4 Effect of Skin Pain Severity on Individual Aspects of the DLQI in Atopic Dermatitis Any skin pain
DLQI response, no. (%) Not at all/Not relevant
1. Itching and/or burning of skin No Mild Moderate Severe Very severe 2. Self-conscious about lesions No Mild Moderate Severe Very severe 3. Ability to shop, take care of home, and garden No Mild Moderate Severe Very severe 4. Clothing decisions No Mild Moderate Severe Very severe 5. Socializing or leisure activities No Mild Moderate Severe Very severe 6. Sports No Mild Moderate Severe Very severe 7-1. Work or study in past week (yes/no) No Mild Moderate Severe Very severe 7-2. Work or study overall No Mild Moderate Severe Very severe 8. Relationship with partner, friend, or relative No Mild Moderate Severe Very severe 9. Sexual function No Mild Moderate Severe Very severe 10. Effect of treatment on quality of life No Mild Moderate Severe Very severe Abbreviation: DLQI, Dermatology Life Quality Index.
P value A little
A lot
Very much
22 (10.5) 6 (6.3) 0 (0.0) 0 (0.0) 1 (2.2)
109 (52.2) 51 (53.1) 39 (38.2) 4 (6.6) 3 (6.7)
50 (23.9) 29 (30.2) 44 (43.1) 28 (45.9) 10 (22.2)
28 (13.4) 10 (10.4) 19 (18.6) 29 (47.5) 31 (968.9)
<.001
64 (30.6) 35 (36.5) 25 (24.5) 4 (6.6) 3 (6.7)
91 (43.5) 36 (37.5) 35 (34.3) 19 (31.2) 9 (20.0)
27 (12.9) 13 (13.5) 18 (17.7) 16 (26.2) 6 (13.3)
27 (12.9) 12 (12.5) 24 (23.5) 22 (36.1) 27 (60.0)
<.001
158 (75.6) 74 (77.1) 53 (52.0) 22 (26.1) 8 (17.8)
32 (15.3) 14 (14.6) 26 (25.5) 13 (21.3) 12 (26.7)
15 (7.2) 6 (6.3) 18 (17.7) 14 (23.0) 6 (13.3)
4 (1.9) 2 (2.1) 5 (4.9) 12 (19.7) 19 (42.2)
<.001
84 (40.2) 31 (32.6) 21 (20.6) 10 (16.7) 5 (11.1)
67 (32.1) 34 (35.8) 32 (31.4) 13 (21.7) 7 (15.6)
35 (16.8) 18 (19.0) 21 (20.6) 21 (35.0) 12 (26.7)
23 (11.0) 12 (12.6) 28 (27.5) 16 (26.7) 21 (46.7)
<.001
120 (57.4) 57 (59.4) 43 (42.2) 14 (23.0) 6 (13.3%)
56 (26.8) 27 (28.1) 28 (27.5) 13 (21.3) 14 (31.1%)
23 (11.0) 7 (7.3) 22 (21.6) 22 (36.1) 10 (22.2%)
10 (4.8) 5 (5.2) 9 (8.8) 12 (19.7) 15 (33.3%)
<.001
148 (70.8) 64 (66.7) 59 (58.4) 21 (34.4) 17 (37.8)
37 (17.7) 20 (20.8) 15 (14.9) 14 (23.0) 4 (11.1)
16 (7.7) 5 (5.2) 20 (19.8) 11 (18.0) 4 (8.9)
8 (3.8) 7 (7.3) 7 (6.9) 15 (24.6) 19 (42.2)
<.001
193 (92.8) 91 (95.8) 79 (77.5) 37 (60.7) 24 (53.3)
15 (7.2) 4 (4.2) 23 (22.6) 24 (39.3) 21 (46.7)
139 (70.2) 66 (69.5) 56 (60.9) 19 (39.6) 16 (44.4)
51 (25.8) 24 (25.3) 26 (28.3) 21 (43.8) 12 (33.3)
7 (3.5) 5 (5.3) 9 (9.8) 5 (10.4) 6 (16.7)
1 (0.5) 0 (0.0) 1 (1.1) 3 (6.3) 2 (5.6)
.001
153 (73.2) 73 (76.0) 55 (53.9) 27 (45.0) 15 (33.3)
39 (18.7) 23 (24.0) 36 (5.3) 13 (21.7) 13 (28.9)
9 (4.3) 0 (0.0) 6 (5.9) 11 (18.3) 7 (15.6%
8 (3.8) 0 (0.0) 5 (4.9) 9 (15.0) 10 (22.2)
<.001
179 (85.7) 87 (90.6) 76 (74.5) 46 (76.7) 26 (57.8)
12 (5.7) 7 (7.3) 17 (16.7) 7 (11.7) 5 (11.1)
12 (5.7) 1 (1.0) 5 (4.9) 4 (6.7) 2 (4.4)
6 (2.9) 1 (1.0) 4 (3.9) 3 (5.0) 12 (26.7)
<.001
105 (50.2) 49 (51.0) 30 (29.4) 14 (23.3) 8 (17.8)
68 (32.5) 32 (33.3) 44 (43.1) 14 (23.3) 18 (40.0)
30 (14.4) 12 (12.5) 20 (19.6) 16 (26.7) 5 (11.1)
6 (2.9) 3 (3.1) 8 (7.8) 16 (26.7) 14 (31.1)
<.001
<.001