Psychocutaneous Medicine

Transcription

1 Vitiligo Disese Triggers: Psychologicl Stressors Preceding the Onset of Disese Jonthn I. Silverberg, MD, PhD, MPH; Nnette B. Silverberg, MD Prctice Points Psychologicl stressors (eg, loss of loved one) tht occurred within 2 yers prior to vitiligo onset should be considered s potentil disese triggers. Psychologicl stressors hve been ssocited with symptoms of bdominl crmping nd itching/burning in vitiligo ptients but not disese extent or distribution. Vitiligo is the loss of skin pigmenttion cused by utoimmune destruction of melnocytes. Little is known bout the impct of psychologicl stressors preceding vitiligo onset on symptoms ssocited with vitiligo nd the extent of disese. We performed questionnire-bsed study of 1541 dults with vitiligo to evlute the impct of psychologicl stressors in this ptient popultion. Psychologicl stressors should be considered s potentil disese triggers in vitiligo ptients, nd screening of vitiligo ptients for psychologicl stressors nd ssocited symptoms should be included in routine ssessment. Cutis. 2015;95: Vitiligo is the loss of skin pigmenttion cused by utoimmune destruction of melnocytes. Multiple pthogenic fctors for Dr. JI Silverberg is from the Deprtments of Dermtology, Preventtive Medicine, nd Medicl Socil Sciences, Northwestern University, Chicgo, Illinois. Dr. NB Silverberg is from the Deprtment of Dermtology, Mount Sini St. Luke s-roosevelt nd Beth Isrel Medicl Centers of the Ichn School of Medicine t Mount Sini, New York, New York. The uthors report no conflict of interest. This study ws registered on July 21, 2011, t with the identifier NCT The etbles re vilble in the Appendix online t Correspondence: Nnette B. Silverberg, MD, Deprtment of Dermtology, 1090 Amsterdm Ave, Ste 11D, New York, NY (nsilverb@chpnet.org). vitiligo hve been described, including CD8 T lymphocyte/t helper 1 infiltrtes in lesionl skin 1,2 with incresed expression of IFN-γ 3 nd tumor necrosis fctor α, 3-6 decresed trnsforming growth fctor β, 7 nd circulting utontibodies ginst tyrosine hydroxylse. 8 Additionlly, severl studies hve found high prevlence of ntecedent psychologicl stressors in vitiligo ptients, suggesting tht specific stressors my trigger nd/or excerbte vitiligo The reltionship between ntecedent psychologicl stressors nd vitiligo extent hs not been well studied. Potentil mechnisms for stress-triggered vitiligo include incresed ctecholmines 13 nd neuropeptides, 14 which hve been found in vitiligo ptients. However, the complex reltionship between stressors nd subsequent vitiligo is not well defined. We hypothesized tht persistent stressors re ssocited with incresed vitiligo extent. Vitiligo is clssiclly considered to be silent pigmentry disorder with few or no symptoms. Prior studies hve demonstrted tht one-third of vitiligo ptients report skin symptoms (eg, pruritus, burning), which my be specificlly ssocited with erly-onset disese Further, we observed tht some vitiligo ptients report bdominl crmping ssocited with their disese. Few studies hve described the burden of skin symptoms nd other ssocited symptoms in vitiligo or their determinnts. We conducted prospective questionnirebsed study of 1541 dult vitiligo ptients to identify psychologicl fctors tht my precede vitiligo onset. We hypothesized tht some types of VOLUME 95, MAY

2 stressors tht occur within 2 yers prior to disese onset would hve specific ssocitions with vitiligo nd/or somtic symptoms. Methods Study Popultion nd Questionnire Distribution This prospective questionnire-bsed study ws pproved by the institutionl review bord t St. Luke s-roosevelt Hospitl Center (now Mount Sini St. Luke s-roosevelt) (New York, New York) for dults (>18 yers; mle or femle) with vitiligo. The survey ws vlidted in pper formt t St. Luke s-roosevelt Hospitl Center nd distributed online to members of nonprofit support groups for vitiligo vulgris, s previously described. 15 Questionnire The priori im of this questionnire ws to identify psychologicl fctors tht my precede vitiligo onset. The questionnire consisted of 77 items (55 closed questions nd 22 open questions) pertining to prticipnt demogrphics/ vitiligo phenotype nd psychologicl stressors preceding vitiligo onset. The questions relted to this study nd response rtes re listed in etble 1. Responses were verified by screening for noninteger or implusible vlues (eg, 0 or 100 yers of ge). Smple Size The primry outcome used for smple size clcultion ws the potentil ssocition between vitiligo nd the presence of ntecedent psychologicl stressors. Using 2-tiled test, we determined tht smple size of 1264 prticipnts would hve 90% power t α.05 nd bseline proportion of 0.01 (1% presumed prevlence of vitiligo) to detect n odds rtio (OR) of 2.5 or higher. 18 Dt nd Sttisticl Anlysis Closed question responses were nlyzed using descriptive sttistics. Open-ended question responses were nlyzed using content nlysis. Relted comments were coded nd grouped, with similrities nd differences noted. All dt processing nd sttistics were done with SAS version 9.2. Age t dignosis (yers) nd number of ntomic sites ffected were divided into tertiles for sttisticl nlysis due to wide skewing. Logistic regression models were constructed with numbers of reported deths or stressors per prticipnt within the 2 yers prior to vitiligo onset s independent vribles (0, 1, or >2), nd symptoms ssocited with vitiligo s dependent vribles. Adjusted ORs were clculted from multivrite models tht included sex, current ge (continuous), nd comorbid utoimmune disese (binry) s covrites. Liner interction terms were tested nd were included in finl models if sttisticlly significnt (P.05). Ordinl logistic regression ws used to nlyze the reltionship between stressors (nd other independent vribles) nd number of ntomic sites ffected with vitiligo (tertiles). Ordinl logistic regression models were constructed to exmine the impct of psychologicl stressors on pruritus secondry to vitiligo (not relevnt combined with not t ll, little, lot, very much) s the dependent vrible. The proportionl odds ssumption ws met in both models, s judged by score testing (P.05). Binry logistic regression ws used to nlyze lterlity, body surfce re (BSA) greter thn 25%, nd involvement of the fce nd/or body with vitiligo lesions (binry). Binry logistic regression models were constructed with impct of psychologicl stressors preceding vitiligo onset on comorbid bdominl crmping nd specific etiologies s the dependent vribles. There were 20 cndidte stressors occurring within the 2 yers prior to vitiligo onset. Selection methods for predictors were used to identify significnt covrites within the context of the other covrites included in the finl models. The results of forwrd, bckwrd, nd stepwise pproches were similr, nd the stepwise selection output ws presented. Missing vlues were encountered becuse some prticipnts did not respond to ll the questionnire items. A complete cse nlysis ws performed (ie, missing vlues were ignored throughout the study). Dt imputtion ws considered by multiple imputtions; however, there were few or no differences between the estimtes from the 2 pproches. Therefore, finl models did not involve dt imputtion. The sttisticl significnce for ll estimtes ws considered to be P.05. However, P vlue ner.05 should be interpreted with cution given the multiple dependent tests performed in this study with incresed risk for flsely rejecting the null hypothesis. Results Survey Popultion Chrcteristics One thousnd seven hundred prticipnts strted the survey; 1632 completed the survey (96.0% completion rte) nd 1553 hd been dignosed with vitiligo by physicin. Twelve prticipnts were excluded becuse they were younger thn 18 yers, leving 1541 evluble prticipnts. Five hundred thirty-eight prticipnts (34.9%) hd comorbid utoimmune disorders. Demogrphics nd disese phenotypes of the study prticipnts re listed in Tble 1. Stressors Preceding Vitiligo Onset Eight hundred twenty-one prticipnts (56.6%) experienced t lest one deth or stressor within 2 yers prior to vitiligo onset (Tble 2), including deth of loved one (16.6%) nd stressful life events (51.0%) within the 2 yers prior to the onset of vitiligo, especilly work/finncil problems (10.8%), end of long-term reltionship (10.2%), nd fmily problems (not otherwise specified)(7.8%). Two hundred (13.5%) 256 CUTIS

3 Tble 1. Demogrphics nd Disese Phenotype in Prticipnts With Physicin-Dignosed Vitiligo Prticipnt Responses (N 1541) Sex, n (%) Mle 433 (28.6) Femle 1080 (71.4) Age, y Men (SD) 43.1 (13.4) Durtion of vitiligo, y Men (SD) 18.1 (13.3) Age t vitiligo onset, y Men (SD) 24.9 (15.0) BSA ffected, n (%) 1% 25% 854 (55.7) 26% 50% 350 (22.8) 51% 75% 162 (10.6) 76% 100% 166 (10.8) No. of ntomic sites ffected Men (SD) 10.7 (6.7) Distribution, n (%) Either fce or body 376 (27.7) Both fce nd body 983 (72.3) Lterlity, n (%) Unilterl/midline 107 (7.0) Bilterl 1416 (93.0) Abbrevitions: SD, stndrd devition; BSA, body surfce re. Vlues do not equl 1541 for ll vribles becuse not ll prticipnts responded to ech question. Percentges reflect the totl number of responses for ech respective question. prticipnts reported experiencing 1 deth nd 46 (3.1%) reported multiple deths. Five hundred prticipnts (33.6%) reported experiencing 1 stressor nd 259 (17.4%) reported multiple stressors. Stressors Not Associted With Vitiligo Extent The number of deths or stressors prticipnt within the 2 yers prior to vitiligo onset were not ssocited with BSA, lterlity, or distribution of lesions (Tble 3 nd etble 2 etble 4). Symptoms Associted With Vitiligo Five hundred twenty-two prticipnts (34.5%) reported intermittent bdominl crmping, including premenstrul nd/or menstrul crmping in women (9.7%), food-relted bdominl crmping (4.4%), inflmmtory bowel syndrome (IBS)(2.6%), nxiety-relted bdominl crmping (1.5%), utoimmune gstrointestinl disorders (1.2%), nd other etiologies (20.4%). Five hundred ten prticipnts reported itching nd/or burning ssocited with vitiligo lesions (35.1%). Intermittent bdominl crmping overll ws ssocited with BSA greter thn 75% (OR, 1.65; 95% confidence intervl (CI), ; P.004). However, specific etiologies of bdominl crmping were not significntly ssocited with BSA (P>.11). In contrst, itching nd/or burning from vitiligo lesions ws ssocited with BSA greter thn 25% (OR, 1.53; 95% CI, ; P.0001). Assocition Between Number of Stressors nd Symptoms in Vitiligo A history of multiple stressors (>2) within the 2 yers prior to vitiligo onset ws ssocited with intermittent bdominl crmping overll (OR, 1.84; 95% CI, ; P.0001), including premenstrul nd/or menstrul crmping in women (OR, 1.84; 95% CI, ; P.01), IBS (OR, 3.29; 95% CI, ; P.01), nd utoimmune gstrointestinl disorders (OR, 4.02; 95% CI, ; P.02)(eTble 5). These ssocitions remined significnt in multivrite models tht included ge, sex, nd BSA s covrites. However, history of 1 stressor or deth or multiple deths in the 2 yers prior to vitiligo onset ws not ssocited with ny etiology of bdominl crmping. Experiencing 1 (OR, 1.43; 95% CI, ; P.005) or multiple stressors (OR, 1.51; 95% CI, ; P.007) lso ws ssocited with itching nd/or burning secondry to vitiligo. This ssocition remined significnt in multivrite model tht included ge, sex, nd BSA s covrites. However, history of 1 or multiple deths in the 2 yers prior to vitiligo onset ws not ssocited with itching nd/or burning. Assocition Between Specific Stressors nd Vitiligo Symptoms Perimenstrul (premenstrul nd/ or menstrul) crmping in women ws ssocited with fmily problems (not otherwise specified) within the 2 yers prior to vitiligo onset (Tble 4). Food-relted bdominl crmping ws ssocited with school- nd/or test-relted stressors. Dignosis of IBS ws ssocited with helth problems or surgery nd being victim of buse within the 2 yers prior to onset of vitiligo. Autoimmune gstrointestinl disorders were ssocited with moving to new home/ region, helth problems or surgery, nd witness to violent crime or deth. Finlly, itching nd/or burning VOLUME 95, MAY

4 Tble 2. Self-reported Stressors Occurring Within 2 Yers of Vitiligo Onset (N 1541) Prticipnt Responses, n (%) Did loved one pss wy within the 2 yers prior to developing vitiligo? Yes 246 (16.6) No 1237 (83.4) If yes, plese specify who pssed wy? b Prent 95 (6.3) Grndprent 82 (5.5) Son/dughter 10 (0.7) Other fmily member (eg, sibling, cousin, unt/uncle, niece/nephew) 61 (4.1) Friend 23 (1.5) Pet 1 (0.1) No. of deths prticipnt (83.4) (13.5) 2 38 (2.6) 3 6 (0.4) 4 0 (0) 5 0 (0) 5 2 (0.1) Did you hve ny stressful life events within the 2 yers prior to the onset of vitiligo? Yes 759 (51.0) No 728 (49.0) If yes, wht occurred? c Work nd finncil problems 160 (10.8) End of long-term reltionship (eg, divorce, brekup) 152 (10.2) Fmily problems NOS 116 (7.8) Reltionship problems (eg, rguments, infidelity, deteriortion) 89 (6.0) Illness or injury of loved one 78 (5.2) Son or dughter 18 (1.2) Other fmily member or friend 60 (4.0) Moving to new home/region 77 (5.2) School- nd/or test-relted problems (eg, licensing exmintions, poor grdes, difficult clsses) 72 (4.8) Helth problems or surgery 67 (4.5) Loss of job 65 (4.4) Hving or rising children 62 (4.2) Abuse (physicl, emotionl, or sexul) 31 (2.1) Trum (eg, cr ccident, burn) 30 (2.0) Bseline nxiety, nervousness, or pnic 21 (1.4) 258 CUTIS

5 Prticipnt Responses, n (%) If yes, wht occurred? c (continued) Pregnncy 21 (1.4) Adolescence nd puberty 13 (0.9) Infertility 10 (0.7) Depression 10 (0.7) Substnce buse (eg, lcohol, nrcotics) 6 (0.4) Witness to violent crime or deth 8 (0.5) Other 21 (1.4) prticipnt (49.0) (33.6) (12.6) 3 60 (4.0) 4 11 (0.7) 5 1 (0.07) nd deths prticipnt (43.4) (30.9) (16.3) 3 97 (6.7) 4 27 (1.9) >5 12 (0.8) Abbrevition: NOS, not otherwise specified. Vlues do not equl 1541 for ll vribles becuse not ll prticipnts responded to ech question. Percentges reflect the totl number of responses for ech respective question. b Accounts for multiple losses. c Accounts for multiple stressors. of vitiligo lesions ws ssocited with work nd finncil problems. Comment The present study found high frequency of stressful life events nd deths of loved ones occurring within the 2 yers preceding vitiligo onset. A history of multiple stressors but not deths of loved ones ws ssocited with more frequent symptoms in vitiligo ptients, including itching nd/or burning nd intermittent bdominl pin. Specific stressors were ssocited with intermittent bdominl crmping, which occurred in pproximtely one-third of vitiligo ptients. Abdominl crmping ws relted to menses in women, nxiety, foods, IBS, utoimmune gstrointestinl disorders, nd other etiologies of bdominl crmping, which underscores the complex reltionship between stressors, vitiligo, nd inflmmtion. It is possible tht stressrelted immune bnormlities occur in vitiligo, which my influence the development of other utoimmune disorders. Alterntively, bdominl symptoms my precede nd perhps contribute to psychologicl stressors nd impired qulity of life in vitiligo ptients; however, the cross-sectionl nture of the study did not llow us to elucidte this temporl reltionship. The present study found tht 56.6% of prticipnts experienced 1 or more deths (17%) nd/ or stressful life events (51%) within the 2 yers VOLUME 95, MAY

6 Tble 3. Assocition Between BSA nd No. of Stressors/Deths Reported Within 2 Yers of Vitiligo Onset Independent No. of deths reported per prticipnt b BSA, n (%) prior to vitiligo onset. These results re consistent with prior smller studies tht demonstrted high frequency of stressful events preceding vitiligo onset. A cse-controlled study found stressful events in 12 of 21 (57%) Romnin children with vitiligo, which ws higher thn controls. 19 Another questionnire-bsed, cse-controlled study compred heterogeneous group of 32 dolescent nd dult Romnin ptients with vitiligo nd found higher odds of stressful event in women preceding vitiligo dignosis compred to controls. 10 A retrospective nlysis of 65 Crotin ptients with vitiligo lso reported tht 56.9% (37/65) hd some ssocited psychologicl fctors. 9 Another retrospective study of 31 dults with vitiligo found incresed occurrence of 3 or more uncontrollble events, decresed perceived socil support, nd incresed nxiety in vitiligo ptients versus 116 other dermtologic disese controls. 12 A questionnire-bsed study found incresed berevements, chnges in sleeping nd eting hbits, nd personl injuries/illnesses in 73 British dults with vitiligo compred to 73 other ge- nd sex-mtched dermtologic disese controls. 11 All of these studies were limited by smll smple size, nd the ptient popultions were loclized to regionl dermtology referrl center. The present study provided lrger nlysis of stressful life events 1% 25% 25% OR (95% CI) P Vlue (83.6) 544 (83.2) (13.1) 91 (13.9) 1.06 ( ).69 >2 27 (3.3) 19 (2.9) 0.90 ( ).72 reported per prticipnt c (47.3) 335 (51.0) (35.3) 207 (31.5) 0.83 ( ).11 >2 144 (17.3) 115 (17.5) 0.94 ( ).65 Abbrevitions: BSA, body surfce re; OR, odds rtio; CI, confidence intervl. Percentges reflect the totl number of responses for ech respective question. b No. of deths ws determined from responses to: Did loved one pss wy within the 2 yers prior to developing vitiligo? c Stressors re types of emotionl or environmentl stimuli tht re stressful. ws determined from responses to: Did you hve ny stressful life events within the 2 yers prior to the onset of vitiligo? preceding vitiligo onset nd included diverse ptient popultion. The present study found tht stressful life events nd deths of loved one re not ssocited with vitiligo extent nd distribution. This finding suggests tht stressful life events my ct s vitiligo triggers in geneticlly predisposed individuls, but ultimtely the disese course nd prognosis re driven by other fctors, such s incresed systemic inflmmtion or other immunologic bnormlities. Indeed, Silverberg nd Silverberg 20 nd other investigtors 21,22 reported reltive deficiencies of 25-hydroxyvitmin D, 23 vitmins B 6 nd B 12, nd folic cid, 20 s well s elevted serum homocysteine levels in vitiligo ptients. Incresed serum homocysteine levels were ssocited with incresed BSA of vitiligo lesions. 20 Elevted serum homocysteine levels lso hve been ssocited with incresed inflmmtion in coronry rtery disese, 24 psorisis, 25,26 nd in vitro. 27 These lbortory nomlies likely reflect n underlying predisposition towrd vitiligo, which might be triggered by stress responses or secondrily ltered immune responses. The present study hd severl strengths, including being prospective with lrge smple size. The ptient popultion included lrge smple of men nd women with representtion of vrious dult ges nd vitiligo extent. However, this study 260 CUTIS

7 Tble 4. Psychologicl Stressors Are Predictors of Abdominl Crmping nd Itching in Prticipnts With Vitiligo OR (95% CI) P Vlue Premenstrul nd/or menstrul crmping Fmily problems NOS 2.32 ( ).004 Anxiety-relted bdominl crmping None N/A N/A Food-relted bdominl crmping School- nd/or test-relted problems (eg, licensing exmintions, poor grdes, difficult clsses) Inflmmtory bowel syndrome 2.75 ( ).03 Helth problems or surgery 3.54 ( ).03 Victim of buse (physicl, emotionl, or sexul) 8.23 ( ).0003 Autoimmune gstrointestinl disorders b Moving to new home/region 4.34 ( ).03 Helth problems or surgery 5.24 ( ).01 Witness to violent crime or deth 9.51 ( ).048 Itching nd/or burning Work nd finncil problems 1.63 ( ).006 Abbrevitions: OR, djusted odds rtios; CI, confidence intervl; NOS, not otherwise specified; NA, not pplicble. Binry logistic regression models were constructed with vrious etiologies of bdominl crmping (yes/no) s the dependent (outcome) vrible. The independent (explntory) vribles included stressors within 2 yers of vitiligo onset, including (1) trum, (2) school- nd/ or test-relted problems, (3) fmily problems NOS, (4) reltionship problems (eg, rguments, infidelity, deteriortion), (5) end of long-term reltionship, (6) work nd finncil problems, (7) moving to new home/region, (8) helth problems or surgery, (9) bseline nxiety (ie, nxiety disorder in the bsence of stress-induced trigger), (10) substnce buse (eg, lcohol, nrcotics), (11) buse (physicl, emotionl, or sexul), (12) dolescence nd puberty, (13) hving or rising children, (14) witness to violent crime or deth, (15) depression, (16) infertility, (17) pregnncy, (18) illness or injury of son/dughter, (19) illness or injury of nother fmily member or friend, nd (20) deth of loved one (ll binry). All vribles were tested in the model using forwrd, bckwrd, nd stepwise selection with the sme results. Sttisticlly significnt explntory vribles included in the finl models re presented. Adjusted odds rtios nd 95% CI were determined. b Autoimmune gstrointenstinl disorders included ulcertive colitis, Crohn disese, nd celic disese. lso hd potentil limittions. Mesures of vitiligo extent were self-reported nd were not cliniclly ssessed. To ddress this limittion, we vlidted the questionnire before posting it online. 15 Invittion to prticipte in the survey ws distributed by vitiligo support groups, which my hve resulted in selection bis towrd prticipnts with greter disese severity or with poorer qulity of life ssocited with vitiligo. Invittion to prticipte in this study ws sent to members of vitiligo support groups, which llowed for recruitment of lrge number of vitiligo ptients despite reltively low prevlence of disese in the generl popultion. However, there re severl chllenges using this pproch for nonvitiligo controls. Using prticipnts with nother dermtologicl disese s control group my yield spurious results. Idelly, lrge rndomized smple of helthy prticipnts with minimiztion of bis should be used for controls, which is n mbitious undertking tht ws beyond the scope of this pilot study nd will be the subject of future studies. Finlly, this nlysis found ssocitions between stressors tht occurred in the 2 yers prior to vitiligo onset with symptomtic disese. We chose brod intervl for stressors becuse erly vitiligo lesions my go unnoticed, mking recognition of stressors occurring within dys or weeks of onset infesible. Further, we considered tht chronic nd prolonged stressors re more likely to hve hrmful VOLUME 95, MAY

8 consequences thn cute stressors. Thus, stressors occurring within more nrrow intervl (eg, 2 months) my not hve the sme ssocition with vitiligo. Future studies re wrrnted to precisely identify the type nd timing of psychologicl stressors preceding vitiligo onset. Conclusion In conclusion, there is high prevlence of stressful life events preceding vitiligo, which my ply n importnt role s disese triggers s well s predict the presence of intermittent bdominl crmping nd itching or burning of skin. These ssocitions indicte tht screening of vitiligo ptients for psychologicl stressors, bdominl crmping, nd itching nd/ or burning of skin should be included in the routine ssessment of vitiligo ptients. References 1. Goronzy J, Weynd CM, Wse I. T cell subpopultions in inflmmtory bowel disese: evidence for defective induction of T8 suppressor/cytotoxic T lymphocytes. Clin Exp Immunol. 1985;61: Ongene K, Vn Geel N, Neyert JM. Evidence for n utoimmune pthogenesis of vitiligo. Pigment Cell Res. 2003;16: Grimes PE, Morris R, Avniss-Aghjni E, et l. Topicl tcrolimus therpy for vitiligo: therpeutic responses nd skin messenger RNA expression of proinflmmtory cytokines. J Am Acd Dermtol. 2004;51: Birol A, Kis U, Kurtipek GS, et l. Incresed tumor necrosis fctor lph (TNF-lph) nd interleukin 1 lph (IL1-lph) levels in the lesionl skin of ptients with nonsegmentl vitiligo. Int J Dermtol. 2006;45: Moretti S, Spllnzni A, Amto L, et l. New insights into the pthogenesis of vitiligo: imblnce of epiderml cytokines t sites of lesions. Pigment Cell Res. 2002;15: Zilie MZ. Decresed proinflmmtory cytokine production by peripherl blood mononucler cells from vitiligo ptients following spirin tretment. Sudi Med J. 2005;26: Bsk PY, Adiloglu AK, Ceyhn AM, et l. The role of helper nd regultory T cells in the pthogenesis of vitiligo. J Am Acd Dermtol. 2009;60: Kemp EH, Emhemd S, Akhtr S, et l. Autontibodies ginst tyrosine hydroxylse in ptients with non-segmentl (generlised) vitiligo. Exp Dermtol. 2011;20: Brisić-Drusko V, Rucevic I. Trigger fctors in childhood psorisis nd vitiligo. Coll Antropol. 2004;28: Mnolche L, Bene V. Stress in ptients with lopeci ret nd vitiligo. J Eur Acd Dermtol Venereol. 2007;21: Ppdopoulos L, Bor R, Legg C, et l. Impct of life events on the onset of vitiligo in dults: preliminry evidence for psychologicl dimension in etiology. Clin Exp Dermtol. 1998;23: Picrdi A, Psquini P, Cttruzz MS, et l. Stressful life events, socil support, ttchment security nd lexithymi in vitiligo. cse-control study. Psychother Psychosom. 2003;72: Slzer BA, Schllreuter KU. Investigtion of the personlity structure in ptients with vitiligo nd possible ssocition with impired ctecholmine metbolism. Dermtology. 1995;190: Al Abdie MS, Senior HJ, Bleehen SS, et l. Neuropeptide nd neuronl mrker studies in vitiligo. Br J Dermtol. 1994;131: Silverberg JI, Silverberg NB. Assocition between vitiligo extent nd distribution nd qulity-of-life impirment. JAMA Dermtol. 2013;149: Silverberg JI, Silverberg NB. Qulity of life impirments in children nd dolescents with vitiligo. Peditr Dermtol. 2014;31: Knwr AJ, Mhjn R, Prsd D. Effect of ge t onset on disese chrcteristics in vitiligo. J Cutn Med Surg. 2013;17: Hsieh FY, Bloch DA, Lrsen MD. A simple method of smple size clcultion for liner nd logistic regression. Stt Med. 1998;17: Mnolche L, Petrescu-Secelenu D, Bene V. Correltion of stressful events with onset of vitiligo in children. J Eur Acd Dermtol Venereol. 2009;23: Silverberg JI, Silverberg NB. Serum homocysteine s biomrker of vitiligo vulgris severity: pilot study. J Am Acd Dermtol. 2011;64: Shker OG, El-Thlwi SM. Is there reltionship between homocysteine nd vitiligo? pilot study. Br J Dermtol. 2008;159: Blci DD, Yonden Z, Yenin JZ, et l. Serum homocysteine, folic cid nd vitmin B12 levels in vitiligo. Eur J Dermtol. 2009;19: Silverberg JI, Silverberg AI, Mlk E, et l. A pilot study ssessing the role of 25 hydroxy vitmin D levels in ptients with vitiligo vulgris. J Am Acd Dermtol. 2010;62: Jonsson T, Ohlin AK, Gottster A, et l. Plsm homocysteine nd mrkers for oxidtive stress nd inflmmtion in ptients with coronry rtery disese prospective rndomized study of vitmin supplementtion. Clin Chem Lb Med. 2005;43: Ckmk SK, Gul U, Kilic C, et l. Homocysteine, vitmin B12 nd folic cid levels in psorisis ptients. J Eur Acd Dermtol Venereol. 2009;23: Mlerb M, Gisondi P, Rdeli A, et l. Plsm homocysteine nd folte levels in ptients with chronic plque psorisis. Br J Dermtol. 2006;155: Shstry S, Jmes LR. Homocysteine-induced mcrophge inflmmtory protein-2 production by glomerulr mesngil cells is medited by PI3 Kinse nd p38 MAPK. J Inflmm (Lond). 2009;6: CUTIS

9 APPENDIX etble 1. Study Questionnire nd Response Rtes (N 1541) Question Wht is your sex (mle/femle)? 99.5 Wht is your ge (in yers)? 99.9 Hve you ever been dignosed with vitiligo by doctor (yes/no)? 99.9 Does the vitiligo ffect both sides of the body (yes/no)? 98.2 How much body surfce re does the vitiligo ffect (1% 25%, 26% 50%, 51% 75%, % 99%, 100%)? On which prts of the body is your vitiligo locted? Sclp, gry hir, eyelids, lips, in the 87.1 mouth, chest, stomch, bck, underrms, rms, elbows, wrists, hnds, fingers, hips, genitls, buttocks, legs, knees, nkles, feet, toes, fce, neck (yes/no) Do you hve intermittent bdominl crmping (yes/no)? 98.1 Do you hve ny other utoimmune diseses other thn vitiligo (yes/no)? 94.6 Did you hve ny stressful life events within the 2 yers prior to the onset of vitiligo 96.5 (eg, divorce, lost job)(yes/no)? If yes, wht occurred? 53.7 Did loved one pss wy within the 2 yers prior to developing vitiligo (yes/no)? 96.2 If yes, plese specify who pssed wy 17.4 Over the lst week, how itchy/sore/pinful/stinging hs your skin been? 93.5 Open-ended question responses were nlyzed using content nlysis. Response Rte, % VOLUME 95, MAY 2015 A1

10 etble 2. Assocition Between Lterlity of Distribution nd No. of Stressors/Deths Reported Within 2 Yers of Vitiligo Onset OR (95% CI) P Vlue Independent Unilterl Bilterl Lterlity of Distribution, n (%) No. of deths reported per prticipnt b 0 87 (85.3) 1139 (83.5) (10.8) 184 (13.5) 1.28 ( ).46 >2 4 (3.9) 41 (3.0) 0.78 ( ).65 reported per prticipnt c 0 48 (48.5) 673 (49.1) (33.3) 460 (33.6) 0.99 ( ).98 >2 18 (18.2) 237 (17.3) 0.94 ( ).83 Abbrevitions: OR, odds rtio; CI, confidence intervl. Percentges reflect the totl number of responses for ech respective question. b No. of deths ws determined from responses to: Did loved one pss wy within the 2 yers prior to developing vitiligo? c Stressors re types of emotionl or environmentl stimuli tht re stressful. ws determined from responses to: Did you hve ny stressful life events within the 2 yers prior to the onset of vitiligo? A2 CUTIS

11 etble 3. Assocition Between No. of Sites Affected nd No. of Stressors/Deths Reported Within 2 Yers of Vitiligo Onset Independent No. of deths prticipnt b Sites Affected, n (%) OR (95% CI) P Vlue Tertile 1 Tertile 2 Tertile (82.3) 398 (84.7) 426 (83.4) (14.5) 56 (11.9) 71 (13.9) 0.96 ( ).74 >2 16 (3.2) 16 (3.4) 14 (2.7) 0.89 ( ).67 prticipnt c (49.0) 224 (47.0) 257 (50.8) (34.3) 167 (35.0) 160 (31.6) 0.92 ( ).41 >2 84 (16.7) 86 (18.0) 89 (17.6) 1.01 ( ).93 Abbrevitions: OR, odds rtio; CI, confidence intervl. Percentges reflect the totl number of responses for ech respective question. b No. of deths ws determined from responses to: Did loved one pss wy within the 2 yers prior to developing vitiligo? c Stressors re types of emotionl or environmentl stimuli tht re stressful. ws determined from responses to: Did you hve ny stressful life events within the 2 yers prior to the onset of vitiligo? VOLUME 95, MAY 2015 A3

12 etble 4. Assocition Between Distribution on Fce nd/or Body nd No. of Stressors/Deths Reported Within 2 Yers of Vitiligo Onset OR (95% CI) P Vlue Independent Fce or Body Fce nd Body Fce nd/or Body Affected, n (%) No. of deths reported per prticipnt b (85.0) 797 (83.5) (11.9) 127 (13.3) 1.14 ( ).49 >2 11 (3.1) 31 (3.2) 1.60 ( ).86 prticipnt c (50.6) 455 (47.4) (32.3) 328 (34.2) 1.13 ( ).38 >2 60 (17.0) 176 (18.4) 1.15 ( ).41 Abbrevitions: OR, odds rtio; CI, confidence intervl. Percentges reflect the totl number of responses for ech respective question. b No. of deths ws determined from responses to: Did loved one pss wy within the 2 yers prior to developing vitiligo? c Stressors re types of emotionl or environmentl stimuli tht re stressful. ws determined from responses to: Did you hve ny stressful life events within the 2 yers prior to the onset of vitiligo? A4 CUTIS

13 etble 5. Assocition Between Symptoms of Abdominl Crmping nd Pruritus nd No. of Reported Deths/Stressors Within 2 Yers of Vitiligo Onset Prticipnt Response, n (%) Independent No Yes Intermittent Abdominl Crmping No. of deths prticipnt d OR (95% CI) b P Vlue OR (95% CI) c P Vlue (82.3) 422 (83.1) (14.3) 70 (13.8) ( ) ( ) >2 30 (3.5) 16 (3.2) 1.01 ( ) prticipnt e ( ) (51.6) 223 (43.7) (33.7) 170 (33.3) ( ) ( ) >2 140 (14.7) 117 (22.9) 1.84 ( ) Premenstrul nd/or Menstrul Crmping No. of deths prticipntd ( ) (83.7) 100 (86.2) (12.7) 15 (12.9) ( ) ( ) 2 38 (3.6) 1 (0.9) ( ) ( ) prticipnt e (48.3) 50 (43.5) (34.4) 32 (27.8) 0.90 ( ) (17.3) 33 (28.7) 1.84 ( ) ( ) ( ) CONTINUED ON NEXT PAGE VOLUME 95, MAY 2015 A5

14 etble 5. (continued) Prticipnt Response, n (%) Independent No Yes Food-Relted Abdominl Crmping No. of deths prticipnt d OR (95% CI) b P Vlue OR (95% CI) c P Vlue (84.0) 40 (83.3) (12.7) 6 (12.5) ( ) ( ) >2 37 (3.3) 2 (4.2) 1.27 ( ) prticipnt e ( ) (48.3) 19 (37.3) (33.5) 20 (39.2) ( ) ( ) >2 203 (18.2) 12 (23.5) 1.68 ( ) Inflmmtory Bowel Syndrome No. of deths prticipnt d ( ) (83.7) 29 (93.6) (12.9) 1 (3.2) ( ) ( ) >2 38 (3.4) 1 (3.2) ( ) ( ) prticipnt e (48.3) 9 (30.0) (33.7) 10 (33.3) 1.59 ( ) >2 204 (18.0) 11 (36.7) 3.29 ( ) ( ) ( ) CONTINUED ON NEXT PAGE A6 CUTIS

15 etble 5. (continued) Prticipnt Response, n (%) Independent No Yes Anxiety-Relted Abdominl Crmping No. of deths prticipnt d OR (95% CI) b P Vlue OR (95% CI) c P Vlue (83.9) 16 (88.9) (12.8) 1 (5.6) ( ) ( ) >2 38 (3.3) 1 (5.6) 1.59 ( ) prticipnt e ( ) (48.0) 7 (38.9) (33.6) 7 (38.9) ( ) ( ) >2 211 (18.4) 4 (22.2) 1.49 ( ) Autoimmune Gstrointestinl Disorders No. of deths prticipnt d ( ) (83.5) 14 (82.4) (13.4) 2 (11.8) ( ) ( ) >2 44 (3.1) 1 (5.9) NE.98 ( ) prticipnt e (49.3) 5 (29.4) (33.6) 5 (29.4) 1.47 ( ) >2 247 (17.1) 7 (41.2) 4.02 ( ) ( ) ( ) CONTINUED ON NEXT PAGE VOLUME 95, MAY 2015 A7

16 etble 5. (continued) Prticipnt Response, n (%) Independent No Yes Itching nd/or Burning No. of deths prticipnt d OR (95% CI) b P Vlue OR (95% CI) c P Vlue (84.4) 402 (81.4) (12.7) 74 (15.0) ( ) ( ) >2 26 (2.8) 18 (3.6) 1.34 ( ) prticipnt e ( ) (52.3) 214 (43.0) (31.6) 184 (36.9) ( ) ( ) >2 148 (16.2) 100 (20.1) 1.51 ( ) ( ) Abbrevitions: OR, odds rtio; CI, confidence intervl; OR, djusted odds rtio; NE, not estimble. Percentges reflect the totl number of responses for ech respective question. b Binry logistic regression models were constructed with etiologies of intermittent bdominl crmping nd pruritus s the dependent (outcome) vribles. c Multivrite logistic regression models included ge (yers), sex, nd body surfce re s covrites. d No. of deths ws determined from responses to: Did loved one pss wy within the 2 yers prior to developing vitiligo? e Stressors re types of emotionl or environmentl stimuli tht re stressful. ws determined from responses to: Did you hve ny stressful life events within the 2 yers prior to the onset of vitiligo? A8 CUTIS