CLINICAL REPORT. Acta Derm Venereol 2015; 95: Line KIBSGAARD 1, Bjørn BAY 2, Mette DELEURAN 1 and Christian VESTERGAARD 1 1

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1 Act Derm Venereol 2015; 95: CLINICAL REPORT A Retrospective Consecutive Cse-series Study on the Effect of Systemic Tretment, Length of Admission Time, nd Co-morbidities in 98 Bullous Pemphigoid Admitted to Tertiry Centre Line KIBSGAARD 1, Bjørn BAY 2, Mette DELEURAN 1 nd Christin VESTERGAARD 1 1 Deprtment of Dermto-Venereology, Arhus University Hospitl, nd 2 School of Public Helth, Section for Epidemiology & Institute of Clinicl Medicine, Deprtment of Obstetrics nd Gynecology, Arhus, Denmrk Bullous pemphigoid (BP) is common blistering disese cused by ntibodies directed ginst hemi-desmosoml proteins BPAG1 nd BPAG2. The disese is chrcterised by intense pruritus nd blistering of the skin. The systemic tretment with the highest level of evidence for BP is systemic glucocorticoids. However, since the disese often occurs in the elderly ptients, nd since the most common co-morbidities re dibetes nd neurologicl diseses, glucocorticoid-spring drugs re often introduced. We retrospectively identified ll BP ptients dmitted to our tertiry clinic over 7-yer period in order to register demogrphy, tretment nd co-morbidities. The most common steroid-spring drugs were zthioprine (87%) nd methotrexte (11%). Less thn 2% were treted with dpsone, rituximb nd cyclosporin A. As expected, we found reltively high rte of neurologicl disorders, dibetes, nd mlignncies, but surprisingly we lso found n incresed rte of crdiovsculr diseses compred to the Dnish popultion in generl. Key words: bullous pemphigoid; systemic tretment; co-morbidities; demogrphy. Accepted Jun 30, 2014; Epub hed of print Jun 30, 2014 Act Derm Venereol 2015; 95: Christin Vestergrd, Deprtment of Dermtology, Arhus University Hospitl, P.P. Oerumsgde 11, DK-8000 Arhus, Denmrk. E-mil: chr-vest@post9.tele.dk Bullous pemphigoid (BP) is the most common utoimmune blistering disese cused by utontibodies in the skin. The disese typiclly ppers in the elderly (1 3) nd is chrcterised by n intensely pruritic rsh dominted by tense blisters rising in norml looking or erythemtous skin (4). The incidence of BP hs been reported to increse over the lst decdes nd ws in 2008 estimted to be 4.3/0,000 person yers (5, 6) with mortlity twice tht of the generl popultion (6). In ddition, significnt ssocition with neurologicl diseses including previous stroke, Prkinson s disese, nd dementi hs been demonstrted (1, 3, 7). The tretment of BP is immunosuppression. The tretment my be systemic or topicl depending on the severity of the disese. Looking t specific outcomes 2015 The Authors. doi:.2340/ Journl Compiltion 2015 Act Dermto-Venereologic. ISSN (3 weeks control nd survivl), the best evidence for therpy is topicl glucocorticoid (2). However, some ptients do not respond sufficiently to topicl tretment. As result, severe cses of BP re commonly treted with systemic gents. The first choice of systemic tretment is orl corticosteroid with recommended doses in the rnge of mg/kg/dy (8). Although higher doses my be more effective, the risk of inexpedient side effects nd 1-yer mortlity hs been proven to rise (2, 9, ). This, dded to the risk of interference with existing comorbidities, mkes tretment with systemic glucocorticoid chllenge to the clinicin. Thus, steroid spring immunomodulting therpy (IMT) such s methotrexte (MTX), zthioprine, cyclosporin A, nd mycophenolte mofetil my be required. The steroid spring effect mong different IMT s hve only been ddressed in few rndomised controlled trils (RCTs). A comprison of zthioprine nd mycophenolte mofetil, s supplementl therpy to orl methylprednisolone, found similr efficcy nd cumultive corticosteroid doses between the 2 groups (11). In 1984, plsm exchnge ws suggested s substntil sving fctor of corticosteroid (12). On the contrry, Guillume nd collegues (9) found no difference in complete remission nd mortlity in 98 BP ptients rndomised to receive either orl prednisolone s monotherpy, in combintion with zthioprine, or in combintion with plsm exchnge. Conclusively they rejected both plsm exchnge nd zthioprine s routine djuvnts to corticosteroids in the mngement of BP. In the bsence of steroid monotherpy rm in the first RCT nd differing results in the following 2, no consistent conclusions bout which IMT to prefer hve been mde. In recent review of the literture on the tretment of BP it is concluded tht systemic s well s topicl glucocorticoids remin the tretments with the highest level of evidence nd recommendtion (). The im of this study ws to retrospectively describe the demogrphy, co-morbidities, tretment, nd tretment outcomes in cohort of ll ptients with BP dmitted to tertiry centre from , in which the use of steroid-spring drugs is common prctice. Further, we hypothesised tht length of dmission, rte of remission nd relpse, nd totl tretment durtion re relted to the initil doses of systemic glucocorticoid.

2 308 L. Kibsgrd et l. METHODS Design nd ptients In this retrospective consecutive cse-series study, medicl records of ll ptients dmitted with the dignoses of BP, t the Deprtment of Dermtology nd Venereology t Arhus University Hospitl during 7-yer period, were investigted. were identified using the ICD system. Dignoses of relevnce were BP (DL12.0), other pemphigoid (DL12.8), nd pemphigoid unspecified (DL12.9). The project ws pproved by the Dnish Dt Protection Agency. Ptient chrcteristics t dmission, systemic tretment during dmission, nd predefined tretment outcomes were recorded in Filemker Pro constructed dtbse. were included if chrcteristic clinicl presenttions of BP such s pruritus, bulle, or positive indirect Nikolsky s sign were described, nd/or if skin biopsies reveled subepiderml bulle nd/or clusters of eosinophils, nd/or if direct immunofluorescence (IF) showed liner deposits of IgG or complement C3 long the bsement membrne zone. In the cses, where the IF turned out negtive ptients were excluded. with primrily mucosl involvement were re-dignosed s hving mucus membrne pemphigoid (MMP) nd excluded. From discriptions in the medicl records, primry skin lesions were retrospectively clssified s mild disese (loclised lesions with miniml skin-ffection less thn 20%), moderte disese (extensive distribution of skin lesions, more thn 20% without signs of infection), or severe disese (protrcted disese, tretment resistnt prior to hospitlistion (if informtion vilble), or extensive distribution of skin lesions with more thn 20% skin ffection nd secondry infection). Skin lesions were defined s bulle or urticril lesions. One trined ssessor performed the clssifiction. Tretment of the ptients ws bsed on the guidelines in the deprtment of dermtology in Arhus. Primry tretments re topicl steroids for the entire body (betmethsone-17-vlerte or clobetsol propionte for body nd extremities nd hydrocortisone-17 butyrte for fce nd skin folds) in combintion with systemic glucocorticoids (prednisolone). Prednisolone ws usully dministered s 37.5 mg/dy nd updosed until effect (no ppernce of new blisters). The deprtment hs no guidelines for the drug of choice s steroid spring drug, which ws t the discretion of the treting doctor. Tretment my hve been strted before confirmtion of dignosis due to the severity of the disese in the ptients. After consolidtion of the IMTs (2 3 weeks) systemic steroid ws tpered with 5 mg/14 dys nd topicl ws tpered to every other dy for 14 dys nd then twice weekly for 3 4 weeks. Outcomes On the first dy of dmission, ptients were typiclly initited on systemic glucocorticoid lterntively pre-hospitlistion dosges were incresed. For ech ptient dosge of systemic glucocorticoid t dmission ws recorded. During dmission, djuvnt immune modulting therpy (IMT) ws initited, typiclly when BP dignoses ws confirmed by histopthology nd/or positive IF. were dischrged when ppernce of new bulle hd been bsent for t lest 2 dys, nd primry skin lesions were strting to re-epithelilise. Thus, men length of primry dmission in dys ws thought to represent the disese course. Approximtely 6 weeks fter dischrge, plnned outptient consulttion ws rrnged. At this clinicl control, ptients were registered s in remission if the ppernce of new blisters hd been bsent for t lest one week, nd if ll skin lesions were objectively heled. As tretment outcomes, totl tretment durtion expressed the totl time in weeks ech ptient received systemic therpy prescribed from our deprtment. Further, we estimted the medin durtion of both systemic glucocorticoid nd IMTs. If new blisters occurred, or if itchy red plques ppered t ny time during the study period, ptients were registered s relpsed. To test our hypothesis, tht tretment outcomes re relted to initil doses of systemic glucocorticoid, ll outcomes were secondrily strtified in low or high initil doses of systemic glucocorticoid t dmission. Subnlyses were performed, to exmine if disese severity ws ssocited with initil doses of systemic glucocorticoid. Further, we investigted whether there ws n ssocition between disese severity nd dmission time or between disese severity nd totl tretment durtion. Sttisticl nlysis In the descriptive nlyses ll continuous vribles re reported with mens nd stndrd devitions (SD) nd ll ctegoricl vribles with percentges. In order to evlute whether tretment outcomes were dependent on initil doses of systemic glucocorticoid, we dichotomised the initil dose into 2 groups. To compre the tretment outcomes between groups receiving either low (< 45 mg/dy) or high dose systemic glucocorticoid (> 45 mg/dy), we used Fisher s exct test for ctegoricl outcome vribles, t-test for continuous outcome vribles following Gussin distributions, nd Wilcoxon Mnn-Whitney U test for continuous non-gussin outcome vribles. p-vlues less thn 0.05 were considered sttisticlly significnt. RESULTS Between Jnury 1, 2006 nd Februry 18, 2013, totl of 117 ptients were identified. Eight ptients were retrospectively dignosed s MMP nd excluded. A totl of 11 ptients were excluded on other criteri. Of these, 4 ptients were initilly misdignosed with finl dignoses of epidermolysis bullos cquisit, scbies, cutneous vsculitis, nd chronic urticri, respectively. Two ptients were exclusively treted in the outptient clinic, nd 5 ptients did not fulfil ny of the predefined inclusion criteri. Bseline chrcteristics nd prehospitlistion tretments of the remining 98 ptients re presented in Tble I. The ge t debut rnged from 50 to 96 yers with men ± SD ge of 78 ± yers. There ws significnt difference between the sexes in men ± SD ge t debut of women 80 ± 11 compred to men (75 ± 9) (p = 0.023). Of the 98 ptients, 62 were women (63%) nd 36 were men (37%) (p = 0.01). In the most elderly popultion (> 80 yers), the gender difference ws even more pronounced with totl of 76% being women. With regrd to comorbidity, totl of 69 ptients (70%) suffered from crdiovsculr diseses (s determined by ICD dignoses: I00 to I99) of which 39 were hypertension. Congestive hert filure, rrhythmis, prior cute myocrdil infrcts, dilted crdiomyopthy, nd vlve diseses mounted the rest. Referring to previous shown ssocitions between BP on one hnd nd dementi, prior stroke, or Prkinsonism on the other (1, 3, 7), it ws notble tht the second most frequent comorbidity ws neurologic disorders which ws present in 36 ptients (37%).

3 Systemic tretment, dmission time nd co-morbidities in bullous pemphigoid 309 Tble I. Bseline chrcteristics nd pre-hospitlistion tretments of ptients dmitted with bullous pemphigoid (n=98) during the study period (Jn 2006 Feb 2013) Chrcteristics Gender, % Mle 37 Femle 63 Age t debut, yers, men ± SD 78 ± Severity, % Mild 3 Moderte 56 Severe 41 Dignose methods, % Objective + Histology + Immunofluorescence Prior tretment, % Topicl steroids Systemic glucocorticoid s monotherpy + immunosupressnts Comorbidities, % Crdiovsculr disese b Neurologic disorders c Lung diseses d Dibetes Cncers e Azthioprine (n = 9), methotrexte (n = 1); b Hypertension (n = 39), crdic disorders (n = 30); c Stroke (n = 12), dementi (n = 17), Prkinsonism (n = 4), epilepsy (n = 2), multiple sclerosis (n = 1); d Asthm (n = 2), chronic obstructive lung disese (n = 16); e Brest cncer, endometril cncer, hed nd neck cncer, prostte cncer, rectl cncer, mlignncies of the nsl cvity, lryngel cncer, coecum cncer, vesicl cncer Tretment outcomes At dmission, 89 out of 98 ptients (91%) were initited or incresed in systemic glucocorticoid. Dosges rnged from to 90 mg with men ± SD of 44 ± 15 mg. Potentil increse in systemic steroid dose ws performed over the first dys of dmission, until n effect ws observed (no new bulle), nd did not depend on the weight of the ptient. Four ptients continued systemic glucocorticoid s monotherpy, wheres 85 ptients were supplied with djuvnt IMTs. Of the 9 ptients not treted with systemic glucocorticoid, one ptient ws treted with MTX s monotherpy, 2 with zthioprine, nd one with cyclosporin A. All tretment strtegies were supplied with dily ppliction of topicl glucocorticoids, nd 5 ptients were sufficiently treted with topicl glucocorticoids lone. The choice of steroid spring IMT ws bsed on individul ssessments depending on comorbidities (existing or prior neoplsms or crdiovsculr disese), blood tests (hemtology, liver nd kidney function), ge, nd history of lcohol buse. As deprtment stndrd, choice of IMT ws lwys conferred with the Deprtment of Oncology in cses of ptients with prior neoplsms. However, the use ws never contrindicted. The vst mjority of our cohort (82%) received zthioprine (rnge mg/dy), wheres MTX (rnge mg/week) ws the second most preferred djuvnt drug (11%). A few cses, resistnt or intolernt to usul tretment strtegies, were treted with lterntive drugs such s mycophenolte mofetil (n = 3), rituximb (n = 1), nd dpson (n = 1). The distribution of IMTs nd outcomes re presented in Tble II. The men ± SD dmission time of the ptients were 14 ± 9 dys. Subnlyses showed tht dmission time ws significntly shorter in ptients receiving low dose predisolone compred to the ptients receiving high dose predisolone (p = 0.02) (Tble III). There ws no significnt difference in the IMT tretment strtegies, 6 weeks remission rte, relpse rte, or the totl tretment length between the low nd high dose predisolone groups. There ws no significnt ssocition between disese severity nd dosge of systemic glucocorticoid t dmission (p = 0.20). Further, we found no significnt ssocition between disese severity on one hnd nd dmission time nd totl tretment durtion on the other (results not shown). DISCUSSION In this retrospective cse series of 98 ptients dmitted with BP 97% suffered from moderte to severe disese. Ten percent of the ptients were dignosed purely on the clssicl clinicl presenttion of the disese. Women ccounted for 63% of the cohort nd were significntly overrepresented (p = 0.01) in concordnce with other studies on BP in Cucsins (2, 3, 5, 7). On the contrry men seem to dominte in Asins (1, 13). Yet, no unmbiguous conclusions hve been mde on the gender-distribution of ptients suffering from BP. Crdivsculr disese ws the most dominnt comorbidity (70%) followed by CNS disorders (37%), Tble II. Tretment, nd tretment outcomes in ll ptients dmitted with bullous pemphigoid (n = 98) Tretment nd outcomes Length of primry dmission, dys, men ± SD 14 ± 9 Dosge of systemic glucocorticoid t dmission, mg, men ± SD 44 ± 15 Durtion of systemic glucocorticoid, weeks, medin, (25/75 percentile),b 20 (/39) Choice of immune modulting therpy c, ptients, n Azthioprine 80 Methotrexte 11 Cyclosporine 5 Mycophenolte mofetil 3 Rituximb 1 Dpson 1 Durtion of immune modulting tretment, weeks, medin, (25/75 percentile) c 21 (9/49) Totl tretment durtion, weeks, medin (25/75 percentile) 29 (11/60) 6 weeks remission, % 74 Relpse d, % 34 Nine ptients did not receive systemic glucocorticoid nd did not contribute to this vlue (n = 89); b From journl review it ws not possible to determine durtion of systemic glucocorticoid in dditionl 4 cses (n = 85); c From the originl cohort (n = 98) 12 ptients did not receive immune modulting therpy > 1 week (n = 86); d At ny time of the study period.

4 3 L. Kibsgrd et l. Tble III. Tretment outcomes strtified by dosges of systemic corticosteroid t dmission Tretment nd outcomes All ptients Systemic glucocorticoid (< 45 mg/dy) (n = 46) Dosge of systemic glucocorticoid t dmission, mg, men ± SD 34 ± 8 56 ± 11 Length of primry dmission, dys, men ± SD* 12 ± 8 17 ± 9 Durtion of systemic glucocorticoid, weeks, medin (25/75 percentile) b 19 (/40) 22 (/35) Immune modulting therpy, % Azthioprine Methotrexte Cyclosporine 4 5 Mycophenolte mofetil 2 5 Rituximb 0 2 Dpson 0 2 Durtion of immune modulting tretment, weeks, medin (25/75 percentile) c 22 (7/45) 18 (9/59) Durtion of totl tretment, weeks, medin (25/75 percentile) 34 (16/60) 25 (11/87) 6 weeks remission, % Relpse, % d Systemic glucocorticoid (> 45 mg/dy) (n = 43) Of 98 ptients, 5 ptients were treted with topicl steroids lone nd 4 ptients with zthioprine, methotrexte or cyclosporine s monotherpy. The remining 89 ptients received systemic glucocorticoid. b Four missing vlues on systemic glucocorticoid were excluded (low dose group (n = 43), high dose group (n = 42)). c With reference to Tble II, dditionlly 4 ptients received IMT s monotherpy nd did not contribute to these vlues (low dose group (n = 41), high dose group (n = 41)). d At ny time of the study period. *Significnt difference (p = 0.02). dibetes (15%), nd mlignncies (including ll types of cncer, Tble I) (14%). It is well known tht BP is ssocited with neurologic disorders (1, 3, 7). Also ccumulted cses of mlignncies nd dibetes mellitus in BP ptients hve previously been shown (14). Crdiovsculr disese hs not been described s n ssocited disorder. Although this study did not include reference group, prllels my be drwn to prevlences in the generl popultion. The prevlence of crdiovsculr diseses in Denmrk (ICD dignoses: I00 to I99) hs been ssessed in report from the Dnish Ntionl Institute of Public Helth from As expected, the prevlence incresed with incresing ge in both sexes. The highest prevlence ws found mong men older thn 85 yers, where totl of 43% ws reported to hve crdiovsculr disese (15). Since the prevlence of crdiovsculr diseses ws considerbly higher in the present study, our results indicte tht there my be n ssocition between BP nd crdiovsculr disese. However, the ptients included in this study re dmitted to specilised centre, nd in limited numbers, which mens tht this ssocition needs to be studied further. Of ll ptients, 91% were treted with systemic glucocorticoids with medin durtion of 20 weeks. Of these ptients 87% received zthioprine s djuvnt therpy, wheres MTX ws second in preference (11.5%). After dichotomising the initil doses of systemic glucocorticoid t dmission (t 45 mg/dy), we found significnt difference in dmission time in fvour of the low dose group (p = 0.02). This my be cused by the fct tht ptients treted with high doses of systemic glucocorticoid were initilly suffering from more severe disese. However, this ssocition could not be shown in the following sub-nlysis. In contrst, rte of remission nd relpse, medin durtion of systemic corticosteroid nd IMTs, nd totl tretment durtion were independent of the dichotomized initil doses of systemic glucocorticoids. As this is not RCT direct comprison of the effect on BP of the initil dose of glucocorticoid is not possible. The evidence-bsed literture, on the steroid-spring effect of zthioprine in treting ptients with BP, consists of 2 RCTs from 1978 nd 1993, respectively (9, 16). The lrgest RCT showed no significnt difference in remission-rtes fter 4 weeks (71 vs. 80.5%) glucocorticoids s monotherpy (n = 31) compred to combintion of glucocorticoid nd zthioprine (n = 36). The uthors concluded tht zthioprine should not represent routine djuvnt tretment (9). In contrst, Burton et l. (16) found significnt reduction (p < 0.01) in men nnul dose of predisolone in ptients treted with zthioprine nd predisolone (n = 12) compred to predisolone lone (n = 13). They concluded tht zthioprine should be stndrd djuvnt to systemic glucocorticoid in treting ptients with BP. Since our study is not RCT with plcebo group, rther descriptive study of given group of ptients, no firm conclusions on effect of steroid spring gents cn be mde. In contrst, systemic glucocorticoid s stndrd tretment of BP hs been thoroughly investigted (2, 9,, 17). Unfortuntely, studies hve lso proved systemic glucocorticoid s poor prognostic fctor for one-yer mortlity (2, 9, ) with infections nd hert diseses being the dominnt cuses of deth (18, 19). The incidence of severe side effects to glucocorticoid (septicemi, dibetes mellitus, psychitric disorders) hve been proven to rise ccording to the dosge (0.5 mg/kg/dy versus 1

5 Systemic tretment, dmission time nd co-morbidities in bullous pemphigoid 311 mg/kg/dy) nd dministrtion form (topicl versus orl) (2). If, s our results implies, this group of ptient hve n incresed risk of crdiovsculr disese, then ddition of steroid spring drugs certinly hs its merits. The strengths of our study re both the long study period, nd the vlidtion of ll BP dignoses in terms of review of ech individul medicl record. Further, totl of 80 BP ptients received n identicl combintion of systemic glucocorticoid nd zthioprine. All dt were extrcted from one of only 5 specilised centres in Denmrk covering popultion of pproximtely 1.6 million people. As our deprtment consults the most severe cses in our region outcomes might be ffected by selection bis. On the contrry, the sme specilists ssessed ll ptients, nd tretment strtegies were conducted referring to the sme stndrd procedures. However, especilly the long-term outcomes, such s relpse rte, could be bised by disese severity or ptient complince nd must be interpreted with cution. In the vst mjority of ptients, end of follow-up ws cused by successfully completed tretment. However, in smll number of cses, end of follow-up ws due to bsence from outptient controls or deth, which might underestimte the size of ppertining outcomes. Additionlly it should be remembered tht this study is not rndomised prospective study, but retrospective cse-series study. In conclusion, we found tht our ptients hd n incresed rte of crdiovsculr disese s compred to the known prevlence of these diseses in the Dnish popultion. However, further studies re needed to confirm this ssocition. As previously shown, our results lso suggest n ssocition between BP nd neurologicl diseses, nd we found reltively high prevlences of mlignncies nd dibetes mong the BP ptients in our popultion. Mny of these comorbidities re potentilly worsened by glucocorticoids, nd the clinicin should consider these comorbidities in ptients suffering from BP when prescribing tretment. Combined with the knowledge of infections nd hert diseses being dominnt contributors to incresed oneyer mortlity fter receiving systemic glucocorticoids (18, 19), we believe tht steroid spring strtegies re necessity in these ptients. Whether zthioprine or e.g. methotrexte should be the first choice of steroid spring therpy must be studied with rndomised controlled tril. The uthor declre no conflict of interest. REFERENCES 1. Chen YJ, Wu CY, Lin MW, Chen TJ, Lio KK, Chen YC, et l. Comorbidity profiles mong ptients with bullous pemphigoid: A ntionwide popultion-bsed study. Br J Dermtol 2011; 165: Joly P, Roujeu JC, Benichou J, Picrd C, Dreno B, Delporte E, et l. A comprison of orl nd topicl corticosteroids in ptients with bullous pemphigoid. N Engl J Med 2002; 346: Lngn SM, Groves RW, West J. 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