British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012

NHS Evidence has accredited the process used by the British Association of Dermatologists to produce guidelines. Accreditation is valid for 3 years from May 2010 and is applicable to guidance produced using the processes described in the British Association of Dermatologists’ guidelines development manual (Bell & Ormerod, 2009). More information on accreditation can be viewed at http://www.evidence.nhs.uk. The overall objective of the guideline is to provide up‐to‐date, evidence‐based recommendations for the management of bullous pemphigoid (BP). The document aims to update and expand on the previous guidelines by: (i) offering an appraisal of all relevant literature since January 2002, focusing on any key developments; (ii) addressing important, practical clinical questions relating to the primary guideline objective; (iii) providing guideline recommendations and, where appropriate, with some health economic implications discussing potential developments and future directions. The guideline is presented as a detailed review with highlighted recommendations for practical use in the clinic (see section 14.0), in addition to an updated patient information leaflet [available on the British Association of Dermatologists’ (BAD) website; http://www.bad.org.uk]. The guideline development group consisted of consultant dermatologists. The draft document was circulated to the BAD membership, the British Dermatological Nursing Group (BDNG), the Primary Care Dermatological Society (PCDS) and the Pemphigus Vulgaris Network for comments, and was peer reviewed by the Clinical Standards Unit of the BAD (made up of the Therapy and Guidelines subcommittee) prior to publication. This set of guidelines has been developed using the BAD’s recommended methodology1 and with reference to the Appraisal of Guidelines Research and Evaluation (AGREE II) instrument.2 Recommendations were developed for implementation in the National Health Service (NHS) using a process of considered judgment based on the evidence. PubMed, MEDLINE and EMBASE databases were searched up to June 2012 for meta‐analyses, randomized and nonrandomized controlled clinical trials, case series, case reports and open studies involving bullous pemphigoid, with no language exclusions; search terms and strategies are detailed in Appendix S1 online (see Supporting information). Additional relevant references were also isolated from citations in the reviewed literature, as well as (independent) targeted searches carried out by coauthors. Working in pairs, the authors screened the identified titles, and those relevant for first‐round inclusion were selected for further scrutiny. The abstracts for the shortlisted references were then reviewed and the full papers of relevant material were obtained; disagreements in the final selections were resolved by discussion with the entire development group. Additional selection criteria included relevant publications on the management of childhood BP. The structure of the 2002 guidelines was then discussed and re‐evaluated, and different coauthors were allocated separate subsections. Each coauthor then performed a detailed appraisal of the selected literature with discussions with the entire development group to resolve any issues, e.g. with the quality of evidence and making the appropriate recommendations. All subsections were subsequently collated and edited to produce the final guideline. This document has been prepared on behalf of the BAD and is based on the best data available when the document was prepared. It is recognized that under certain conditions it may be necessary to deviate from the guidelines and that the results of future studies may require some of the recommendations herein to be changed. Failure to adhere to these guidelines should not necessarily be considered negligent, nor should adherence to these recommendations constitute a defence against a claim of negligence. The proposed revision date for this set of recommendations is scheduled for 2017; where necessary, important interim changes will be updated on the BAD website. BP is an autoimmune subepidermal blistering disease that typically affects the elderly but may rarely present in children and younger adults. Autoantibodies of IgG type (and less commonly IgA, IgM and IgE) attack components of the adhesion complex of the basement membrane zone (BMZ) and result in subepidermal blistering. The two main autoantigens are BP230 (BPAg1) and BP180 (BPAg2, collagen XVII). BP is the most common immunobullous disease in Western Europe with a reported incidence of 43 per million per year in the U.K.3 and 7–13 per million per year in other parts of Europe.4–6 The mean age of onset is around 80 years. Recently it has been shown that BP is associated with neurological disease such as cerebrovascular disease, dementia, Parkinson disease, epilepsy and multiple sclerosis.7–10 These conditions pre‐date BP and hence are considered as risk factors. There are a number of anecdotal case reports suggesting an association between BP and some drugs.11–15 A recent small case series reported BP occurring in five diabetic patients taking an oral hypoglycaemic agent, gliptin (dipeptidyl peptidase‐IV inhibitor), together with metformin.16 To date there are three epidemiological studies on the subject of BP and drugs.8, 17, 18 Two French case–control studies, both by the same author, have described a significant relationship with the use of spironolactone and neuroleptics.8, 17 A recent U.K. case–control study found an association only with furosemide after adjusting for cardiovascular and neurological disease.18 The mechanism by which drugs may induce BP has not been studied. There is no conclusive evidence for an association with malignancy or other autoimmune diseases. Tense blisters are often seen on erythematous or normal‐looking skin of limbs and trunk and may be widespread or localized. Bullae and/or erosions may be present in the oral and genital mucosa. Pruritus alone or associated with erythema and/or urticated plaques may precede formation of bullae by weeks or months; in some cases bullae may not become clinically apparent. A skin biopsy from a fresh blister stained with haematoxylin and eosin shows subepidermal clefting and an inflammatory infiltrate mainly consisting of eosinophils; however, the diagnosis is confirmed with immunofluorescence studies (IF). A biopsy for direct IF (DIF) is taken from uninvolved skin about 1 cm away from a fresh blister and is immediately snap‐frozen in liquid nitrogen or transported in either Michel’s transport medium or normal (0·9%) saline. If using saline, the biopsy must be processed within 24–48 h;19 with Michel’s medium prompt handling is to be preferred, but a longer delay of up to 2 weeks may still yield results.20 Indirect IF (IIF) is performed on serum, and if this is not obtainable, on blister fluid. The characteristic DIF picture in BP is a linear deposition of IgG and/or C3 along the BMZ. Other immunoglobulins, including IgA, IgM and IgE, may also be present. Substrates used for IIF include monkey oesophagus and normal human skin; the latter can be split using molar saline. Antibodies in BP serum usually detect antigens at the roof of the salt‐split skin. most cases this may to BP from other immunobullous such as and some cases of membrane pemphigoid in both of which are on the of the split skin. recent has as an for some autoimmune bullous diseases. of to both BP180 and BP230 can be with available with the BP180 the BP230 The is an important of the BP180 and is used in BP180 to detect that with disease results using the same were reported in of with The is not available in the U.K. but is a in selected cases and in IF studies the for bullous may in and however, such as age of of the disease, of and of are important in the DIF and salt‐split IIF are in BP from other subepidermal linear disease, and in bullous in the group and may also be by erythema and and skin should be recognized and with is BP is usually a disease with a clinical that may from to years. the the disease is associated with significant and a that of the elderly age at onset and are factors. available are associated with and may be in patients with BP. the year is in patients with of should to with where are or and to and inflammatory The of on the the of the BP and the of the of the of recommendations and of evidence Appendix was to be in BP in clinical studies the and has become as the of The in most cases is with of and blistering typically within after which the is The most commonly used drugs are and which are to be and were recognized in these studies and in the randomized controlled involving in the of BP in controlled for the of bullous pemphigoid including a of controlled for the of bullous pemphigoid including a of The of of was in patients with widespread of to to of of the significant either 1 or for 3 was by All patients to the but in of the oral blistering less within 2 patient within 1 of the and three between 1 and the The of were and from the studies are the best for and and are of of in widespread BP are within weeks in about of Clinical that the the disease, the the of is to 1 this has not been A of patients with BP to such of the and is It is not to a of that be and for all patients with BP. which these criteria for a of patients for patients with for for or If inflammatory or are or within the can be as and the of should then be A of the of at by about or to then by to is The then be by 1 about of cases will at some the that the previous is to be the for that patients with widespread BP not to these or on other alone or in addition to the may be to of The of in BP is to be and is usually with a should be at of are appropriate in and and in any patient at risk of are to or for at 3 with BP (and also patients with were reported to have of and a incidence of suggesting risk of and and a are usually recommended and have been shown to be in if from the of in patients with immunobullous may of and oral and should be taken at a different studies have the use of as for both and and two recent with a of confirmed this all including clinically skin was with oral in the of A significant of the was shown in disease blisters a for disease and the group blisters a no significant were found between and for disease and and to were seen in all but were in the 1 group. the same group a with per on disease and or of skin at 3 weeks was by all patients in both The of used the study were in the in the which is a in There was no the between the and no significant in between The main in both were cardiovascular and and There were also which included skin and There was no significant between the two in terms of year 1 the was disease disease and in the it was also disease disease the of the study an for age and after which a of the was in with with an in the risk of or to the A recent of in the U.K. that of use as in BP and in BP. It is used as an to the only A of of use is to use it to with All are based on valid are an for BP and to have less with 1 of per use in disease may be by practical of patient or of to the and may be associated with and should be considered for in is still a commonly used in BP. It is in of up to as an to for the of as an to in BP has been in only two and with reported a in a a only found no in in patients with alone with those with and were reported in patients A recent with patients with 1 as to was in of patients in both but this included no no can be as to the of The was to produce with were at and of was in out of patients with but with 43 the were the of with for a be an important in some health can be with to risk by prior of a that is available in the U.K. and a normal not and of and are There is evidence of to addition of to for the of BP. of it is recommended that only be considered as an to where has been and the disease is not or where the of are and the development of the guideline in 2002 there have been no relevant publications the of BP with with are used in the of BP. A reported that about of the use a of and as a for a in the U.K. that of use as of management of is used in the U.K. by and A of of that are that are for the U.K. are based on valid The most reported was by and with was only in two is under with for the of the results are in There are small small and case reports on and The small patients with patients 2 per and weeks of there were and five in the with five five and disease in the group. Two in the group were for at the results were not the available for all five in the group disease two of the three in the group with The was in of and There are case reports and small series that the of usually in with It was in the within however, some patients or in There are only two case series involving and and case of the of in children and should be considered for in children and in with A may be seen within weeks of and may be considered as in in with from case of as in there is no evidence for as a of The both for the and are not is used between and usually at and then to to has been used at of at and at should be in as should and in patients with has a and is not the of A cases of and have been has a and has been used by some in the U.K. evidence. blister formation is the and must be at a to There are no controlled involving for the of BP. Two small case series of and patients both reported that of can be at either as a or in with This was confirmed by a recent case series of patients with or in with The patients per per patients and of patients only to or with or of or patient patients were with The was for for and for and for the group. after a of and and 2 The to was the cases were for disease and there to be a of cases in the patients as was in five patients of and age was associated with but there was no significant between the and The most important of are and is which should be considered in the elderly and may the for disease on the to some but this is not Evidence from these case series that can be at either as a or in with or is an of in and and is a used in the of since It has been reported as in BP in of in a small number of case both as an to and as a disease a including was with as an to This not include a no can be as to the of either as a There was no between the two was to produce with were associated with of with associated with but less 43 discussed in section is evidence is for the of in BP. There are no with to the use of either or either as or as in the management of BP. series a of patients have reported with or with either or These were either as or in with The was around in three but only of in the to be in onset with A series reported a in patients in was to with and series of patients reported a of at 2 weeks in patients with in with and The series was with no no was as to there was any There are case reports of alone or with oral used in childhood to and should be in those of and and all patients of and in the The of and is in the this age these should be considered only if other are or and at to be by in to a of has been as an in blistering diseases. cases of in BP is to a of patients in small series and case used as a some patients and with occurring within 2 either further or with or has been commonly used with oral and other A case series reported on patients with pemphigoid or in there were significant and other or was with 2 in 3 and with were weeks and with between The of in all The not all other were also was a further with a mean of further of is well but per of 2 in a U.K. guidance on use is available from the of Health should only be considered as an in patients with disease where is or when there is with or to other an open patients with BP with of of and 2 the of both drugs were All patients and for The of after weeks was 2 per in most The mean was about of that reported for and 3 The risk of was and were patient to which after malignancy has been to and the authors that a of 1 or of 1 should not be a study from the same a was between patients with BP with alone and those with and The of was based on disease and patient to was at about in patients or if the was 2 weeks it was to and after a further weeks to 2 The mean of and the mean of were both in the group. from an in the normal in no were to as an to should be considered as an to other if these have or are or is for cases have been reported in which to have a in the only case series the of in patients were with in of and with significant involving and results with studies, the authors not a with the but no cases on is other drugs used for BP. It may rarely be considered for of the use of in BP is to two reports from the same with a of patients with of were seen in two out of cases with patients on to the addition of and two of these after the was of serum in most of the patients not but was reported to be in only be recommended in the of BP. It may rarely have a in cases but is to be by in the case reports have described a to with the It has mainly been used for and reported two cases of disease with multiple including oral but not of of oral and was seen within 2 data were not a case of pemphigoid, of oral and use of to these with the of with for 2 of the oral other has been used as the for disease and also in pemphigoid in a The use of is by and with It may be as an in and disease the of skin a reported cases of BP have been with and the agent, The is and is by significant of of evidence This the which may be from the for a reported patients including two children with BP have been with The in most cases was a for by in some was usually seen after All cases disease and all but two were with other was used as a in two cases with BP and with but no reported of other and to disease were seen in three of Two patients weeks and 2 years after the from and and a was with a series of of of evidence There are no or case series, and there is evidence as to these or induce BP. was used in the of a patient with BP and but in use of for was to have Two other reports with with Other of of evidence a that was used to and with BP but with no reported data for the A to of has been used to a patient with and in with in a patient with BP and disease Additional was in the and the patient with of after a year with is no longer drugs are and may be associated with further evidence is in BP an with Other small case series and anecdotal case reports have used different of with A with BP and inflammatory disease was with in with that of is a by which are from the the to the a case as an for with a of and have no in the of in cases of BP or when of drugs is necessary to and these may be used as BP is in childhood and It may the disease but there may be a for of the and in is well recognized in pemphigoid may be in weeks or to there are no childhood or The most commonly used is 1 to 2 in some Other with reported are as or with as well as and both as or with There are a small number of case reports for the use of and in two separate cases of disease in was in and in there is no evidence to any in childhood and and that should be to such as and of of evidence There are no studies on this and the recommendations are based on the of the should be if as this may are or in where are or with such as the of the blisters may be with a the but the blister roof in If there are of and open such as as a or or or may be used for a to the and or may be with a such as or in with It is important to that such of are included in with of BP is a disease and patients should be are in and all should be for and to that are controlled to of or or to the that are not disease is an should be to at this should be on clinical criteria by IF the of the autoimmune blistering in parts of the the evidence for is and questions that to be include the is the of oral or the be for disease of different The for oral has not been as to disease of should a or a in be have a evidence for but are used in different and it is not which is most the use of as an to other be used as a when to the skin including has but also as well as practical in be using to skin of disease the be are used and may be a for some The with is in and is to in If are of that to all drugs of this and are the both and there is some evidence to the use of and there is not conclusive evidence of a with any of these BP is a disease both clinically and it is not to in which may be to the with disease but it is to Other of patients for and to are addition to the with oral for other clinical the of associated with and are under or the five patients seen with is there of the relevant and important of and the five patients seen with BP in there was to with oral for the five patients seen with BP and is there evidence of the with the of the on of the five patients were with for was there a of as full and appropriate of evidence are in the BP is a disease, from the of and when it is disease is disease and patient including the to use must be taken There are or other evidence to There is some evidence to the discussed which are also in of of evidence is from case series using to skin from the of the authors with this and also by from studies of to disease using to the entire (see main of of evidence is from case series using to skin from the of the authors with this and also by from studies of to disease using to the entire (see main and have evidence of and the most used may be used as an to any other or used as a either to or all the skin as an to have a evidence for data in but are used and may be a for patients with of or and for There is some evidence to the use of and are to of and as well as the and Pemphigus Vulgaris of evidence with a of evidence should not be used as a for making a randomized controlled of randomized controlled National for Health and Clinical of and are of the guideline development with by This is an updated guideline prepared for the British Association of Dermatologists’ (BAD) Clinical Standards up of the Therapy & Guidelines of the Clinical Standards Unit National National Dermatological Nursing Clinical Standards Guidelines produced in 2002 by the British Association of reviewed and updated Appendix S1 search