British association of dermatologists guidelines for the management of bullous pemphigoid 2012

British Association of Dermatologists’ guidelines for themanagement of bullous pemphigoid 2012V.A. Venning,1 K. Taghipour,2 M.F. Mohd Mustapa,3 A.S. Highet4 and G. Kirtschig5 1Department of Dermatology, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, U.K.
2Department of Dermatology, Whittington Hospital, Magdala Avenue, London N19 5NF, U.K.
3British Association of Dermatologists, Willan House, 4 Fitzroy Square, London W1T 5HQ, U.K.
4York Hospital, Wigginton Road, York YO31 8HE, U.K.
5Vrije Universtiteit, PO Box 7057, Amsterdam NL-1007 MB, the Netherlands The overall objective of the guideline is to provide up-to-date,evidence-based recommendations for the management of bul- lous 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 clinicalquestions relating to the primary guideline objective; (iii) pro- viding guideline recommendations and, where appropriate, with some health economic implications discussing potentialdevelopments and future directions.
V.A.V., K.T., A.S.H. and G.K. are members of the guideline development group, The guideline is presented as a detailed review with high- with technical support provided by M.F.M.M.
lighted recommendations for practical use in the clinic (seesection 14.0), in addition to an updated patient information This is an updated guideline prepared for the British Association of Dermatologists’ leaflet [available on the British Association of Dermatologists’ (BAD) Clinical Standards Unit, made up of the Therapy & Guidelines (T&G) (BAD) website; http://www.bad.org.uk].
Subcommittee. Members of the Clinical Standards Unit are: J.R. Hughes (Chairman T&G), J. McLelland, A.J. McDonagh, S. Punjabi, D.A. Buckley, I. Nasr, V.J. Swale, C.E. Duarte Williams, P.M. McHenry, S. Wagle (British National Formulary), S.
Amin (British National Formulary), R. Davis (British Dermatological Nursing 2.0 Stakeholder involvement and peer review Group), S.E. Haveron (BAD Scientific Administrator), M.F. Mohd Mustapa (BAD The guideline development group consisted of consultant der- matologists. The draft document was circulated to the BAD Guidelines produced in 2002 by the British Association of Dermatologists; reviewed (BDNG), the Primary Care Dermatological Society (PCDS) andthe Pemphigus Vulgaris Network for comments, and was peer reviewed by the Clinical Standards Unit of the BAD (made upof the Therapy and Guidelines subcommittee) prior to publi- NHS Evidence has accredited the process used by the British Association of Dermatolo- gists to produce guidelines. Accreditation is valid for 3 years from May 2010 and isapplicable to guidance produced using the processes described in the British Associationof Dermatologists’ guidelines development manual (Bell & Ormerod, 2009). More in-formation on accreditation can be viewed at http://www.evidence.nhs.uk.
This set of guidelines has been developed using the BAD’s rec-ommended methodology1 and with reference to the Appraisalof Guidelines Research and Evaluation (AGREE II) instrument.2Recommendations were developed for implementation in theNational Health Service (NHS) using a process of consideredjudgment based on the evidence. PubMed, MEDLINE and EM-BASE databases were searched up to June 2012 for meta-analy-ses, randomized and nonrandomized controlled clinical trials,case series, case reports and open studies involving bullouspemphigoid, with no language exclusions; search terms and BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214 Guidelines for the management of bullous pemphigoid 2012, V.A. Venning et al. 1201 strategies are detailed in Appendix S1 online (see Supporting Europe.4–6 The mean age of onset is around 80 years. Recently it has been shown that BP is associated with neurological Additional relevant references were also isolated from cita- disease such as cerebrovascular disease, dementia, Parkinson tions in the reviewed literature, as well as (independent) tar- disease, epilepsy and multiple sclerosis.7–10 These conditions geted searches carried out by coauthors. Working in pairs, the pre-date BP and hence are considered as risk factors. There are authors screened the identified titles, and those relevant for first- a number of anecdotal case reports suggesting an association round inclusion were selected for further scrutiny. The abstracts between BP and some drugs.11–15 A recent small case series for the shortlisted references were then reviewed and the full reported BP occurring in five diabetic patients taking an oral papers of relevant material were obtained; disagreements in the hypoglycaemic agent, gliptin (dipeptidyl peptidase-IV inhibi- final selections were resolved by discussion with the entire de- tor), together with metformin.16 To date there are three epi- velopment group. Additional selection criteria included relevant demiological studies on the subject of BP and drugs.8,17,18 publications on the management of childhood BP.
Two French case–control studies, both by the same author, The structure of the 2002 guidelines was then discussed have described a significant relationship with the use of spir- and re-evaluated, and different coauthors were allocated sepa- onolactone and neuroleptics.8,17 A recent U.K. case–control rate subsections. Each coauthor then performed a detailed study found an association only with furosemide after adjust- appraisal of the selected literature with discussions with the ing for cardiovascular and neurological disease.18 The mecha- entire development group to resolve any issues, e.g. with the nism by which drugs may induce BP has not been quality of evidence and making the appropriate recommenda- studied. There is no conclusive evidence for an association tions. All subsections were subsequently collated and edited to with malignancy or other autoimmune diseases.
Tense blisters are often seen on erythematous or normal-looking This document has been prepared on behalf of the BAD and is skin of limbs and trunk and may be widespread or localized. Bul- based on the best data available when the document was pre- lae and ⁄or erosions may be present in the oral and genital pared. It is recognized that under certain conditions it may be mucosa. Pruritus alone or associated with erythema and ⁄or urti- necessary to deviate from the guidelines and that the results of cated plaques may precede formation of bullae by weeks or future studies may require some of the recommendations months; in some cases bullae may not become clinically apparent.
herein to be changed. Failure to adhere to these guidelinesshould not necessarily be considered negligent, nor should adherence to these recommendations constitute a defenceagainst a claim of negligence.
7.1 Laboratory diagnosis of bullous pemphigoid A skin biopsy from a fresh blister stained with haematoxylin and eosin shows subepidermal clefting and an inflammatory The proposed revision date for this set of recommendations is infiltrate mainly consisting of eosinophils; however, the diag- scheduled for 2017; where necessary, important interim nosis is confirmed with immunofluorescence studies (IF). A changes will be updated on the BAD website.
biopsy for direct IF (DIF) is taken from uninvolved skin about1 cm away from a fresh blister and is immediately snap-frozenin liquid nitrogen or transported in either Michel’s transport medium or normal (0Æ9%) saline. If using saline, the biopsymust be processed within 24–48 h;19 with Michel’s medium prompt handling is to be preferred, but a longer delay of up BP is an autoimmune subepidermal blistering disease that typi- to 2 weeks may still yield results.20 Indirect IF (IIF) is per- cally affects the elderly but may rarely present in children and formed on serum, and if this is not obtainable, on blister younger adults. Autoantibodies of IgG type (and less com- fluid. The characteristic DIF picture in BP is a linear deposition monly IgA, IgM and IgE) attack components of the adhesion of IgG and ⁄ or C3 along the BMZ. Other immunoglobulins, complex of the basement membrane zone (BMZ) and result in including IgA, IgM and IgE, may also be present. Substrates subepidermal blistering. The two main autoantigens are BP230 used for IIF include monkey oesophagus and normal human (BPAg1) and BP180 (BPAg2, collagen XVII).
skin; the latter can be split using molar saline. Antibodies inBP serum usually detect antigens at the roof of the salt-splitskin. In most cases this may help to differentiate BP from other immunobullous diseases such as epidermolysis bullosa BP is the most common immunobullous disease in Western acquisita (EBA) and some cases of mucous membrane Europe with a reported incidence of 43 per million per year pemphigoid (MMP), in both of which antibodies are deposit- in the U.K.3 and 7–13 per million per year in other parts of ed on the dermal aspect of the split skin.
BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214 1202 Guidelines for the management of bullous pemphigoid 2012, V.A. Venning et al.
Over recent years, enzyme-linked immunosorbent assay 1950s,25,26 and has become established as the mainstay of (ELISA) has emerged as an additional diagnostic technique for treatment. The effect in most cases is rapid, with suppression some autoimmune bullous diseases. Serum levels of antibodies of inflammation and blistering typically achieved within to both BP180 and BP230 can be measured with commercially 1–4 weeks, after which the dose is gradually reduced. The available ELISA kits, with the BP180 ELISA being more sensitive most commonly used drugs are prednisone and predniso- than the BP230 ELISA.21,22 The NC16A domain is an important lone which are assumed to be bioequivalent. Serious dose- pathogenic epitope of the BP180 antigen and is used in BP180 dependent metabolic and immunosuppressive adverse effects ELISA to detect antibody titres that reportedly correlate with dis- were recognized in these original studies and in the four ran- ease activity.21 In one study, false-positive ELISA results using the domized controlled trials (RCTs) involving systemic steroids same commercial kits were reported in 7Æ4% of sera with nega- in the treatment of BP listed in Table 1.27–30 tive IIF.23 The ELISA is currently not widely available in the U.K.
The effect of very high doses of systemic steroid was but is a useful additional diagnostic tool in selected cases and in assessed in eight patients with severe widespread BP, of whom research. IF studies remain the gold standard for diagnosis.
six had failed to respond to standard doses of systemic ste-roid.31 Seven of the eight had significant medical comorbidity.
Intravenous patients), or 15 mg kg)1 daily (six patients) for 3 days, was Autoimmune bullous diseases may overlap in morphology and immunopathology; however, factors such as age of onset, responded rapidly to the intravenous methylprednisolone, but course of the disease, absence of scarring and extent of mucosal in spite of the oral prednisone, blistering (albeit less severely involvement are important in differentiating the diagnosis. DIF than initially) recurred within 2 weeks. One patient died and salt-split IIF are useful in distinguishing BP from other sub- within 1 week of the intravenous methylprednisolone, and epidermal diseases, namely linear IgA disease, MMP and EBA.
three died between 1 and 4Æ5 months following the treatment.
Blisters occur in genetic bullous diseases, in particular the The causes of death were cardiac arrest, infection and conges- epidermolysis bullosa group and may also be caused by insect bites, burns, oedema, cellulitis, erythema multiforme and con- General conclusions from the studies are: tact dermatitis. Viral and bacterial skin infections should be 1 Systemic steroids are the best established treatment for BP; recognized and treated before treatment with immunosuppres- 2 Immunosuppressive and metabolic adverse effects occur and 3 Doses of prednisolone of 0Æ75–1Æ0 mg kg)1 daily in wide- spread BP are effective within 1–4 weeks in about 60–90% BP is usually a self-limiting disease with a clinical course that Clinical experience suggests that the more severe the dis- may last from months to years. During the active stage, the ease, the larger the dose of steroid is required (up to 1 mg disease is associated with significant morbidity and a mortality kg)1 daily), although this has not been rigorously proven. A twice that of the general elderly population.3 Older age at minority of patients with BP respond poorly to such doses of onset and frail general condition are poor prognostic factors.
systemic steroid; increasing the dose confers little additional Many available treatments are associated with toxicity and may benefit and is significantly more toxic.
be poorly tolerated in patients with BP. Mortality during the It is not possible to identify a starting dose of prednisolone first year is significantly higher in patients treated with high (or prednisone) that would be maximally effective and mini- doses of systemic corticosteroids (prednisolone equivalent mally toxic for all patients with BP. Doses which might meet >40 mg daily).24 Treatment should aim to control symptoms these criteria for a majority of patients are: with minimum adverse effects where possible. Options are 1 0Æ75–1 mg kg)1 for patients with severe involvement; broadly divided into anti-inflammatory drugs, immunosup- pressive or immunomodulating drugs, and procedures aiming 3 0Æ3 mg kg)1 for mild or localized disease.
to remove circulating pathogenic antibodies and inflammatory If new inflammatory or blistered lesions are few or absent mediators. The choice of treatment depends on the individual within 4 weeks, the treatment can be regarded as successful patient’s circumstances especially the severity of the BP and and the dose of steroid should then be gradually reduced. A reduction of the daily dose of prednisolone at fortnightly inter- For the definitions of the strength of recommendations and vals, initially by about one-third or one-quarter down to 15 mg daily, then by 2Æ5 mg decrements down to 10 mg daily,is suggested. The dose could then be reduced by 1 mg eachmonth. In about 50% of cases relapse will occur at some point 8.1 Systemic steroids (strength of recommendation A; during the dose-reduction period, indicating that the previous dose is likely to be the minimal effective dose for that patient.
Systemic corticosteroid therapy was demonstrated to be effec- For patients with widespread BP who do not respond to tive in BP in uncontrolled clinical studies during the these doses, or who relapse on unacceptably high doses, other BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214 Guidelines for the management of bullous pemphigoid 2012, V.A. Venning et al. 1203 BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214 1204 Guidelines for the management of bullous pemphigoid 2012, V.A. Venning et al.
agents, alone or in addition to the systemic steroid, may be also cutaneous side-effects, which included purpura, severe preferable to higher doses of steroid.
The duration of systemic steroid treatment in BP is likely to There was no significant difference between the two groups be many months and is sometimes indefinite. Gastric protec- in terms of year 1 mortality rate. In the standard regimen, tion, usually with a proton pump inhibitor, should be consid- mortality was 38% (58 ⁄ 153) [moderate disease 32% (21 ⁄ 65), ered. Measures aimed at minimizing loss of bone density are severe disease 42% (37 ⁄ 88)] and in the mild regimen it was also 38% (58 ⁄ 153) [moderate disease 28% (19 ⁄ 69), severe 50 years, and in any patient at increased risk of fragility frac- disease 46% (41 ⁄ 90)]. However, the report of the study gives ture, who are expected to take prednisolone 7Æ5 mg or more an adjusted analysis (Cox model adjusted for age and Karnof- daily for at least 3 months.32 Patients with BP (and also sky score), after which a beneficial effect of the mild regimen patients with pemphigus vulgaris) were reported to have was observed in participants with moderate BP, with an lower levels of vitamin D, and a higher incidence of severe almost twofold decrease in the risk of death or life-threatening hypovitaminosis D, than controls, suggesting additional risk of adverse events relative to the standard regimen (hazard ratio bone density loss.33 Calcium and vitamin D supplementation 0Æ54, 95% confidence interval 0Æ30–0Æ97; P = 0Æ039).
and a bisphosphonate are usually recommended and have A recent survey of 1135 dermatologists in the U.K. (326 been shown to be effective in preserving bone density, if responses, 28Æ7%) showed that 98% of respondents use topi- given from the start of systemic steroid therapy in patients cal steroids as sole treatment in localized BP and 34% in gen- with immunobullous diseases.34 Calcium may impair absorp- eralized BP. It is routinely used as an adjunct (92%), mostly tion of mycophenolate mofetil (MMF) and oral bisphospho- applied to the lesions only (86%). A total of 34% of respon- nates and should be taken at a different time.
dents use topical steroids until remission is achieved while66% continue to use it to deal with relapses. All quotedpercentages are based on valid responses.40 8.2 Topical corticosteroids (strength of recommendation Very potent topical steroids (clobetasol propionate) are an effective treatment for BP and they seem to have less serious Uncontrolled studies have suggested the successful use of topi- adverse effects compared with 1 mg kg)1 of prednisone per cal steroids as first-line treatment for both localized and mod- day.38 However, their use in extensive disease may be limited erate disease,35–37 and two recent RCTs with a total of 653 by practical factors (e.g. ability of patient or availability of participants confirmed this view.30,38,39 carer to apply the treatment) and they may be associated with Topical clobetasol propionate 0Æ05% cream (20 g) applied systemic absorption and adverse events. When feasible they all over twice daily, including clinically unaffected skin (total should be considered for first-line treatment, especially in daily dose 40 g), was compared with oral prednisone (1 mg kg)1 daily) in the treatment of BP.30 A significant ben-efit of the former was shown in extensive disease (more than 8.3 Azathioprine (strength of recommendation D; level of 10 new blisters a day) for disease control, adverse events and mortality. In the moderate-disease group (fewer than 10 newblisters a day) no significant differences were found between After systemic steroids, azathioprine is still a commonly used clobetasol propionate cream and prednisone 0Æ5 mg kg)1 daily drug in BP. It is mostly employed in doses of up to for disease control, adverse events and mortality. Morbidity 2Æ5 mg kg)1 daily as an adjunct to systemic steroids for its and mortality attributable to corticosteroid treatment were presumptive steroid-sparing effect. However, the efficacy of seen in all groups but were significantly higher in the predni- azathioprine as an adjunct to prednisolone in BP has been addressed in only two RCTs and with conflicting results. One In 2009 the same group compared clobetasol propionate small, nonblinded RCT reported a 45% reduction in cumula- cream 20 g twice a day (standard regimen) with 10–30 g per tive prednisolone dosage over a 3-year period.41 Conversely, a day depending on disease severity and body weight (mild reg- larger RCT lasting only 6 months found no difference in imen).38 Regression or healing of skin lesions at 3 weeks was remission rates in patients treated with steroids alone com- achieved by nearly all patients in both regimens. The median pared with those receiving combination treatment with pred- cumulative doses of steroid cream used during the study per- nisolone and azathioprine. In fact, more adverse effects were iod were 5760 g in the standard regimen vs. 1314 g in the reported in patients receiving azathioprine.29 mild regimen, which is a 70% reduction in cumulative doses.
A more recent nonblinded RCT with 73 patients compared There was no difference regarding the relapses between the azathioprine (2Æ0 g kg)1 daily) with MMF 1 g twice daily as mild and standard regimens, indicating no significant differ- adjuncts to methylprednisolone (0Æ5 mg kg)1 daily).42 Remis- sion was achieved in 100% of patients in both groups but this The main severe side-effects in both groups were diabetes trial included no steroid-only arm, so no conclusions can be mellitus (n = 34 standard, n = 18 mild), cardiovascular and drawn as to the superiority of adjunctive treatment over ste- neurovascular disorders (n = 35 standard, n = 21 mild), and roids alone. The azathioprine arm was slightly faster to severe infections (n = 32 standard, n = 27 mild). There were produce remission than MMF (median 28Æ6 days compared BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214 Guidelines for the management of bullous pemphigoid 2012, V.A. Venning et al. 1205 with 42 days). Both treatments were similarly effective at pre- participants available for long-term follow-up, all five in the venting relapses and had similar numbers of adverse events.
tetracycline group remained disease free (mean 17Æ5 weeks) Hepatotoxicity was documented in six out of 37 patients trea- while two of the three in the steroid group had repeated flares ted with azathioprine but more infections occurred with with tapered-off treatment (mean 21Æ3 weeks). The side-effect MMF.42,43 Although the treatments were equally effective, the profile was in favour of tetracycline and nicotinamide. There 5Æ5-fold higher cost of MMF (2 g daily) compared with aza- are several additional case reports and small series that thioprine (2 mg kg)1 daily for a 75-kg patient) could be an describe the beneficial effect of tetracyclines, usually in com- important consideration in some health economies.
bination with nicotinamide. It was helpful in the majority Azathioprine dose can be optimized with regard to myelo- within 1–3 weeks; however, some patients received topical or suppression risk by prior assay of thiopurine methyltransferase even systemic corticosteroids in addition.46–52 (TPMT) activity, a test that is now widely available in the There are only two case series involving 11 and 15 patients, U.K. and relatively inexpensive.44 However, a normal TPMT and many case reports, of the beneficial effect of erythromycin level does not totally preclude myelotoxicity and regular mon- in children and adults.53–55 Erythromycin should be consid- itoring of blood counts and liver function are essential.
ered for treatment, particularly in children (adult dose 1000– There is currently insufficient evidence of benefit to recom- 3000 mg daily), and perhaps in combination with topical cor- mend routine addition of azathioprine to systemic steroids for ticosteroids. A beneficial effect may be seen within 1–3 weeks the control of BP. In view of its side-effect profile, it is recom- mended that azathioprine only be considered as an adjunctive In conclusion, tetracyclines and nicotinamide may be consid- treatment to prednisolone where response has been inadequate ered as treatment in adults, perhaps in combination with topical and the disease is not suppressed, or where the side-effects of corticosteroids. However, apart from one case report of niacin- existing therapy are troublesome and unacceptable.
amide (nicotinamide) as monotherapy in localized BP, there is noevidence for its effectiveness as a sole treatment of BP.56 The opti-mum doses, both for the antibiotics and nicotinamide, are not 8.4 Anti-inflammatory antibiotics and nicotinamide established. Nicotinamide is used between 500 and 2500 mg (strength of recommendation D; level of evidence 4) daily, usually started at 500 mg daily and then gradually Since the development of the last guideline in 2002 there have increased to 1500–2500 mg daily to minimize gastric side- been no additional relevant publications regarding the treatment effects. Tetracycline has been used at doses of 500–2000 mg of BP with antibiotics. However, antibiotics with anti-inflamma- daily, doxycycline at 200–300 mg daily and minocycline at 100– tory effects are used widely in the treatment of BP. A German 200 mg daily. Tetracycline should be avoided in renal impair- survey reported that about 10% of the dermatologists use a ment as should doxycycline and minocycline in patients with combination of antibiotics and nicotinamide as a first-line treat- hepatic impairment. Minocycline has a worse side-effect profile ment for BP;45 a survey in the U.K. showed that 80% of respon- and is therefore not the first choice of antibiotic. A few cases of dents use antibiotics as part of their management of BP.40 minocycline-associated pneumonia and eosinophilia have been Mostly doxycycline is used in the U.K. (40%), followed by described, necessitating immediate withdrawal. Lymecycline has minocycline (31%) and lymecycline (19%). A total of 63% of a beneficial side-effect profile and has been successfully used by respondents thought that antibiotics are sometimes effective, some dermatologists (408 mg twice daily) in the U.K. without while 28% thought that they are never effective (all quoted per- published evidence. When blister formation is suppressed suffi- centages for the U.K. survey are based on valid responses).40 ciently the antibiotics and nicotinamide must be reduced slowly, The most reported side-effect was gastrointestinal upset, fol- one at a time, over several months to avoid relapse.
lowed by pigmentation and Candida infection; hypersensitivitysyndrome with hypereosinophilia was only mentioned in two 8.5 Methotrexate (strength of recommendation D; level responses. An RCT is under way, comparing doxycycline (200 mg daily) with prednisolone (0Æ5 mg kg)1 daily) for theinitial treatment of BP; the results are expected in 2013 (http:// There are no controlled trials involving methotrexate (MTX) for the treatment of BP. Two small prospective case series of There are one small RCT,46 small uncontrolled trials and 11 and 16 patients both reported that relatively low doses of case reports on antibiotics and nicotinamide (niacinamide).
MTX (max. 15 mg weekly) can be effective at controlling BP, The small RCT compared six patients who received prednisone either as a monotherapy57 or in combination with topical ste- (40–80 mg daily) with 14 patients who received tetracycline roids.58 This was confirmed by a recent retrospective multi- 2 g per day and nicotinamide 1500 mg daily. After 8 weeks centre case series of 70 patients treated with MTX alone, or in of treatment there were one complete and five partial respond- ers in the steroid group, compared with five complete The largest retrospective analysis60 compared 138 consecutive responders, five partial responders, one nonresponder and one patients: 61 patients received MTX plus concomitant topical ste- disease progression in the tetracycline group. Two participants roids (2Æ5–17Æ5 mg per week, median dose 5 mg per week); 37 in the tetracycline group were unavailable for follow-up at patients received MTX and prednisolone plus concomitant topi- 8 weeks; the results were not statistically significant. Of the cal steroids until cessation of new blisters; 15 patients received BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214 1206 Guidelines for the management of bullous pemphigoid 2012, V.A. Venning et al.
prednisolone only (6–40 mg daily, median dose 12 mg daily) management of BP. Four retrospective series covering a total owing to pre-existing contraindications or adverse effects with of 110 patients have reported experience with dapsone MTX, or because of physician or patient preference; 25 patients 50–200 mg daily or (rare cases) with either sulfapyridine or were treated with topical betamethasone gel only.
sulfamethoxypyridazine 1–1Æ5 g daily. These were employed The 2-year remission was 43% for MTX, 35% for MTX and either as sole treatments or in combination with topical ste- prednisolone, 0% for prednisolone and 83% for the topical ste- roids. The response rate was around 45% in three series,64–66 roid group. Remission occurred after a median treatment time but only 15% (six of 41) in the fourth.67 Response seems to of 11 (MTX), 20 (MTX and prednisolone) and 2 months (topi- be slower in onset than with systemic steroids. A single, small, cal steroid). The median cumulative MTX dose to achieve remis- uncontrolled series reported a possible steroid-sparing effect in sion was 210 mg (range 20–1350 mg). Being retrospective, the patients in whom dapsone was added to existing treatment cases were unmatched for disease severity and there appears to with prednisolone and azathioprine.68 Another series of 62 be a higher proportion of mild cases in the patients receiving patients reported a complete remission rate of 32% at 2 weeks MTX as monotherapy. MTX was discontinued in five patients in patients treated with dapsone 0Æ5–1Æ0 mg kg)1 daily in because of adverse effects (gastrointestinal symptoms, anaemia, combination with systemic methylprednisolone 0Æ5 mg kg)1 liver dysfunction and alveolitis). Increasing age was significantly daily and topical steroids. The series was retrospective with no associated with decreasing survival, but there was no significant comparator arm so no conclusion was possible as to whether difference between the various treatments and survival rates.60 The most important toxicities of MTX are myelosuppres- There are individual case reports of dapsone (either alone sion, hepatotoxicity and pneumonitis. MTX is excreted renally, or with oral steroids) used successfully in childhood BP.70,71 which should be considered in the elderly and may explain Glucose-6-phosphate dehydrogenase deficiency predisposes the low doses required for disease control.61 Many investiga- to haematological side-effects and should be excluded in pre- tors recommend folic acid 5 mg on the non-MTX days to disposed races (e.g. those of African, Middle Eastern and South reduce some adverse effects, but this is not proven.
Asian origin), and all patients receiving dapsone need very fre- Evidence from these case series suggests that MTX can be quent monitoring of blood count and liver function in the effective at controlling BP, either as a monotherapy or in com- early months. The side-effect profile of dapsone and sulfona- bination with topical or systemic steroids.
mides is potentially hazardous in the elderly. In this agegroup, these treatments should be considered only if othertreatments are ineffective or contraindicated, and treatment 8.6 Mycophenolate mofetil (level of evidence 1-) started at low doses (50 mg daily) to be increased by 50 mg MMF is an inhibitor of purine synthesis in activated T and B daily in 2-weekly steps to a maximum of 150–200 mg daily.
cells and is a generally well-tolerated immunosuppressiveagent used in the prevention of renal graft rejection since 8.8 Intravenous immunoglobulins (strength of 1997. It has been reported as effective in controlling BP in doses of 0Æ5–1 g twice daily in a small number of individualcase reports, both as an adjunct to systemic prednisolone62 Intravenous immunoglobulin (IVIg) has been widely tried as and as a monotherapy following disease relapse.63 an immunomodulatory agent in various autoantibody-medi- In a nonblinded RCT including 73 patients, MMF (1 g ated blistering diseases. Excluding cases of MMP, experience in twice daily) was compared with azathioprine (2 g kg)1 daily) BP is confined to a total of fewer than 41 patients in small as an adjunct to methylprednisolone (0Æ5 mg kg)1 daily).42 retrospective series and case reports.72–77 When used as a sole This trial did not include a steroid-only arm so no conclusions treatment, some patients achieved rapid and dramatic, albeit can be drawn as to the superiority of either adjunctive treat- short-lived responses, with relapse occurring within 2 weeks, ment over corticosteroids as a monotherapy. There was no necessitating either further infusion or treatment with corti- difference between the two treatments, although MMF was costeroids or azathioprine.72,73,77 IVIg has been more com- slightly slower to produce remission than azathioprine (med- monly used concomitantly with oral prednisolone and other ian 42 days compared with 28Æ6 days). Both treatments were agents.75,77 A retrospective case series reported on 15 patients associated with similar numbers of adverse events, with MMF with severe, unstable steroid-dependent pemphigoid or in being associated with more infections but less hepatotoxicity whom there were significant treatment side-effects, and other than azathioprine.42,43 As discussed in section 8.3, MMF is immunosuppressants or immunomodulatory agents had failed.
considerably more costly than azathioprine. Further evidence Treatment was with polyvalent immunoglobulin 2 g kg)1 is needed for the role of MMF in BP.
administered in equally divided doses over 3 days and over-lapping with preceding treatments. Treatment cycles wererepeated initially every 4 weeks until remission, and thereafter 8.7 Dapsone and sulfonamides (strength of with intervals between cycles gradually increasing. The IVIg permitted gradual withdrawal of prednisolone There are no RCTs with respect to the use of either dapsone 5 months in all 15 patients. The report does not make clear or sulfonamides, either as sole treatments or as adjuncts in the BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214 Guidelines for the management of bullous pemphigoid 2012, V.A. Venning et al. 1207 withdrawn. Remission was maintained over a further 17– In the only case series detailing the effects of cyclophos- 26Æ5 months with a mean of 14Æ9 further cycles of IVIg.77 phamide in BP, 10 patients were treated with systemic ste- IVIg is well tolerated but expensive, costing £5320Æ00 per roid in doses of 1–1Æ9 mg kg)1 daily prednisone equivalent cycle of 2 g kg)1 in a 70-kg patient.78 U.K. guidance on its and with cyclophosphamide 100 mg daily.85 Three patients, use is available from the Department of Health (http:// who had medical comorbidities, died; four others suffered www.dh.gov.uk).79 IVIg should only be considered as an significant adverse effects involving marrow toxicity and sep- adjunctive treatment in patients with very severe disease where ticaemia. Comparing their results with published studies, the rapid control is needed, or when there is failure with or con- authors did not perceive a steroid-sparing effect with the cyclophosphamide, but they had no control cases on steroidalone.
Cyclophosphamide is more toxic than other immunosup- 8.9 Chlorambucil (strength of recommendation D; level pressive drugs used for BP. It may rarely be considered for In an open study, 23 patients with BP completed treatment withinitial doses of prednisolone of 40–60 mg daily and chlorambu- cil approximately 0Æ1 mg kg)1 daily. After 2 weeks, the dosesof both drugs were gradually reduced.80 All patients responded Reported experience of the use of ciclosporin in BP is limited and none required treatment for more than 12 months. The to two reports from the same centre with overlapping cases, maintenance dose of chlorambucil after 6 weeks was 2 mg per comprising a total of seven patients treated with high doses of day in most cases. The mean total steroid requirement was 6–8 mg kg)1 daily.86 Good responses were seen in two out of 1866 mg, about 50% of that previously reported for prednisone four cases treated with ciclosporin alone. Three patients who and azathioprine (3688 mg over 3 years).41 had relapsed on prednisone responded to the addition of The risk of haematological toxicity, especially thrombocyto- ciclosporin, and two of these relapsed after the ciclosporin penia, was emphasized, and blood counts were initially moni- was discontinued. Elevation of serum creatinine occurred in tored weekly. One patient discontinued chlorambucil due to most of the patients (details not given) but was reported to be marrow suppression, which recovered after discontinuation.
Haematological malignancy has been attributed to chlorambu- Ciclosporin cannot be recommended in the routine treat- cil and the authors suggest that a cumulative dose of 1 g, or ment of BP. It may rarely have a place in refractory cases but treatment duration of 1 year, should not be exceeded.
its value is likely to be limited by renal toxicity, especially in In a second study from the same centre, a retrospective comparison was made between patients with BP treated withprednisolone alone (26 patients), and those treated with pred- nisolone and chlorambucil (19 patients).81 The dose of pred-nisolone was 20–60 mg daily based on disease severity and 8.12.1 Topical tacrolimus (strength of recommendation D; patient size, reduced according to response. Chlorambucil was started at about 0Æ1 mg kg)1 daily (0Æ05 mg kg)1 daily in‘very Individual case reports have described a response to topical treatment with the calcineurin inhibitor, tacrolimus. It has 0Æ05 mg kg)1 daily, and after a further 4 weeks to 2 mg daily.
mainly been used for localized and limited generalized dis- The mean cumulative dose of prednisolone (2685 vs.
ease. Chu et al.87 reported two cases of generalized disease 4074 mg), and the mean duration of therapy (215 vs.
treated with multiple systemic agents including oral steroids 392 days), were both statistically significantly lower in the but not topical steroids. Application of tacrolimus ointment chlorambucil group. Apart from an asymptomatic reduction in 0Æ1%, 3–5 g daily, allowed reduction of oral steroids and platelet count below the normal range in one patient, no improvement was seen within 2 weeks, although follow-up adverse effects were attributed to chlorambucil.
data were not reported. In a case of mild vesicular pemphig- Chlorambucil as an adjunct to systemic steroids should be oid, reduction of oral steroids and use of potent topical ste- considered as an alternative to other more established immu- roids led to new vesicles; these ceased with the substitution nosuppressants if these have failed or are poorly tolerated or of topical steroids with tacrolimus ointment 0Æ1% (twice contraindicated. Careful monitoring is required for possible daily for 2 weeks), allowing withdrawal of the oral ste- roids.88 In other reports, topical tacrolimus has been used asthe sole agent for localized disease and also in vulval pem-phigoid in a child.89–91 The use of topical tacrolimus is lim- ited by local irritation and its price compared with topical Three cases have been reported in which cyclophosphamide steroids. It may be useful as an alternative in localized and appeared to have a beneficial effect in otherwise refractory limited disease without the disadvantage of causing skin BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214 1208 Guidelines for the management of bullous pemphigoid 2012, V.A. Venning et al.
disease was treated with plasma exchange in combination withextracorporeal photochemotherapy that allowed reduction of Only a few reported cases of BP have been treated with tumour necrosis factor-a antagonists and the anti-CD20 agent, Immunoapheresis is a procedure by which immunoglobu- rituximab. The outcome is variable and success is limited by lins are removed from the circulation without the need to replace the plasma. Only a few case reports108–110 describe Rituximab (strength of recommendation D; level of evidence 3) This chime- immunoapheresis as an adjuvant treatment for BP, allowing ric murine–human monoclonal antibody targets CD20, the B cell- remission with a reduced dose of systemic steroids.
specific cell surface antigen, following which B cells may be Plasmapheresis and immunoapheresis have no role in the depleted from the circulation for 6–12 months. Only a few routine treatment of BP, although in cases of refractory BP or reported patients including two children with BP have been trea- when reduction of immunosuppressive drugs is necessary due ted with rituximab.92–98 The dosing regimen in most cases was a to intolerance and adverse effects, these modalities may be weekly infusion (375 mg m)2) for 4 weeks, followed by repeat infusion in some cases; improvement was usually seen after4 weeks. All treated cases had refractory disease and all but twowere treated concomitantly with other immunosuppressants. Rit- uximab was used as a monotherapy in two cases with concomi- BP is rare in childhood and infancy. It may mimic the adult dis- tant BP and chronic lymphocytic leukaemia with good initial ease but there may be a greater predilection for involvement of outcome but no reported follow-up data.94 In general, rituximab the palms and soles in infants; localized vulval involvement is allowed gradual withdrawal of other immunosuppressants and led well recognized in later childhood. Childhood pemphigoid may to disease remission, although serious adverse events were seen in be short-lived, remitting in weeks or months.111,112 Owing to three of eight cases. Two patients died 6 weeks and 2 years after its rarity, there are no trials covering childhood or infantile cases.
the treatment from nosocomial pneumonia and bacterial sepsis, The most commonly used treatment is prednisolone 1 mg kg)1 respectively, and a 2-year-old boy was left with persistent hypo- daily, increasing to 2 mg kg)1 daily in some cases.112 Other gammaglobulinaemia following a series of infections.92,95 treatments with reported benefit are potent topical steroids Antitumour necrosis factor-a agents (strength of recommendation D; level alone, erythromycin as monotherapy or with nicotinamide, as of evidence 3) There are no trials or large case series, and there well as sulfapyridine and dapsone, both as sole treatment, or is conflicting evidence as to whether these agents treat or with prednisolone.70,71,112,113 There are a small number of case induce BP. Etanercept was used successfully in the treatment reports for the use of IVIg,114,115 MMF,116 and in two separate of a patient with BP and psoriasis,99 but in another case, long- cases of severe recalcitrant disease in infancy, rituximab was term use of etanercept for rheumatoid arthritis was thought to effective in one93 and subcutaneous omalizumab in another.103 have induced BP.15 Two other reports describe adalimumab- Although there is no evidence to support any particular induced BP, one with features overlapping with MMP.100,101 treatment strategy in childhood and infantile BP, its generally Other biologic agents (strength of recommendation D; level of evidence 3) short-lived and benign nature suggests that preference should Omalizumab, a humanized monoclonal antibody that inhibits be given to low-toxicity treatments such as erythromycin and IgE binding, was used successfully to treat one infant and one topical steroids (strength of recommendation D; level of evidence 3).
adult with refractory BP but with no reported follow-up datafor the adult case.102,103 A monoclonal antibody to interleu-kin-2 receptor of T cells (daclizumab, anti-CD25) has been used to treat a patient with BP, and in combination with There are no studies on this topic and the following recom- rituximab in a patient with BP and concomitant graft-versus- mendations are based on the personal experience of the host disease (GVHD).95,104 Additional immunosuppressive authors. Blisters should generally be left intact if possible treatment was needed in the first patient, and the patient with as this may help prevent secondary bacterial infection. When GVHD, although cleared of blisters, died after a year with they are particularly large or in sites where they are trouble- sepsis. Daclizumab is no longer produced.
some or interfere with function, such as the sole of the foot, Biological drugs are expensive and may be associated with blisters may be pierced with a sterile needle releasing the potentially serious adverse effects; until further supportive evi- fluid, but leaving the blister roof in place. If there are exten- dence is available, their role in BP remains limited.
sive areas of erosion and open raw areas, antiseptics such aspotassium permanganate as a bath or soaks, or antiseptic-con- 8.12.3 Plasmapheresis and immunoapheresis (strength of taining bath oils [e.g. Dermol 600Ò (Dermal Laboratories, One RCT27 showed an apparent steroid-sparing effect with High Wycombe, U.K.)] may be used for a few days to dry plasmapheresis (plasma exchange) whereas another RCT did the lesions and prevent infection. Painful eroded or raw areas not.29 Other small case series and anecdotal case reports have may be covered with a low-adhesion dressing such as Mepi- telÒ (Mo¨lnlycke, Dunstable, U.K.) or AtraumanÒ (Hartmann, outcomes.105–107 A child with BP and inflammatory bowel Heywood, U.K.) held in place with soft elasticated viscose BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214 Guidelines for the management of bullous pemphigoid 2012, V.A. Venning et al. 1209 stockinette [e.g. ComfifastÒ (Synergy, Swindon, U.K.), Tubi- BLISTER trial, comparing prednisolone 0Æ5 mg kg)1 daily with fastÒ (Mo¨lnlycke)]. It is important to ensure that such areas of doxycycline 200 mg daily, is currently in progress and is erosion are included in treatment with topical steroids (clobe- expected to report in 2013 (http://www.ukdctn.org/ongo- tasol propionate) [Strength of recommendation D (good practice point)].
ing/blister/). If tetracyclines are of benefit, does that applyequally to all drugs of this class, and what are the optimaldose(s) considering both efficacy and adverse effects? BP is frequently a chronic disease and ideally patients should 12.4 Azathioprine, methotrexate, dapsone and be followed until they are in complete remission and off all treatment. Patients should be monitored for drug side-effectsand to ensure that symptoms are controlled to their satisfac- Although there is some evidence to support the use of azathi- tion without excessive doses of topical or systemic treatment.
oprine, MTX, dapsone and chlorambucil, there is not yet con- Occasional itching or lesions (if acceptable to the patient) in- clusive evidence of a steroid-sparing effect with any of these dicates that they are not being overtreated. Once their disease is stable, an attempt should be made to wean treatment atroughly 2–4 weekly intervals; this should be done on clinical BP is a heterogeneous disease both clinically and immunopa-thologically. However, it is not possible to define reliably sub- groups in which more aggressive treatment may be justified.
Despite being the commonest of the autoimmune blistering dis- ELISA titres to the immunodominant NC16A epitope correlate eases in many parts of the world, the evidence base for optimum with disease activity but it is unknown whether titres predict treatment is relatively incomplete and patchy. Important ques- response to treatments. Other means of stratifying patients for tions that remain to be addressed include the following.
prognosis and responsiveness to specific treatment are needed.
1 What is the optimum starting dose of oral prednisolone, In addition to the current RCT comparing doxycycline with oral prednisolone for BP, several other clinical trials investigat- 2 How might the starting dose be stratified for disease of dif- ing the effect of rituximab, leflunomide associated with topical corticosteroids, and NPB-01 (IVIg) are under way or being 3 The ideal protocol for weaning oral steroids has not been clarified so as to minimize cumulative dosage while main-taining disease control.
4 At what level of steroid requirements should a second drug 1 In the last five consecutive patients seen with BP, is there clear documentation of the relevant and important comor-bidities of diabetes and hypertension? 2 In the last five consecutive patients seen with BP in whom 1 Topical steroids have a good evidence base for efficacy but there was intention to treat with oral corticosteroid, did are used in many different ways and it is not known which they receive provision for bone protection? method is most effective. Is the optimum use of topical ste- 3 In the last five consecutive patients seen with BP and trea- roids as an adjunct to other treatments? Should they be used ted, is there evidence of the patients’ satisfaction with the outcome of the treatment on control of their symptoms? 2 Clobetasol propionate 20 g twice daily when applied to the 4 In the last five consecutive patients who were treated with whole skin surface, including unaffected skin, undoubtedly systemic medication for BP, was there a clear documenta- has efficacy but also toxicity, as well as practical difficulties tion of pretreatment tests (such as full blood count, liver in application. Would similar benefits be obtained using function tests, glucose, renal function, blood pressure) and topical steroids applied to lesional skin only? 3 For what severity of disease might the above approach be Details of evidence are given in the text. BP is a serious disease, causing considerable distress from the symptoms of Anti-inflammatory antibiotics are widely used and may be a itching and blistering; when severe it is potentially life-threat- safer treatment than systemic steroids for some patients. The ening. Good disease control is therefore essential. Both disease BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214 1210 Guidelines for the management of bullous pemphigoid 2012, V.A. Venning et al.
Very potent topical steroids alone (applied to lesional skin) Systemic corticosteroids 0Æ3 mg kg)1 daily (weaning dose once control achieved) ± very potent topical steroids appliedto lesional skin (strength of recommendation A) Anti-inflammatory antibiotics ± very potent topical Doxycycline 200 mg ⁄ dayOxytetracycline 1 g ⁄ dayLymecycline 408 mg twice dailyMinocycline 100 mg ⁄ dayErythromycin 1–2 g ⁄ day(strength of recommendation D) Systemic corticosteroids 0Æ5–1Æ0 mg kg)1 daily (weaning dose once control achieved) ± very potent topical steroids(strength of recommendation A) Very potent topical steroids 5–15 g twice daily to whole skin surface (if patient or carer is capable) (strength of recommendation A) Anti-inflammatory antibiotics ± very potent topical steroids applied to lesional skin (as above)(strength of recommendation D) For disease of any severity not responding Consider switching to or the addition of: Systemic corticosteroids 0Æ5–1Æ0 mg kg)1 daily unacceptably high doses of existing treatment (weaning dose once control achieved) ± very potenttopical steroids (strength of recommendation A) Anti-inflammatory antibiotics (as above) with or without nicotinamide 500–2500 mg daily (strength of recommendation D) Azathioprine 1–2Æ5 mg kg)1 daily (strength of recommendation D)Methotrexate 5–15 mg weekly (strength of recommendation D)Dapsone 50–200 mg daily (strength of recommendation D)Chlorambucil 0Æ05–0Æ1 mg kg)1 daily (strength of recommendation D) For cases refractory to all the above, other Mycophenolate mofetil 0Æ5–1 g twice daily modalities to be considered in exceptional CyclophosphamidePlasmapheresis(also see main text) IVIg, intravenous immunoglobulin. aThis level of evidence is derived from case series using clobetasol propionate applied to lesional skinonly, from the experience of the authors with this practice and also by extrapolation from studies of moderate to severe disease using clobe-tasol propionate to the entire body surface (see main text).
severity and patient comorbidities, including the ability to use topical treatments effectively, must be taken into consider- We are very grateful to Prof. Hywel Williams (BLISTER trial; ation. There are few rigorous RCTs or other high-quality evi- Queen’s Medical Centre, Nottingham), Miss Lesley Exton dence to inform treatment choice. There is some evidence to (BAD Information Scientist), Miss Sara Haveron (BAD Scien- support the treatments discussed below, which are also sum- tific Administrator), Dr Catherine Smith (St John’s Institute of Dermatology, London) and Dr Simon Meggitt (Royal Victoria Both systemic and topical steroids have good evidence of Infirmary, Newcastle), as well as the BDNG, PCDS and Pem- efficacy and remain the most widely used first-line treatments.
Topical steroids may be used as an adjunct to any other treat-ment or used as a monotherapy, either locally applied tolesions (for localized disease) or all over the skin (if feasible) as an alternative to systemic steroids. Anti-inflammatory anti- 1 Bell HK, Ormerod AD. Writing a British Association of Dermatol- biotics have a smaller evidence base for efficacy (trial data ogists clinical guideline: an update on the process and guidance expected in 2013) but are widely used and may be a safer for authors. Br J Dermatol 2009; 160:725–8.
treatment for patients with comorbidities of diabetes or hyper- 2 Brouwers M, Kho ME, Browman GP et al. AGREE II: advancing tension, and for children. There is some evidence to support guideline development, reporting and evaluation in healthcare.
the use of azathioprine, MTX, dapsone and chlorambucil.
Can Med Assoc J 2010; 182:E839–42.
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103 Dufour C, Souillet AL, Chaneliere C et al. Successful management Appendix S1 Literature search strategies.
of severe infant bullous pemphigoid with omalizumab. Br J Derma- Please note: Wiley-Blackwell are not responsible for the 104 Mockenhaupt M, Grosber M, Norganer J. Daclizumab: a novel content or functionality of any supporting materials supplied therapeutic option in severe bullous pemphigoid. Acta Derm Venereol by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.
BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214 1214 Guidelines for the management of bullous pemphigoid 2012, V.A. Venning et al.
At least one meta-analysis, systematic review, or RCT rated as 1 + +, and directly applicable to the target High-quality meta-analyses, systematic reviews A systematic review of RCTs or a body of evidence of RCTs, or RCTs with a very low risk of bias consisting principally of studies rated as 1 + , directly applicable to the target population and reviews of RCTs, or RCTs with a low risk of bias demonstrating overall consistency of results Meta-analyses, systematic reviews of RCTs, Evidence drawn from a NICE technology appraisal A body of evidence including studies rated as 2 + +, High-quality systematic reviews of case–control directly applicable to the target population and demonstrating overall consistency of results, or High-quality case–control or cohort studies Extrapolated evidence from studies rated as 1 + + or 1+ with a very low risk of confounding, bias or A body of evidence including studies rated as 2 + , directly applicable to the target population and demonstrating overall consistency of results, or Extrapolated evidence from studies rated as 2 + + bias or chance and a moderate probability Extrapolated evidence from studies rated as 2 + , or Case–control or cohort studies with a high D (GPP)A good practice point (GPP) is a recommendation for risk of confounding, bias or chance and a best practice based on the experience of the guideline RCT, randomized controlled trial; NICE, National Institute for Health aStudies with a level of evidence ‘–’ should not be used as a basis formaking a recommendation. RCT, randomized controlled trial.
BJD Ó 2012 British Association of Dermatologists 2012 167, pp1200–1214

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