Abstract

Background

Bullous pemphigoid (BP) is the most common autoimmune blistering disease. Oral steroids are the standard treatment. We have updated this review, which was first published in 2002, because several new treatments have since been tried.

Objectives

To assess the effects of treatments for bullous pemphigoid.

Search methods

We updated searches of the following databases to November 2021: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched five trial databases to January 2022, and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs).

Selection criteria

RCTs of treatments for immunofluorescence‐confirmed bullous pemphigoid.

Data collection and analysis

At least two review authors, working independently, evaluated the studies against the review's inclusion criteria and extracted data from included studies. Using GRADE methodology, we assessed the certainty of the evidence for each outcome in each comparison. Our primary outcomes were healing of skin lesions and mortality.

Main results

We identified 14 RCTs (1442 participants). The main treatment modalities assessed were oral steroids, topical steroids, and the oral anti‐inflammatory antibiotic doxycycline. Most studies reported mortality but adverse events and quality of life were not well reported. We decided to look at the primary outcomes 'disease control' and 'mortality'.

Almost all studies investigated different comparisons; two studies were placebo‐controlled. The results are therefore based on a single study for each comparison except azathioprine. Most studies involved only small numbers of participants. We assessed the risk of bias for all key outcomes as having 'some concerns' or high risk, due to missing data, inappropriate analysis, or insufficient information.

Clobetasol propionate cream versus oral prednisone

Compared to oral prednisone, clobetasol propionate cream applied over the whole body probably increases skin healing at day 21 (risk ratio (RR 1.08, 95% confidence interval (CI) 1.03 to 1.13; 1 study, 341 participants; moderate‐certainty evidence). Skin healing at 21 days was seen in 99.8% of participants assigned to clobetasol and 92.4% of participants assigned to prednisone. Clobetasol propionate cream applied over the whole body compared to oral prednisone may reduce mortality at one year (RR 0.73, 95% CI 0.53 to 1.01; 1 study, 341 participants; low‐certainty evidence). Death occurred in 26.5% (45/170) of participants assigned to clobetasol and 36.3% (62/171) of participants assigned to oral prednisone. This study did not measure quality of life. Clobetasol propionate cream may reduce risk of severe complications by day 21 compared with oral prednisone (RR 0.65, 95% CI 0.50 to 0.86; 1 study, 341 participants; low‐certainty evidence).

Mild clobetasol propionate cream regimen (10 to 30 g/day) versus standard clobetasol propionate cream regimen (40 g/day)

A mild regimen of topical clobetasol propionate applied over the whole body compared to the standard regimen probably does not change skin healing at day 21 (RR 1.00, 95% CI 0.97 to 1.03; 1 study, 312 participants; moderate‐certainty evidence). Both groups showed complete healing of lesions at day 21 in 98% participants. A mild regimen of topical clobetasol propionate applied over the whole body compared to the standard regimen may not change mortality at one year (RR 1.00, 95% CI 0.75 to 1.32; 1 study, 312 participants; low‐certainty evidence), which occurred in 118/312 (37.9%) participants. This study did not measure quality of life. A mild regimen of topical clobetasol propionate applied over the whole body compared to the standard regimen may not change adverse events at one year (RR 0.94, 95% CI 0.78 to 1.14; 1 study, 309 participants; low‐certainty evidence).

Doxycycline versus prednisolone

Compared to prednisolone (0.5 mg/kg/day), doxycycline (200 mg/day) induces less skin healing at six weeks (RR 0.81, 95% CI 0.72 to 0.92; 1 study, 213 participants; high‐certainty evidence). Complete skin healing was reported in 73.8% of participants assigned to doxycycline and 91.1% assigned to prednisolone. Doxycycline compared to prednisolone probably decreases mortality at one year (RR 0.25, 95% CI 0.07 to 0.89; number needed to treat for an additional beneficial outcome (NNTB) = 14; 1 study, 234 participants; moderate‐certainty evidence). Mortality occurred in 2.4% (3/132) of participants with doxycycline and 9.7% (11/121) with prednisolone. Compared to prednisolone, doxycycline improved quality of life at one year (mean difference 1.8 points lower, which is more favourable on the Dermatology Life Quality Index, 95% CI 1.02 to 2.58 lower; 1 study, 234 participants; high‐certainty evidence). Doxycycline compared to prednisolone probably reduces severe or life‐threatening treatment‐related adverse events at one year (RR 0.59, 95% CI 0.35 to 0.99; 1 study, 234 participants; moderate‐certainty evidence).

Prednisone plus azathioprine versus prednisone

It is unclear whether azathioprine plus prednisone compared to prednisone alone affects skin healing or mortality because there was only very low‐certainty evidence from two trials (98 participants). These studies did not measure quality of life. Adverse events were reported in a total of 20/48 (42%) participants assigned to azathioprine plus prednisone and 15/44 (34%) participants assigned to prednisone.

Nicotinamide plus tetracycline versus prednisone

It is unclear whether nicotinamide plus tetracycline compared to prednisone affects skin healing or mortality because there was only very low‐certainty evidence from one trial (18 participants). This study did not measure quality of life. Fewer adverse events were reported in the nicotinamide group.

Methylprednisolone plus azathioprine versus methylprednisolone plus dapsone

It is unclear whether azathioprine plus methylprednisolone compared to dapsone plus methylprednisolone affects skin healing or mortality because there was only very low‐certainty evidence from one trial (54 participants). This study did not measure quality of life. A total of 18 adverse events were reported in the azathioprine group and 13 in the dapsone group.

Authors' conclusions

Clobetasol propionate cream applied over the whole body is probably similarly effective as, and may cause less mortality than, oral prednisone for treating bullous pemphigoid. Lower‐dose clobetasol propionate cream applied over the whole body is probably similarly effective as standard‐dose clobetasol propionate cream and has similar mortality. Doxycycline is less effective but causes less mortality than prednisolone for treating bullous pemphigoid. Other treatments need further investigation.

Author(s)

Sanjay Singh, Gudula Kirtschig, Vinayak N Anchan, Ching-Chi Chi, Kathy Taghipour, Robert J Boyle, Dedee F Murrell

Abstract

Plain language summary

Treatments for bullous pemphigoid

Which treatments work best for bullous pemphigoid (a rare, itchy skin disease that causes blisters)?

Key messages

• A cream, containing topical steroid clobetasol propionate, applied on the entire skin surface is as effective as oral steroids (prednisone), causes less severe unwanted or harmful effects, and may decrease deaths.

• Initiating treatment with doxycycline (200 mg/day), an antibiotic with anti‐inflammatory effect, leads to an acceptable short‐term blister control compared to the oral steroid prednisolone (0.5 mg/kg/day), and is superior in long‐term safety aspects, including deaths.

What is bullous pemphigoid?

Bullous pemphigoid is the most common autoimmune blistering disease. In autoimmune diseases, the body's immune system mistakes its own tissues as foreign and attacks them. In bullous pemphigoid, this causes blisters on the skin. Bullous pemphigoid usually occurs in the elderly, but may also affect younger people.

How is bullous pemphigoid treated?

Until recently, the leading treatment for bullous pemphigoid was oral steroids which suppress inflammation and the body's own immune system. However, given over a long period of time, oral steroids will cause severe adverse (i.e. harmful) effects.

This review assessed studies which investigated the effectiveness of other treatment options for bullous pemphigoid; for example, a steroid cream applied on the skin and the anti‐inflammatory antibiotic medicine, doxycycline.

What did we want to find out?

We wanted to find out which treatments work best for bullous pemphigoid with respect to the healing of blisters (efficacy) and reduction in adverse effects, such as death.

What did we do?

We searched for studies that looked at treatments for bullous pemphigoid. We compared and summarised their results, and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 14 studies including 1442 people with bullous pemphigoid. The main treatments assessed were oral steroids, topical steroids, and the oral anti‐inflammatory antibiotic doxycycline. Other treatments tested were oral (i.e. taken by mouth) immunosuppressives (medicines that keep your immune system in check) and immunoglobulins (also called antibodies. Antibodies are proteins that your immune system makes to fight germs, for example).

‐ Topical steroid cream, clobetasol propionate, applied over the whole body (40 grams of cream applied per day, with the amount decreased over 12 months) is an effective and safe treatment for bullous pemphigoid.

‐ Treatment with a lower amount of clobetasol propionate cream (10 to 30 grams per day, decreased over 4 months) is equally effective and safe.

‐ Prednisolone, an oral corticosteroid, in the dose of 0.5 mg/kg/day, may be adequate to control disease in most people and reduces adverse effects compared to higher doses of oral corticosteroid.

‐ Initiating treatment with 200 mg/day of doxycycline leads to acceptable blister control compared to oral prednisolone (0.5 mg/kg/day) and is safer.

‐ A study with 20 participants suggests that nicotinamide (a form of vitamin B₃)and tetracycline (an antibiotic used to treat a wide variety of infections) may be an effective alternative to prednisone and may decrease treatment‐associated death.

‐ Adding azathioprine, a drug which suppresses the immune system, to an oral corticosteroid does not improve disease control; it may lead to a reduced need for oral corticosteroid.

‐ Further research is needed to fully understand the effectiveness of alternatives to oral steroids (such as dapsone or immunoglobulins), as well as the effectiveness of giving other medicines alongside an oral steroid.

What are the limitations of the evidence?

Except for the studies on topical clobetasol cream and doxycycline, the studies included relatively few participants. The methodological quality of these studies was further limited because of unclear methods of allocating people to different treatment groups; lack of masking (participants and researchers knew which treatments were given to which people, which are not good conditions for fair assessment); and the exclusion of people who dropped out of the studies from treatment analysis.

We are confident about the efficacy of initiating treatment with doxycycline and moderately confident about the efficacy of topical clobetasol cream for the treatment of bullous pemphigoid.

How up to date is this evidence?

The evidence is current to 11 November 2021.

Author(s)

Sanjay Singh, Gudula Kirtschig, Vinayak N Anchan, Ching-Chi Chi, Kathy Taghipour, Robert J Boyle, Dedee F Murrell

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

• Starting doses of prednisolone greater than 0.75 mg/kg/day may not give additional benefit. Starting doses of prednisolone of 0.5 mg/kg/day may be adequate for disease control in most people with bullous pemphigoid. This is expected to reduce the incidence and severity of adverse reactions (especially death) associated with treatment.
• Very potent topical steroid (clobetasol propionate) applied over the entire body is an effective treatment for bullous pemphigoid. It seems to have less serious adverse effects compared to high‐dose systemic steroids; however, its use in extensive disease may be limited by practical factors (ability of participant or availability of carer to apply the treatment). When feasible, it should be considered for first‐line treatment, especially in localised disease. However, if large quantities are needed to be applied topically, it may be associated with systemic absorption and adverse events. It is advisable to carefully monitor adverse effects when using topical steroid therapies, including changes in serum cortisol levels, especially when applied to large areas. Milder regimens (lower doses of clobetasol propionate cream applied over the whole body) are safe and effective in moderate and extensive bullous pemphigoid.
• The effectiveness of the addition of plasma exchange, azathioprine, mycophenolate mofetil, dapsone, or mepolizumab to prednisolone or prednisone has not been established. The effect of adding nicotinamide to tetracycline has not been established. The addition of a Chinese traditional herbal medicine to prednisone was not beneficial.
• The effectiveness of high‐dose intravenous immunoglobulins in addition to conventional treatment in treatment‐resistant patients is of unknown benefit and may be associated with severe adverse events.
• A strategy of starting treatment with doxycycline (200 mg/day) is an effective approach for most people with bullous pemphigoid, and results in fewer adverse effects compared to initial treatment with prednisolone. Future studies may show that people with severe disease may benefit less from this approach.

Implications for research 

• The optimum dose for treatment with doxycycline is not known; this needs further investigation.
• The approach for people with severe disease may be different from that for people with mild and moderate disease. Combined treatment of oral prednisolone and doxycycline may be beneficial; this needs further investigation.
• People with dementia or with other neurological disorders suffering from bullous pemphigoid are under‐investigated. Future trials should pay special attention to these populations.
• The efficacy of doxycycline therapy may be compared with topical steroid therapy.
• Masked randomised controlled trials comparing topical steroids with low doses of prednisolone/prednisone are needed.
• The effect of agents such as azathioprine, mycophenolate mofetil, dapsone, methotrexate, or mepolizumab in addition to steroids is still not known and may need further investigation. However, the publications of ongoing trials on methotrexate are awaited.
• The effect of nicotinamide alone or with tetracycline needs further investigation.
• The efficacy and safety of newer biologic therapies (monoclonal antibodies) should be investigated in randomised controlled trials.
• Future trial should include uniform effectiveness and safety measures to make trials comparable. A set of core outcomes for autoimmune blistering diseases needs to be established.

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