NIHR DC Discover

NIHR Signal Doxycycline may be a safer first option for treating a blistering skin condition

Published on 4 July 2017

doi: 10.3310/signal-000435

Doxycycline (an established antibiotic) may be a safer first option than the standard steroid treatment for people with the autoimmune skin condition bullous pemphigoid. The condition causes severe, itchy blistering.

This NIHR-funded study showed that people started on doxycycline were 19% less likely to have severe, life-threatening or fatal events during the next 12 months than those who started a steroid (prednisolone). Blister control was considered acceptable for both treatments (74% treatment success with doxycycline at six weeks compared to 91% with a steroid).

Whole-body steroid cream treatment might give better results, but is not always practical. Oral steroids are often used instead. This study also suggests that doctors and informed patients might consider a trial of doxycycline first, only switching to an oral steroid if needed.

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Why was this study needed?

Bullous pemphigoid is an intensely itchy condition which causes large blisters on the skin. It affects about one in 10,000 people in the UK each year, mainly aged over 70. The oral steroid prednisolone is standard treatment. It usually controls the condition quickly, but carries the risk of serious side effects, including mood disorders and infections. Whole-body, daily, application of potent topical steroid creams has been shown to work, but can be difficult for elderly patients.

Antibiotics in the tetracycline group, such as doxycycline, have been used to treat bullous pemphigoid, because they have an anti-inflammatory effect. But there is not much research on their use.

A survey of UK dermatologists found most were willing to accept a 25% reduction in the effect of controlling blisters in the short term, for a reduction in serious adverse effects of treatment of at least 20%, compared to prednisolone. The study was designed to see if doxycycline was worse (or no worse) than this. 

What did this study do?

The Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) study was a non-inferior randomised controlled trial carried out in dermatology clinics in the UK and Germany.

Researchers recruited 278 patients. They were randomly assigned to start either 0.5mg/kg body weight prednisolone or 200mg doxycycline daily, for six weeks. After six weeks, blistering was assessed independently, and doctors were able to switch treatment if necessary. People could use up to 30g steroid cream as required for the first three weeks, and again after six weeks.

Researchers recorded all serious adverse events possibly related to treatment, for up to 12 months.

This was a well-designed trial across multiple centres and the results are likely to be reliable. As the researchers knew that steroid treatment is effective, they designed the trial to see if doxycycline was an “acceptable” alternative within the margin of being 25% less effective with a 90% confidence limit up to 37% less effective.

What did it find?

  • Prednisolone worked better for blister control, with 74% of people taking doxycycline and 91% of people taking prednisolone having three or fewer blisters after six weeks’ treatment. This gave a difference of 18.6% after adjusting for disease severity (90% confidence interval [CI] 11.1 to 26.1) which was within the acceptable upper margin for non-inferiority of 37%.
  • Fewer people had adverse events with doxycycline. Within 12 months of treatment, 18% of people taking doxycycline and 36% of people taking prednisolone had severe, life-threatening or fatal events related to treatment - an adjusted difference of 19% (95% CI 7.9 to 30.1.
  • While there was no association between the relative success of either treatment and the severity of the disease, both treatments were less successful in patients with more severe disease.

What does current guidance say on this issue?

The British Association of Dermatologists 2012 guideline on bullous pemphigoid recommends use of systemic and topical steroids. It says that anti-inflammatory antibiotics such as tetracyclines are used widely and “may be considered as treatment in adults, perhaps in combination with topical corticosteroids”.

It also recommends considering the use of nicotinamide, a form of Vitamin B3. However, they stress that at the time of writing, there were no large randomised controlled trials on which to base these recommendations.

What are the implications?

The study provides much-needed evidence about the comparative efficacy and safety of two widely-used drugs for bullous pemphigoid, which should help doctors and patients decide which treatment is preferable for the individual.

Dermatologists could propose a trial of doxycycline in conjunction with topical steroids as a first treatment strategy. This might be most appropriate for those most at risk of serious side effects from systemic oral steroid treatment.

This evidence could strengthen the recommendations in future updates to guidelines on this topic.

Citation and Funding

Hywel C Williams, Fenella Wojnarowska, Gudula Kirtschig, et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial. Lancet. 2017;389(10079):1630-38.

This project was funded by the National Institute for Health Research Technology Assessment Programme. 

Bibliography

NHS Choices. Bullous Pemphigoid. London: Department of Health; 2015.

Venning VA, Taghipour K, Mohd Mustapa MF, et al. British Association of Dermatologists' guidelines for the management of bullous pemphigoid 2012. Br J Dermatol. 2012;167:1200-14.

Why was this study needed?

Bullous pemphigoid is an intensely itchy condition which causes large blisters on the skin. It affects about one in 10,000 people in the UK each year, mainly aged over 70. The oral steroid prednisolone is standard treatment. It usually controls the condition quickly, but carries the risk of serious side effects, including mood disorders and infections. Whole-body, daily, application of potent topical steroid creams has been shown to work, but can be difficult for elderly patients.

Antibiotics in the tetracycline group, such as doxycycline, have been used to treat bullous pemphigoid, because they have an anti-inflammatory effect. But there is not much research on their use.

A survey of UK dermatologists found most were willing to accept a 25% reduction in the effect of controlling blisters in the short term, for a reduction in serious adverse effects of treatment of at least 20%, compared to prednisolone. The study was designed to see if doxycycline was worse (or no worse) than this. 

What did this study do?

The Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) study was a non-inferior randomised controlled trial carried out in dermatology clinics in the UK and Germany.

Researchers recruited 278 patients. They were randomly assigned to start either 0.5mg/kg body weight prednisolone or 200mg doxycycline daily, for six weeks. After six weeks, blistering was assessed independently, and doctors were able to switch treatment if necessary. People could use up to 30g steroid cream as required for the first three weeks, and again after six weeks.

Researchers recorded all serious adverse events possibly related to treatment, for up to 12 months.

This was a well-designed trial across multiple centres and the results are likely to be reliable. As the researchers knew that steroid treatment is effective, they designed the trial to see if doxycycline was an “acceptable” alternative within the margin of being 25% less effective with a 90% confidence limit up to 37% less effective.

What did it find?

  • Prednisolone worked better for blister control, with 74% of people taking doxycycline and 91% of people taking prednisolone having three or fewer blisters after six weeks’ treatment. This gave a difference of 18.6% after adjusting for disease severity (90% confidence interval [CI] 11.1 to 26.1) which was within the acceptable upper margin for non-inferiority of 37%.
  • Fewer people had adverse events with doxycycline. Within 12 months of treatment, 18% of people taking doxycycline and 36% of people taking prednisolone had severe, life-threatening or fatal events related to treatment - an adjusted difference of 19% (95% CI 7.9 to 30.1.
  • While there was no association between the relative success of either treatment and the severity of the disease, both treatments were less successful in patients with more severe disease.

What does current guidance say on this issue?

The British Association of Dermatologists 2012 guideline on bullous pemphigoid recommends use of systemic and topical steroids. It says that anti-inflammatory antibiotics such as tetracyclines are used widely and “may be considered as treatment in adults, perhaps in combination with topical corticosteroids”.

It also recommends considering the use of nicotinamide, a form of Vitamin B3. However, they stress that at the time of writing, there were no large randomised controlled trials on which to base these recommendations.

What are the implications?

The study provides much-needed evidence about the comparative efficacy and safety of two widely-used drugs for bullous pemphigoid, which should help doctors and patients decide which treatment is preferable for the individual.

Dermatologists could propose a trial of doxycycline in conjunction with topical steroids as a first treatment strategy. This might be most appropriate for those most at risk of serious side effects from systemic oral steroid treatment.

This evidence could strengthen the recommendations in future updates to guidelines on this topic.

Citation and Funding

Hywel C Williams, Fenella Wojnarowska, Gudula Kirtschig, et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial. Lancet. 2017;389(10079):1630-38.

This project was funded by the National Institute for Health Research Technology Assessment Programme. 

Bibliography

NHS Choices. Bullous Pemphigoid. London: Department of Health; 2015.

Venning VA, Taghipour K, Mohd Mustapa MF, et al. British Association of Dermatologists' guidelines for the management of bullous pemphigoid 2012. Br J Dermatol. 2012;167:1200-14.

Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial

Published on 7 March 2017

H Williams, F Wojnarowska, G Kirtschig, J Mason, T Godec, E Schmidt, J Chalmers, M Childs, S Walton, K Harman, A Chapman, D Whitham, A Nunn on behalf of the UK Dermatology Clinical Trials Network BLISTER Study Group

The Lancet , 2017

Background Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. Methods We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3–9, 10–30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1–3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3–5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604. Findings Between March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1–26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9–30·1), p=0·001. Interpretation Starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term. Funding NIHR Health Technology Assessment Programme

Bullous pemphigoid is an auto-immune disease in which the immune system attacks the membrane between two layers of skin cells, the dermis and epidermis. The skin layers start to separate and fluid builds up, forming blisters. Causes are unknown, although triggers are thought to include sunburn and certain medications.

Expert commentary

Williams et al set new standards for clinical trial design in this pragmatic, non-inferiority, randomised controlled trial comparing doxycycline and prednisolone as the initial treatment strategy for bullous pemphigoid. To date, potent topical steroids or systemic steroids have been prescribed to control the widespread blistering that characterises this immuno-bullous disorder.

However, systemic steroids tend to be problematic for long term use when most affected patients are elderly. This study establishes doxycycline as a novel treatment option for bullous pemphigoid, and is therefore likely to decrease the need for systemic steroids in the treatment of this disorder.

Professor Alex Anstey, Consultant Dermatologist, Ysbyty Gwynedd, Bangor, Gwynedd, Wales

Expert commentary

Bullous pemphigoid is a relatively common skin disease which causes skin blisters particularly in the elderly. It can be severe and last for several years. Standard treatment has been with oral steroid tablets which are effective but associated with potentially serious side-effects. This study has compared steroid tablets with a daily 200mg dose of oral doxycycline which is an antibiotic. It showed that at least in the short term, doxycycline can produce a similar level of control of blisters to oral steroids. A major advantage of doxycycline is a significantly reduced rate of serious side-effects compared to steroids.

Dr Richard Logan, Consultant Dermatologist, Princess of Wales Hospital, Bridgend, Wales