NIHR Signal Two drugs only partially helpful for pyoderma gangrenosum

Published on 28 September 2015

This NIHR trial found no difference in the healing of pyoderma gangrenosum over six weeks in adults treated with prednisolone or ciclosporin. Pyoderma gangrenosum is a rare serious skin condition causing painful ulcers, and over half of ulcers had failed to heal after six months of either treatment. There were more serious side effects – mostly serious infections – in patients using prednisolone, though both drugs caused some harms in two thirds of patients. With little to choose between the drugs for benefit, it may be best to select the treatment based on the features of individuals that make them prone to the different adverse effects of each drug.

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Why was this study needed?

Pyoderma gangrenosum is a rare skin condition causing painful ulcers that can become infected though it is not caused by infection, indeed the cause is unknown. In the UK one to two people a year will develop the condition in a population of 200,000.

The only previous randomised controlled trial in pyoderma gangrenosum was a small study, including 30 adults, which compared a biological treatment not normally prescribed for this condition with placebo. As there is so little useful evidence, the NIHR funded this study to compare the treatment of pyoderma gangrenosum using the common steroid prednisolone, thought to have benefit but some side-effects, with ciclosporin, the immunosuppressant drug, thought by clinicians to be more effective albeit with significant but different side-effects.

What did this study do?

This randomised controlled trial, called STOP GAP, included 112 adults with pyoderma gangrenosum in the UK. They were randomised to receive, by mouth, prednisolone up to 0.75mg per kg per day (max 75mg) or ciclosporin up to 4mg per kg per day (max 400mg).

The main outcome of interest was speed of healing over six weeks. This was assessed using digital photographs of ulcer size. Assessors were unaware of the treatment given, reducing possible bias in the interpretation of the photographs. Patients and their clinicians were aware of the treatment they were taking.

What did it find?

  • There was no difference in the main outcome, speed of healing, between the two treatments over six weeks. Average reduction in ulcer size per day was 0.14 square cm using prednisolone compared with 0.21 square cm using ciclosporin but this difference became insignificant at 0.003 square cm per day, when differences in the two groups were accounted for.
  • There was no significant difference between the two groups for any of the other outcomes: time to healing (defined as when sterile dressings were no longer needed), overall treatment response, self-reported pain, quality of life, time to recurrence of ulcers and number of treatment side effects.
  • Side effects, reported by around two-thirds of participants, varied depending on the treatment. Ciclosporin was more commonly associated with kidney problems (30%), nausea (20%) and headaches (8%); prednisolone with raised blood sugar (9%) and new cases of diabetes (6%).
  • Seven serious side effects were reported with prednisolone, six of which were serious infections. Two serious side effects were reported using ciclosporin, one of which was acute kidney failure.

What does current guidance say on this issue?

There are no UK or international guidelines on treating pyoderma gangrenosum. Patient information from NHS Choices and the British Association of Dermatologists list a number of treatment options. These include: steroid creams applied directly to the ulcer, drug treatment with antibiotics, steroids such as prednisolone, or immunosuppressant drugs like ciclosporin.

What are the implications?

Prednisolone and ciclosporin both helped ulcer healing to an equal degree. But there were differences in types of side effects. Therefore, shared decisions about treatment options should be mindful of the specific possible side effects, especially if patients have other conditions making them more vulnerable to certain side effects.

Fewer than half of ulcers had healed at six weeks, suggesting that neither treatment was particularly effective in treating pyoderma gangrenosum. Because this trial did not have a placebo comparison, it is possible that neither drug affected the pyoderma gangrenosum.

Although ciclosporin is used to treat pyoderma gangrenosum in the UK, it is used “off-label”, which means that it is not currently licensed for use in this condition. The study authors note that ciclosporin is more expensive than prednisolone, but the cost of treatment was not measured in this study.

Citation

Ormerod AD, Thomas KS, Craig FE, et al. Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial. BMJ. 2015;350:h2958.

This project was funded by the National Institute for Health Research Programme Grants for Applied Research, project number RP-PG-0407-10177.

Bibliography

BAD. Pyoderma gangrenosum. London: British Association of Dermatologists; updated 2013.

Brooklyn TN, Dunnill MG, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut. 2006;55:505-9.

NHS Choices. Pyoderma gangrenosum. London: NHS Choices; updated 2015.

Why was this study needed?

Pyoderma gangrenosum is a rare skin condition causing painful ulcers that can become infected though it is not caused by infection, indeed the cause is unknown. In the UK one to two people a year will develop the condition in a population of 200,000.

The only previous randomised controlled trial in pyoderma gangrenosum was a small study, including 30 adults, which compared a biological treatment not normally prescribed for this condition with placebo. As there is so little useful evidence, the NIHR funded this study to compare the treatment of pyoderma gangrenosum using the common steroid prednisolone, thought to have benefit but some side-effects, with ciclosporin, the immunosuppressant drug, thought by clinicians to be more effective albeit with significant but different side-effects.

What did this study do?

This randomised controlled trial, called STOP GAP, included 112 adults with pyoderma gangrenosum in the UK. They were randomised to receive, by mouth, prednisolone up to 0.75mg per kg per day (max 75mg) or ciclosporin up to 4mg per kg per day (max 400mg).

The main outcome of interest was speed of healing over six weeks. This was assessed using digital photographs of ulcer size. Assessors were unaware of the treatment given, reducing possible bias in the interpretation of the photographs. Patients and their clinicians were aware of the treatment they were taking.

What did it find?

  • There was no difference in the main outcome, speed of healing, between the two treatments over six weeks. Average reduction in ulcer size per day was 0.14 square cm using prednisolone compared with 0.21 square cm using ciclosporin but this difference became insignificant at 0.003 square cm per day, when differences in the two groups were accounted for.
  • There was no significant difference between the two groups for any of the other outcomes: time to healing (defined as when sterile dressings were no longer needed), overall treatment response, self-reported pain, quality of life, time to recurrence of ulcers and number of treatment side effects.
  • Side effects, reported by around two-thirds of participants, varied depending on the treatment. Ciclosporin was more commonly associated with kidney problems (30%), nausea (20%) and headaches (8%); prednisolone with raised blood sugar (9%) and new cases of diabetes (6%).
  • Seven serious side effects were reported with prednisolone, six of which were serious infections. Two serious side effects were reported using ciclosporin, one of which was acute kidney failure.

What does current guidance say on this issue?

There are no UK or international guidelines on treating pyoderma gangrenosum. Patient information from NHS Choices and the British Association of Dermatologists list a number of treatment options. These include: steroid creams applied directly to the ulcer, drug treatment with antibiotics, steroids such as prednisolone, or immunosuppressant drugs like ciclosporin.

What are the implications?

Prednisolone and ciclosporin both helped ulcer healing to an equal degree. But there were differences in types of side effects. Therefore, shared decisions about treatment options should be mindful of the specific possible side effects, especially if patients have other conditions making them more vulnerable to certain side effects.

Fewer than half of ulcers had healed at six weeks, suggesting that neither treatment was particularly effective in treating pyoderma gangrenosum. Because this trial did not have a placebo comparison, it is possible that neither drug affected the pyoderma gangrenosum.

Although ciclosporin is used to treat pyoderma gangrenosum in the UK, it is used “off-label”, which means that it is not currently licensed for use in this condition. The study authors note that ciclosporin is more expensive than prednisolone, but the cost of treatment was not measured in this study.

Citation

Ormerod AD, Thomas KS, Craig FE, et al. Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial. BMJ. 2015;350:h2958.

This project was funded by the National Institute for Health Research Programme Grants for Applied Research, project number RP-PG-0407-10177.

Bibliography

BAD. Pyoderma gangrenosum. London: British Association of Dermatologists; updated 2013.

Brooklyn TN, Dunnill MG, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut. 2006;55:505-9.

NHS Choices. Pyoderma gangrenosum. London: NHS Choices; updated 2015.

Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial

Published on 14 June 2015

Ormerod, A. D.,Thomas, K. S.,Craig, F. E.,Mitchell, E.,Greenlaw, N.,Norrie, J.,Mason, J. M.,Walton, S.,Johnston, G. A.,Williams, H. C.

Bmj Volume 350 , 2015

OBJECTIVE: To determine whether ciclosporin is superior to prednisolone for the treatment of pyoderma gangrenosum, a painful, ulcerating skin disease with a poor evidence base for management. DESIGN: Multicentre, parallel group, observer blind, randomised controlled trial. SETTING: 39 UK hospitals, recruiting from June 2009 to November 2012. PARTICIPANTS: 121 patients (73 women, mean age 54 years) with clinician diagnosed pyoderma gangrenosum. Clinical diagnosis was revised in nine participants after randomisation, leaving 112 participants in the analysis set (59 ciclosporin; 53 prednisolone). INTERVENTION: Oral prednisolone 0.75 mg/kg/day compared with ciclosporin 4 mg/kg/day, to a maximum dose of 75 and 400 mg/day, respectively. MAIN OUTCOME MEASURES: The primary outcome was speed of healing over six weeks, captured using digital images and assessed by blinded investigators. Secondary outcomes were time to healing, global treatment response, resolution of inflammation, self reported pain, quality of life, number of treatment failures, adverse reactions, and time to recurrence. Outcomes were assessed at baseline and six weeks and when the ulcer had healed (to a maximum of six months). RESULTS: Of the 112 participants, 108 had complete primary outcome data at baseline and six weeks (57 ciclosporin; 51 prednisolone). Groups were balanced at baseline. The mean (SD) speed of healing at six weeks was -0.21 (1.00) cm(2)/day in the ciclosporin group compared with -0.14 (0.42) cm(2)/day in the prednisolone group. The adjusted mean difference showed no between group difference (0.003 cm(2)/day, 95% confidence interval -0.20 to 0.21; P=0.97). By six months, ulcers had healed in 28/59 (47%) participants in the ciclosporin group compared with 25/53 (47%) in the prednisolone group. In those with healed ulcers, eight (30%) receiving ciclosporin and seven (28%) receiving prednisolone had a recurrence. Adverse reactions were similar for the two groups (68% ciclosporin and 66% prednisolone), but serious adverse reactions, especially infections, were more common in the prednisolone group. CONCLUSION: Prednisolone and ciclosporin did not differ across a range of objective and patient reported outcomes. Treatment decisions for individual patients may be guided by the different side effect profiles of the two drugs and patient preference. Trial registration Current Controlled Trials ISRCTN35898459.

The exact cause of pyoderma gangrenosum is not known. It sometimes occurs in people who have another health condition such as inflammatory bowel disease, rheumatoid arthritis and some forms of blood cancer. It can also occur in people who have had surgery or other trauma to the skin. However, in around half of people, there is no obvious cause.

Author commentary

Being told you have a rare skin disease without evidence for treatment is demoralising, yet obtaining good evidence is challenging. Thanks to the collaborative efforts of the UK Dermatology Trials Network and NIHR, we tested the two most commonly used oral treatments for pyoderma gangrenosum - prednisolone and ciclosporin - and found that neither was much good. Half of ulcers remained unhealed at 6 weeks and adverse reactions occurred in around two thirds of participants. This trial yields useful data on serious adverse reactions to inform shared decision making. Topical corticosteroids are a safer option for limited early pyoderma gangrenosum.

Hywel Williams, NIHR Senior Investigator, Professor of Dermato-Epidemiology and Co-Director of the Centre of Evidence-Based Dermatology, University of Nottingham