Treatment of pyoderma gangrenosumBMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h3175 (Published 12 June 2015) Cite this as: BMJ 2015;350:h3175
- Jan Robert Mekkes, dermatologist
- 1Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
Pyoderma gangrenosum is a rare, severe skin disease in which progressive ulceration develops spontaneously or after skin trauma. Unrecognised pyoderma gangrenosum may result in the destruction of an entire leg or arm or large parts of the trunk, and the condition is potentially lethal. Patients with severe disease are usually treated with immunosuppressants such as prednisolone. Because of the rarity of the disease, clinical trials are scarce.
In this issue, Ormerod and colleagues carried out a randomised controlled trial (doi:10.1136/bmj.h2958) to compare the two most commonly used treatments for pyoderma gangrenosum—prednisolone and ciclosporin.1 This multicentre trial with 112 participants showed ciclosporin and prednisolone to be of comparable effectiveness. The groups did not differ in speed of ulcer healing. Roughly two thirds of participants in both groups experienced adverse reactions. Those treated with prednisolone reported more serious infections (11.3% v 0%). Those treated with ciclosporin reported more renal toxicity (30.5% v 1.9%). The authors concluded that both treatments were useful and that choice of agent should be driven by patient characteristics and the likelihood of specific side effects. Both drugs were less effective than expected—ulcers healed in only 47% of the participants within six months. New and better treatments are clearly needed. Prednisolone and ciclosporin are relatively cheap compared to newer immunosuppressants, such as biologics. They have been on the market for many years, and the patents have expired. It is difficult to obtain funding for clinical trials evaluating these drugs and it is therefore admirable that the authors were able to complete this investigator initiated study, with help of independent government funding (National Institute for Health Research). Thanks to their efforts we now have documented evidence on the efficacy of these two standard treatments for pyoderma gangrenosum. This paves the way for future trials: new treatments can be compared head to head with prednisolone or ciclosporin.
Pyoderma gangrenosum is often misdiagnosed. It is so rare that primary care doctors see few cases and may assume that the lesion is an infection and treat it with antibiotics. Surgeons may misdiagnose pyoderma gangrenosum as wound necrosis and remove necrotic tissue surgically. Surgery or any skin trauma makes the disease worse. Pyoderma gangrenosum may even be triggered by skin trauma,2 a process known as pathergy. Pathergy is not exclusive to pyoderma gangrenosum, but it does support the diagnosis, which must be made on clinical grounds. No diagnostic tests exist. Skin necrosis after trauma can also occur in Behçet’s disease, calciphylaxis cutis, and critical limb ischaemia.
The opposite also occurs when doctors misdiagnose other conditions as pyoderma gangrenosum—for instance, infections caused by Streptococcus pyogenes, Pseudomonas aeruginosa, and Blastomyces dermatitidis, calciphylaxis cutis, antiphospholipid syndrome, squamous cell carcinoma, and cutaneous T cell lymphoma.2
The cause of pyoderma gangrenosum is unknown. It can be associated with inflammatory bowel diseases, arthritis, haematological malignancies, and several other diseases, including auto-inflammatory disorders (PAPA syndrome, PAPASH syndrome) and acneiform dermatoses (hidradenitis suppurativa).2 3 In some of these disorders there is an overproduction of interleukin 1 or tumour necrosis factor α.2 3
Despite a limited evidence base, there is a long list of possible treatments. Most are anti-inflammatory agents.4 Smaller lesions that are not rapidly expanding can be managed with topical ointments of clobetasol propionate, tacrolimus, or ciclosporin. The usual treatment for more severe cases is oral prednisolone 1 mg/kg/day, or ciclosporin 3-5 mg/kg/day divided into two doses. Other options include azathioprine, mycophenolate mofetil, dapsone, sulfasalazine, intravenous immunoglobulins, methotrexate, cyclophosphamide, tacrolimus, thalidomide, rituximab, tumour necrosis factor α inhibitors (infliximab, adalimumab, etanercept, certolizumab), interleukin 1 antagonists (anakinra), and ustekinumab (anti- interleukin 12 and anti- interleukin 23).3 4 5 6 Extensive ulcerations must be treated by experts in wound care, and hyperbaric oxygen can be used to accelerate healing. Pain management is an important part of treatment. Pyoderma gangrenosum can be extremely painful, and it is wise to consult an experienced anaesthesiologist.
Tumour necrosis factor α inhibitors are the most widely used of the newer drugs.5 7 8 9 They are usually employed when patients do not respond to standard treatment. Case series and small randomised controlled trials suggest they can be effective, but there is a subset of patients who do not respond. Among other options, one case report describes successful use of ustekinumab.10 Another describes successful use of the interleukin 1 receptor antagonist anakinra, in a patient with an auto-inflammatory disorder called PAPA syndrome, although the same treatment failed in a patient with Crohn’s disease.11 12 Gevokizumab, a monoclonal antibody that binds to interleukin 1 β, is currently being investigated in a randomised controlled trial (www.clinicaltrials.gov NCT02326740).
There remains little evidence for any recommended treatment, partly because trials of rare diseases are challenging. Recruitment and funding are difficult, and placebo controlled trials are considered unethical because pyoderma gangrenosum is a rapidly progressive disorder that can destroy large areas of skin within a few days. The only placebo controlled trial so far has tested infliximab. The observation period had to be short (two weeks), and after these two weeks the control group also received infliximab. In most studies, the study drug is added to standard treatment in the intervention group.
Pyoderma gangrenosum is severe and difficult to treat. Ormerod and colleagues found that current standard treatments are not good enough and provide a baseline against which all other options can be compared in future studies. Developing and testing new treatments for this devastating disorder will be a challenge, but not an insurmountable one. Robust trials of treatments for rare diseases such as pyoderma gangrenosum are possible, and they must be done.
Cite this as: BMJ 2015;350:h3175
Competing interests: I have read and understood the BMJ policy on declaration of interests and declare the following: none.
Provenance and peer review: Commissioned; not externally peer reviewed.