Rare disease round-up: Pyoderma gangrenosum

Pyoderma gangrenosum (PG) is a rare, painful and complex autoimmune skin condition that can present significant diagnostic and treatment challenges.¹  

To provide expert insights into this challenging disease, we spoke with Dr Benjamin Kaffenberger, a dermatologist at The Ohio State University (Columbus, OH, USA) specializing in the management of complex medical dermatologic conditions.

 

Q. What are the key clinical features of pyoderma gangrenosum?

PG is a painful, reactive, cutaneous ulcerating condition. While many patients do not have a clear underlying condition, more than half have a systemic inflammatory disorder. The most frequent association is with inflammatory bowel diseases, such as ulcerative colitis or Crohn’s disease. However, rheumatoid arthritis, psoriatic arthritis, other autoimmune arthritis syndromes and haematologic blood disorders can also act as precipitating factors.

A typical presentation is an individual with one of these underlying diseases who experiences a minor trauma, such as scraping their shin, or undergoing surgery. This trauma can then trigger a flare, which begins with papules, pustules, blisters, or nodules. Instead of healing normally, these wounds can deteriorate, becoming deeper and wider, developing purple borders and rapidly progressing to a very painful ulceration. Several ulcers may develop at the same time or over months to years. Histologically, PG exhibits substantial neutrophil infiltration, suggesting activated neutrophils as a potential disease driver.

Q. What other known risk factors should we look out for? 

There are two distinct populations affected by this condition. 

PG can occur in young adults, including children, and in that younger age group, it is most often associated with Crohn’s disease or ulcerative colitis. Then there is an older population (typically 40–60 years of age) reflecting a bimodal incidence. While ulcerative colitis remains the most common underlying condition, in this age group, we also see a higher prevalence of rheumatoid arthritis and haematologic blood disorders as significant contributing factors to the disease. Although not dramatically different, PG appears to be slightly more common in women than men, with an estimated female-to-male ratio of approximately 60:40.

Q. How does pyoderma gangrenosum impact patients’ daily lives?

PG has a significant impact. Several factors contribute to this, including the location and visibility of the ulceration, as well as the amount of drainage from the wound. These ulcers can be extremely large and often appear in highly visible areas. They may also develop in locations critical for movement and flexibility, causing discomfort with even the slightest body movement leading to a loss of mobility.

They can also affect essential aspects of medical management and self-care. About 30% of patients with PG have inflammatory bowel disease, and in many cases, the condition first appears after an ostomy is placed. This can happen whether the ostomy was part of a curative attempt for ulcerative colitis with a colectomy or following diseased bowel requiring resection in Crohn’s disease.

In these cases, when an ulceration develops around the ostomy site, it is not only extremely painful but also interferes with the ability to maintain a proper seal. Some patients struggle to keep their ostomy bag or skin barrier in place, leading to persistent leakage throughout the day because of the large, critical wound surrounding the site.

In all cases, early diagnosis and appropriate treatment are essential to minimize morbidity and sequelae.

Q. What challenges can clinicians face in making an accurate diagnosis?

Diagnosing PG can be extremely challenging. For a long time, there were no validated diagnostic criteria, so diagnosis was primarily made by exclusion. Leading publications at the time simply emphasized ruling out other potential causes of ulceration before considering PG.

The problem here was that there was no standardized approach to ruling out other causes. One clinician’s method could differ significantly from another’s; what I might have done could be very different from what someone in California, an expert in Alabama, or a general practitioner or wound care specialist in Chicago would have done. This lack of consistency made diagnosis even more challenging.

However, there are now some published, and validated, diagnostic criteria, so diagnosis is no longer entirely reliant on exclusion. One of the most commonly used tools is the PARACELSUS score, though several others have also now been published.² The PARACELSUS criteria assesses various characteristics, such as whether the ulcer developed after trauma and whether a biopsy shows a heavy neutrophilic infiltrate. When a patient accumulates enough points based on these features, a diagnosis of PG becomes highly likely.

While this approach represents an improvement over past methods, diagnosing PG remains challenging. Misdiagnosis can result in delays in appropriate treatment and unnecessary debridement, which can trigger further ulceration and disease progression and may even then worsen the condition.

Q. What is the estimated incidence in terms of the patient population? 

Officially, the incidence is estimated to be between one and ten cases per 100,000 patients. However, I tend to think the actual incidence may be higher. One of the biggest challenges is diagnosing patients, particularly in the early phase of the disease. In the early stages, there are often characteristic findings, but a significant number of patients go through 18 to 24 months of non-healing, chronic wounds (large, multiple and unspecified) without a clear diagnosis. My bias, or rather my perspective, is that many of these patients likely have a chronic form of PG where the acute features are no longer apparent.

Q. What does the standard treatment approach look like for patients with pyoderma gangrenosum?

There are currently no FDA- or EMA-approved treatments for PG. As a result, management relies on the best available evidence, which primarily supports the use of four different medications.

In the short term, treatment typically involves prednisone or cyclosporine, with the choice depending on the patient’s comorbidities. Both medications are considered equally effective. They also act quickly, which is particularly important for hospitalized patients who require urgent disease control in the initial stages.

However, these treatments are not without challenges, particularly due to their significant side effects. This is especially concerning given the duration of treatment that may be required, particularly for patients with larger wounds.

For example, kidney injury is the primary factor that limits the long-term use of cyclosporine. However, if a patient is being closely monitored and their blood pressure and kidney function remain stable, cyclosporine can be continued safely for 6–12 months or even longer. With prednisone, we must be cautious about long-term complications, including bone demineralization, weight gain, diabetes development, and blood sugar control.

Moving beyond initial treatment, the next medications typically used are the immunosuppressive therapies adalimumab or infliximab, along with their biosimilar variants.

Adalimumab has the advantage of being easier to dose and is often somewhat more affordable; not that it is cheap, but it avoids the additional costs associated with infusion. Infliximab, on the other hand, has slightly stronger evidence supporting its use. While I tend to think infliximab may work a little better, its higher cost and the inconvenience of requiring infusions generally lead me to prefer adalimumab as the first choice.

Q. What investigational treatments are currently being explored for pyoderma gangrenosum?

The landscape is certainly improving, and it is an exciting period, as there seems to be renewed interest in the disease. 

At this year’s AAD Annual Meeting, we presented encouraging phase III trial data on the C5a inhibitor vilobelimab, and are looking forward to sharing further information on our findings shortly.^3,4 It has been several years (close to 5–10 years) since the last phase III study aimed at obtaining pivotal approval for a treatment for PG, so this represents a significant development. 

Targeting C5a, a key component of the complement system involved in inflammation, vilobelimab aims to reduce neutrophilic inflammation, which is believed to play a central role in the pathogenesis of PG.

Beyond C5 inhibition, several novel therapeutics targeting different pathways are also under investigation. Spesolimab, a monoclonal antibody designed to inhibit the interleukin-36 receptor (IL-36R), is one such candidate. Secukinumab, an IL-17 inhibitor, has shown promise in case reports and small studies. Additionally, Janus kinase (JAK) inhibitors, such as baricitinib and tofacitinib, are being explored for PG treatment. Notably, baricitinib is currently being investigated in a phase II clinical trial for PG. Tildrakizumab, an IL-23p19 antagonist, has also emerged as a potential therapy. A recent proof-of-concept open-label clinical trial demonstrated significant reductions in ulcer size, pain and itch, along with improvements in quality of life outcomes in  patients with PG after 12 weeks of treatment. These are in addition to currently available treatments including prednisone, cyclosporine, adalimumab, and infliximab. 

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