Introduction

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by inflammatory ulcers, commonly presenting as single or multiple rapidly evolving painful ulcers with purple margins and purulent drainage, which can lead to secondary infection [1]. The pathogenesis of PG is complex and related to neutrophil dysfunction, autoinflammatory responses, and abnormal immune function [2]. PG can affect individuals of any age, with a prevalence of 5.8 cases per 100,000 adults in the United States of America (USA) [3]. Delayed diagnosis and misdiagnosis are frequent, and PG is frequently misdiagnosed as necrotizing fasciitis, traumatic ulcers, vasculitis, or cutaneous cancers [4,5]. Inappropriate treatment can worsen the condition, leading to increased medical costs, prolonged hospital stays, and poor prognosis [6]. The high misdiagnosis rate is related to a poor understanding of the disease.

Mortality in patients with PG is high and may be related to comorbidities, severe secondary infections of chronic wounds, and immunosuppressive treatments [7,8]. The factors of poor prognosis include increased severity of disease, older age at diagnosis, unresponsiveness to treatment aimed at associated systemic disease, secondary infection, sepsis, the ulcerative (classic) variant of PG, and the bullous variant of PG, particularly if in a patient with hematologic abnormalities [9,10]. Nevertheless, PG remains a poorly understood disease because of its low incidence, and the exact factors associated with a poor prognosis remain uncertain.

Furthermore, the critical role of wound management in preventing secondary infection is often overlooked, and poor knowledge and experience in wound management of PG is key to poor patient outcomes [10,11]. Indeed, the initial management of PG should include optimizing wound care and pain management [12]. Topical therapy (potent or superpotent corticosteroids, tacrolimus, or cyclosporine) can be considered for mild and superficial lesions or as an adjunct to systemic medication for larger and deeper lesions, while systemic corticosteroids or systemic cyclosporine are frequently used as first-line treatment for large, multiple, or rapidly progressive PG lesions [1,10], but the evidence to guide management is limited, calling for additional data on patients with PG.

Therefore, this study aimed to review the clinical characteristics, diagnostic and therapeutic approaches, and wound management of patients with PG.

Materials and methods

Results

Demographics and clinical characteristics

The study included nine male patients with a mean age of 48.6 years (range: 23–71, median 50 years) (Table 1). The PG lesions were found on the limbs of seven patients (7/9), primarily in the lower extremities (5/7). Ulcerative PG was the most common (7/9) among the four subtypes (ulcerative, bullous, pustular, and vegetative). Seven patients developed PG following skin injuries, including venipuncture (2/7), debridement (3/7), and surgery (2/7). Two patients had underlying thrombocytopenia and acute myeloid leukemia (AML). Eight patients were admitted with systemic symptoms such as fever, chills, and fatigue.

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Table 1. Demographics and clinical features of the patients.

https://doi.org/10.1371/journal.pone.0326203.t001

All nine patients were initially diagnosed with other skin conditions (Table 2), including skin infection (4/9), cellulitis (2/9), rash (1/9), and drug extravasation (2/9). The duration from symptom onset to the final definitive PG diagnosis varied from 9 to 42 days (median 18 days), including the time of misdiagnosis at a primary hospital. Eight patients were diagnosed by multidisciplinary collaboration, including the dermatology, infection, wound, and ostomy departments.

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Table 2. Treatment and outcome of the patients.

https://doi.org/10.1371/journal.pone.0326203.t002

Patient outcomes

Six patients were healed, whereas the remaining three died of severe comorbidity (respiratory failure, hepatic failure, and sepsis) or secondary septic shock (Table 2).

Typical case #1.

A 54-year-old male with a history of hypertension was admitted for AML. The patient reported persistent tingling at the venipuncture site after an intravenous infusion in the right forearm. Three days later, the skin at the puncture site was red, swollen, and covered with a black scab (Fig 1a). A silver-based antimicrobial hydrogel and nano-silver medical antibacterial dressing were applied to promote autolytic debridement of the scab, while polymyxin and teicoplanin were used for systemic antibacterial treatment. The wound expanded to 13 × 9 cm (Fig 1b), and skin biopsy revealed mild hyperplasia, hypertrophy of the epidermis, superficial dermal edema, scattered mononuclear cells, and neutrophil infiltration. The patient was diagnosed with ulcerative PG after consulting with dermatologists and wound specialist nurses, and methylprednisolone was then administered intravenously at 60 mg/day (30 mg/Q12 hours). The black scab peeled off after 10 days of steroid treatment, revealing granulation tissue (Fig 1c) with massively purulent exudation. NPWT was performed by wound specialist nurses and was changed every 5–6 days, with negative pressure values of 80–100 mmHg. Two weeks later, the wound had shrunk to 9.0 × 6.5 cm (Fig 1d), and the exudation had significantly reduced; NPWT was discontinued. Silver-contained dressings, mesalt dressings (cleansing dressings with sodium chloride), or recombinant human epidermal growth factor gel was selected depending on the granulation tissue until the wound healed after 3 months (Fig 1e, f).

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Fig 1. The wound of pyoderma gangrenosum on the arm of a patient with acute myeloid leukemia.

(a. Redness, swelling, and black scab formation at the puncture site. b. The wound rapidly expanded to 13 × 9 cm. c. The black scab peeled off after 10 days of steroid treatment. d. Wound after 2 weeks of negative pressure wound therapy. e-f. The wound was shrinking until completely healed after 3 months).

https://doi.org/10.1371/journal.pone.0326203.g001

Typical case #2.

A 50-year-old male patient was hospitalized with a history of cellulitis for over 1 month and a high fever for 6 days, with a maximum temperature of 39.9°C. The patient had been diagnosed with cellulitis at another hospital and received anti-infective treatment and debridement. Subsequently, the ulcer enlarged with massive exudation, and the patient was referred to the hospital. A “petal-like” ulcer of 20 × 15 cm was observed on the right thigh (Fig 2a). The ulcer was dull-red and violaceous with reddened surrounding skin, elevated skin temperature, and copious bloody and purulent exudation. Meropenem and vancomycin were used for systemic anti-infection treatment, and celecoxib for pain management. However, the ulcer remained uncontrolled (Fig 2b). The patient was diagnosed with PG following consultations with dermatologists, infectious disease specialists, rheumatologists, and wound specialist nurses, and methylprednisolone was added to the treatment. Three days later, the wound exudate was significantly reduced, and the edge was crusted (Fig 2c). The wound was exposed with a brace after flushing with normal saline and drying with gauze. The patient was discharged 1 week later in a stable condition (Fig 2d), and the ulcer completely healed 20 days after discharge.

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Fig 2. The wound healing process in the right thigh of a patient with pyoderma gangrenosum.

(a. “Petal-like” ulcer measuring 20 × 15 cm on admission. b. Rapidly expanding wound despite systemic anti-infection treatment. c. Crusting of the wound edges 3 days after hormone treatment. d. Wound at discharge.).

https://doi.org/10.1371/journal.pone.0326203.g002

Discussion

The results highlight that PG is a rare and challenging condition often misdiagnosed as other skin disorders. Ulcerative PG was the most common subtype and triggers such as skin injuries were frequently observed. Effective wound management, including the careful handling of necrotic tissue, exudate, and infection, is essential to support wound healing in PG. Wound specialist nurses should deliver personalized care tailored to both the overall and local wound condition.

There is no clear consensus on the gender distribution of PG. Previous data from the National Inpatient Healthcare Databases in the USA and Spain have showed a male-to-female ratio of 1:1.40 ~ 1:2.02 [9,14]. However, the present study found a male predominance, consistent with the Korean study [7], which may be limited by regional and diagnostic criteria differences and sample size.

Consistent with previous studies [15,16], the current study also found that ulcerative PG was the most common subtype (7/9) and predominantly occurred in the limbs, especially the lower limbs. Skin injuries have been reported as a predisposing factor for PG. Here, seven patients (7/9) developed PG after skin injuries such as intravenous infusion, debridement, or surgery. Skin injuries can trigger the release of cytokines and danger signals, such as autoantigens and IL-36 and IL-8, which play a crucial role in the pathophysiology of PG [2]. The diverse clinical manifestations of PG in different stages and subtypes pose a challenge for clinical diagnosis. All patients in this study were initially diagnosed with other skin conditions such as infection, cellulitis, rash, or drug extravasation. Three patients who died had complications of respiratory failure, hepatic failure, and sepsis on admission, so the severity of comorbidities was considered to be the main cause of death in this group. These observations were consistent with the findings of Abdallah et al. [8], who found that 64% of patients with PG had comorbidities and that comorbidities were strongly associated with mortality. The diagnosis duration of patients with poor outcomes (3/9) ranged from 12 days to >1 month, and two of them had received debridement at other hospitals before definite diagnosis, which may worsen PG and increase the risk of death. Therefore, enhancing knowledge and early recognition of PG among medical professionals is essential to reducing delayed diagnosis and misdiagnosis.

Currently, diagnostic methods for PG are still being explored, and exclusion diagnosis is primarily used, including in the cases reported here. Maverakis et al. [17] developed and validated diagnostic criteria for ulcerative PG based on the Delphi method, with the primary diagnostic criterion being “neutrophil infiltration demonstrated by ulcer-edge biopsy,” in addition to eight secondary criteria. In 2019, Jockenhofer et al. [18] developed the PARACELSUS diagnostic tool, which considers rapid progression, assessment of relevant differential diagnoses, and reddish-violaceous wound borders as the major diagnostic criteria for PG. Four minor and three additional criteria were also identified, with a total score of ≥10 indicating a high probability of PG. Moreover, artificial intelligence (AI) technology has also been attempted to diagnose PG differentially. Birkner et al. [19] developed a deep convolutional neural network that showed a higher sensitivity for PG diagnosis than dermatologists after analyzing 422 wound photos of PG and leg ulcers. Nevertheless, more clinical studies are needed to validate the findings.

The systemic treatment of PG should be formulated based on several factors, including the severity of ulcers, related systemic diseases, patient status, and drug availability [20]. Glucocorticoids are considered first-line drugs for PG treatment because they can rapidly suppress inflammation by reducing the levels of proinflammatory cytokines, chemokines, and cell adhesion molecules [21]. A previous study showed that systemic glucocorticoid therapy at 0.5–1.0 mg/kg/d was effective in 40%−50% of patients with PG [22]. Nevertheless, the complete response rate is closely related to comorbidities and the severity of PG. Cyclosporine is another immunosuppressant commonly used for PG treatment and is reported to be as effective as glucocorticoids [1]. In addition to the above treatments, IVIG is often used as an adjuvant option in combination with glucocorticoids or immunosuppressants and plays multiple roles by regulating the innate immune system and enhancing the effects of glucocorticoids [23]. TNF-α is a pivotal pro-inflammatory cytokine that modulates chemokines including IL-1, IL-6, and IL-8, and promotes and maintains the inflammatory state through synergistic interactions [21]. Adalimumab and infliximab, commonly employed TNF-α inhibitors in PG treatment, can block the binding of TNF-α to its receptor and reduce levels of CRP, IL-1 and IL-6, thereby reducing inflammation. Zaman et al. [24] advocate the use of biologics including TNF-α inhibitors for severe or refractory PG cases, which is consistent with the systematic treatment principles in this study. Four patients with corticosteroid tapering barriers or ulcers progression post-debridement were treated with combination of TNF-α inhibitors and/or IVIG, and the remission rate was 75% (one patient died of severe respiratory failure).

The optimal treatment strategy for PG should include wound care, pain management, and systemic treatment. The “TIME” management principle, which focuses on tissue, infection, moisture balance, and epithelization, can be used to guide the wound care of PG, except for debridement [25,26]. Gentle and moderate cleaning to remove epithelial debris, fibrin, and necrotic tissue is necessary to promote wound healing [12]. The neutrophilic and inflammatory properties lead to excessive wound exudation, so hyper-absorbent dressings such as alginates, silver-contained dressings, or foams can be selected to control the exudation and avoid wound infection and edge maceration [27]. In this study, antimicrobial and hyper-absorbent dressings were the most common and could reduce the frequency of changes and painful irritation. NPWT can reduce edema, stimulate and promote the formation of wound granulation tissue and capillaries, and maintain appropriate wound humidity. Based on a literature review and treatment experience, excessive debridement or surgical treatment at the initial stage is not recommended, as it can stimulate inflammatory reactions and lead to worsened wounds [21]. Therefore, surgical debridement, skin graft, or NPWT should be performed at an appropriate time based on adequate glucocorticoids or immunosuppressive agents to avoid wound deterioration and maximize the effectiveness of surgical treatment.

Conclusions

PG is a rare condition characterized by heterogeneous clinical features and non-specific indicators, making it highly susceptible to misdiagnosis. This can lead to adverse outcomes, such as wound deterioration or even amputation, due to inappropriate treatment. Accurate diagnosis and effective management of PG require multidisciplinary collaboration, with early recognition being crucial to preventing misdiagnosis and its associated complications. Alongside systemic therapy, meticulous and gentle wound care is essential. This includes the personalized use of advanced medical dressings and addressing pain management to enhance patient compliance and comfort. In the future, it is necessary to systematically assess the differences in efficacy and safety between traditional drugs (single/combination regimens) and targeted therapies such as biologics by large-sample randomized controlled trials, as well as to construct standardized integration strategies of systemic therapy and local interventions (e.g., antimicrobial dressings, NPWT) under the multidisciplinary mode.

Acknowledgments

Not applicable.