ABSTRACT

Pyoderma Gangrenosum is a rare neutrophilic dermatosis with multiple different clinical presentations and associated comorbidities. Historically, it has been a challenging disorder to diagnose, as it is difficult to establish this condition based on a clinical presentation. Recently, several studies have attempted to define the prevalence of clinical manifestations of PG in order to improve diagnostic accuracy leading to the development of new diagnostic criteria rather than the traditional approach of a diagnosis of exclusion. Moreover, new biologic treatment modalities have been introduced. Objective: In this study, we aimed to evaluate the management and diagnostic approach of pyoderma gangrenosum in the emergency department. Methodology: PubMed database was used for articles selection, and the following keys were used in the mesh ((“Pyoderma Gangrenosum "[Mesh]). Conclusion: There is no diagnostic gold standard. However, PARACELSUS has been adopted as a novel diagnostic tool. Although the pathophysiology of PG is still incompletely understood. The discovery of new inflammatory cytokines and signal cascades has led to the development of a novel biologic therapy. However, significant research is needed in biologic therapy as it is difficult to assess long-term efficacy, adverse events, and remission rates as outcome measures for PG.

Key Words: Pathergy, Pyoderma Gangrenosum, Biologic therapy, Corticosteroids, Diagnostic criteria.

INTRODUCTION

Pyoderma Gangrenosum (PG) is a rare inflammatory disorder often associated with inflammatory bowel disease (IBD), inflammatory arthropathies, and hematologic malignancies. In the general population, it equally affects patients of both sexes, however, some female dominance is suggested, and it can affect any age group. PG has an overall incidence of 5.8 per 100,000 individuals and a mortality rate of up to 30%. This high rate was found in some series mainly due to complications including infection, scarring, uncontrolled pain, depression, and loss of mobility. [1]

However, given the lack of a gold standard for diagnosis, the exact prevalence has yet to be elucidated since PG is commonly under- or over-diagnosed. [2] The aetiopathogenesis of PG is currently unknown and is hypothesized to be multifactorial, involving both the adaptive and innate immune systems as well as having genetic factors in play. Proper analgesia, wound care, and compression therapy are all important tenets in the management of Pyoderma Gangrenosum. Topical and systemic therapies are used empirically, but no targeted or specific treatment exists, and current therapy largely depends on the severity and progression of the disease. [3, 4]

This review will highlight updates in diagnosing, managing this disease, and will assist physicians in better understanding PG and ultimately improving patient care overall.

METHODOLOGY:

PubMed database was used for articles selection, and the following keys used in the mesh ((“Pyoderma Gangrenosum "[Mesh]). In regards to the inclusion criteria, the articles were selected based on the inclusion of one of the following topics; pyoderma gangrenosum diagnosis and management. Exclusion criteria were all other articles that did not have one of these topics as their primary endpoint.

Review:

The name pyoderma gangrenosum has a historical origin, firstly described by Broque in 1916. In 1930, the disease was given the name PG when it was reported and confirmed as a streptococcal infection. However, it does not cause gangrene and is not an infection (pyoderma). Although this disease affects both sexes, there may be some female dominance [5].  All ages may be affected by the disease, but it predominantly occurs in the fourth and fifth decades of life. The prognosis of PG is commonly good provided that complications are minimal. However,  residual scarring and also recurrence are prevalent even after proper treatment. [6, 7]

Pathophysiology and Associations:

Even after a century, the etiology and pathophysiology of the disease have not been fully understood although it is thought to be a reaction to the dysregulated innate immune system, abnormal chemotaxis, phagocytosis, and neutrophil immigration. Moreover, a lot of genetic factors and mutations have been associated with this condition and have been proposed as possible causes and/or risk factors in the pathophysiology of PG. (Table 1) There is also evidence in PG association with other disorders related to neutrophilic dysfunction, such as IBD [8], rheumatoid arthritis (RA), seronegative arthritis, hematologic disorders, and malignancies such as acute myeloid leukemia (AML). [3, 9] IL-6, a pro-inflammatory cytokine that plays a role in the activation and accumulation of neutrophils, has been found to be elevated in patients with PG lesions. [10]

Approximately 50% of patients presenting with PG are usually having systemic diseases, the rest are mostly idiopathic. [11] These diseases may follow, precede, or occur simultaneously with pyoderma gangrenosum. Moreover, the classification of pyoderma gangrenosum is dependent on the associated conditions into para inflammatory, paraneoplastic, hematologic, idiopathic, and Drug-induced. Drugs that may be concerned as PG triggers include propylthiouracil, isotretinoin, cocaine, and sunitinib (protein kinase inhibitor). [12]

The most common associations with this condition are IBD, arthritis and hematologic. PG is usually associated with mild IBD and represents as the second most cutaneous manifestation occurring in 0.5% of all IBD patients. It is also frequently associated with RA, sometimes as high as 37% of PG cases having RA. Furthermore, the association between hyper-IgE and PG is rare, but high levels of IgE have never been observed in RA-induced PG. [13, 14].

Bullous PG is typically associated with hematological malignancies, especially acute myelogenous leukemia. Other conditions that are often associated with this condition are lymphoma, monoclonal gammopathy, and myelodysplastic syndrome. 70% of the bullous PG follow, accompany, or precede hematological malignances. [15]

Table 1: Pyoderma gangrenosum (PG)-associated genetic syndromes and their specific gene mutations. [3]

Clinical Variants and Features:

Four clinical variants are recognized based on their clinical and histopathological features: ulcerative (including peristomal), bullous, pustular, and vegetative. Peristomal PG (PPG) is a rare neutrophilic dermatosis that comprises about 15% of all cases of pyoderma, characterized by painful, necrotic ulcerations occurring in the area surrounding an abdominal stoma. On the other hand, pustular pyoderma gangrenosum is rare; it often begins as a pustule or group of pustules that later coalesce and ulcerate. Moreover, it mostly occurs with IBD and tends to occur on the trunk and extensor surfaces of the limbs. The other type, bullous pyoderma gangrenosum, presents with rapidly evolving vesicles or bullae with central necrosis affecting the face and upper limbs more than the lower limbs. It is associated mostly with hematological disorders and malignant neoplasms. Lastly, vegetative PG commonly occurs on the trunk as a multiple or single, non-painful lesion and it usually presents in a less aggressive manner than the other varieties. These vegetative lesions often occur as a single lesion in patients who respond to topical treatments better than the other types and are otherwise well [16].

PG generally starts quite suddenly, usually at the site of a minor injury, Thus it may be triggered by surgical procedures; this phenomenon is often referred to as pathergy. The lesion resulted from surgical scars usually begins as a papule, pustule, or blood blister, which breaks down into a collection of small ulcers with a “cat paws” appearance. It is also characterized by a violaceous border that over hags the ulcers bed, which is usually erythematous and indurated. These coalesce and then the central area undergoes necrosis resulting in a single ulcer. Several ulcers may develop simultaneously over months to years. [16-19].

Patients are often presenting with myalgia, arthralgia, malaise, and fever. Lesions are commonly painful, which can be severe. The lesions usually heal with scarring, often in a cribriform or criss-cross pattern, and the epithelium from the borders extends into the ulcer (referred to as Gulliver’s sign). However, the bullous variant of PG may heal with no scars. Early diagnosis and rapid treatment decrease the risk of disfigurement and scarring. [17, 20]

Diagnosis:

The diagnosis is rather difficult and challenging and the condition is frequently misdiagnosed. The diagnosis process usually requires clinicopathological correlation and often is a diagnosis of exclusion, after ruling out the common causes of skin ulceration by histopathology. However, the histopathological differentiation of PG from other ulcerative processes with dermal neutrophilia is challenging and sometimes impossible. [20]

Numerous literature used the proposed diagnostic criteria for classic ulcerative PG by Su et al. (2004). However, in 2018, diagnostic criteria for pyoderma gangrenosum were made following a Delphi consensus, which highlighted 1 major criterion and 8 minor criteria. However, Jockenhöfer et al. developed PARACELSUS score as a separate diagnostic tool for PG (Table 2). [21–23]

Table 2: Proposed diagnostic criteria

Management:

Treatment and management of PG are considered to be challenging as there is no specific protocol for this issue. However, the mainstay of PG treatment is immunosuppressive therapy and corticosteroids. The most commonly used first-line treatment in the management of PG is systemic steroids. In systemic therapy, typical monotherapy can be used in mild cases. [24] Topical and intralesional steroids are used as ulcer size was an important predictive factor in lesion resolution alongside other systemic therapies (ex, prednisone) as improvements are very slow and relapses are very prevalent. [25] Steroids are less effective in treating PG with comorbid IBD when compared with biological therapy. Multiple different biological agents have been proposed for the treatment of PG. Agents targeting TNF-α are the best studied and the main example is Infliximab, which has a rule in associated RCT and restoring the ability of T-regulatory cells to inhibit aberrant cytokine production. The discovery of new inflammatory cytokines and signal cascades has led to the development of novel biologic therapy. These include IL-12 and -23 antagonists, IL-6 antagonists, intravenous immunoglobulin therapy, and phosphodiesterase 4 inhibitors, which had been shown to have satisfying results in healing and in the complete resolution of the PG lesions. However, the whole healing process might be of a more chronic nature can even take years. [20]

Even though treatment of pyoderma gangrenosum is mainly non-surgical. The necrotic tissue should be removed surgically. During the active stage of PG, wide surgical debridement should be avoided as it may lead to the enlargement of the ulcer. Skin grafting and other surgical procedures may be carried out when the active phase of the disease has settled, with special care to minimize trauma. [20]

CONCLUSION:

Pyoderma gangrenosum is a rare non-infectious inflammatory disorder and was usually diagnosed based on the apparent clinical findings and by the exclusion of other ulcerative skin disorders, resulting in misdiagnosis of the condition in many patients. There are no golden standard diagnostic criteria approved for this condition, however, multiple criteria have been proposed to improve the accuracy of diagnosis, most notably PARACELSUS, which is a novel diagnostic tool. Although the pathophysiology of PG is not yet fully understood, multiple treatment options have been adapted with good results in patients. Corticosteroids and biologic therapy are the mainstay of therapy with more options such as inflammatory agents’ antagonists emerging as other options. Nevertheless, more research is needed in these recent treatment models (biologic therapy) as it is difficult to assess long-term efficacy, adverse events, and remission rates as outcome measures for PG are not widely available.

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