INTRODUCTION — Pyoderma gangrenosum (PG) is an uncommon neutrophilic dermatosis that presents as an inflammatory and ulcerative disorder of the skin. In contrast to its name, PG is neither an infectious nor gangrenous condition. The most common presentation of PG is an inflammatory papule or pustule that progresses to a painful ulcer with a violaceous undermined border and a purulent base (picture 1A-E). PG may also present with bullous, vegetative, peristomal, and extracutaneous lesions.
More than half of patients with PG develop the disorder in association with an underlying systemic disease. Inflammatory bowel disease, hematologic disorders, and arthritis represent the most frequent comorbidities.
A diagnosis of PG rests upon the recognition of consistent clinical and histologic findings and the exclusion of other inflammatory or ulcerative cutaneous disorders. There are no pathognomonic, clinical, or histologic findings of PG.
The pathogenesis, clinical manifestations, and diagnosis of PG will be discussed here. The treatment and prognosis of PG and other neutrophilic dermatoses are reviewed separately. (See "Pyoderma gangrenosum: Treatment and prognosis" and "Neutrophilic dermatoses".)
EPIDEMIOLOGY — PG is a rare disorder with an estimated incidence of 3 to 10 cases per million people per year [1]. Individuals of any age may be affected, including children [2-4]. PG most commonly develops in young and middle-aged adults, with an average age of onset between 40 and 60 years [5-8]. Between the sexes, women are more frequently affected [7].
PATHOGENESIS — Consistent with its categorization as a neutrophilic dermatosis, PG is characterized by neutrophil-predominant infiltrates in the skin. Research has begun to elucidate dysregulation in the innate and adaptive immune response, in addition to genetic factors, in the pathogenesis of PG:
●Immune dysregulation – Studies have revealed complex gene expression profiles in the skin of patients with PG. Lesional skin of PG has increased expression of interleukin (IL) 1-beta, IL-1-alpha, IL-8, IL-12, IL-15, IL-17, IL-23, IL-36, and tumor necrosis factor (TNF)-alpha [9-11]. This upregulation leads to a proinflammatory state through increased activation of inflammasomes, dysregulation of the innate immune system, and recruitment and activation of neutrophils [9]. PG tissue also has increased expression of pattern recognition receptors (PRRs), JAK2, and STAT1, implicating both adaptive and innate immune response dysfunction [10]. The complement pathway, particularly C5a and its role in neutrophil activation, chemotaxis, and inflammatory signaling, may also contribute to the complex pathogenesis of PG [12].
●Genetic factors – Genetic susceptibility also likely contributes to the development of PG. Familial cases of PG have been reported [13-16]. In addition, PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome (OMIM #604416), an autosomal dominant disorder, has been linked to mutations in the PSTPIP1/CD2BP1 gene. This mutation leads to decreased inhibition of the inflammasome and, ultimately, increased production of IL-1-beta and autoinflammation [17]. Mutations of the autoinflammatory genes MEFV, NLRP3, NLRP12, NOD2, and LPIN2 have been demonstrated in PG, PASH (pyoderma gangrenosum, acne, and suppurative hidradenitis) syndrome, and other inflammatory conditions, including familial Mediterranean fever, cryopyrin-associated periodic syndrome, Crohn disease, and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome [9]. (See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)", section on 'PAPA syndrome'.)
Further elucidation of the molecular pathways in PG have allowed for more targeted treatments, including TNF-alpha, IL-1, IL-17, IL-23, and IL-6 inhibitors. (See "Pyoderma gangrenosum: Treatment and prognosis".)
CLINICAL MANIFESTATIONS — The clinical manifestations of PG are variable and can be divided into four major subtypes: ulcerative (classic) PG (the most common variant), bullous (atypical) PG, pustular PG, and vegetative PG [18].
Common features — The subtypes of PG share a clinical course characterized by the appearance of an inflammatory papule, pustule, vesicle, or nodule that subsequently expands and breaks down to form an erosion or ulcer. With the exception of vegetative PG, lesion development is often rapid and the level of pain is often greater than expected based upon the appearance of the ulcer [18]. Fever may or may not be present [19].
Pathergy, a term used to describe the induction or exacerbation of PG in sites of incidental or iatrogenic trauma, is frequently mentioned in descriptions of the clinical behavior of PG. However, not all patients with PG exhibit this feature. Data on the proportion of patients with PG who experience pathergy are limited. In a retrospective study of 103 patients with PG, pathergy was documented in the medical records of 31 percent of patients [7]. In a series of 166 patients with PG, 25 (15 percent) experienced 33 episodes of postsurgical recurrence or exacerbation of the disease; factors associated with increased risk of pathergy included open surgical procedures, Mohs surgery, and PG present at the time of procedure [20].
Subtypes — Descriptions of the major variants of PG are provided below:
●Ulcerative (classic) pyoderma gangrenosum – The ulcerative variant of PG represents the vast majority of cases of PG. Ulcerative PG typically begins as a tender, inflammatory papule, pustule, or vesicle that develops on normal-appearing skin or at a site of trauma (picture 2A-B). The lower extremities and trunk are the most common sites of involvement, though lesions may occur in other areas [1].
The initial inflammatory lesion subsequently expands peripherally and degenerates centrally, leading to ulcer formation (picture 1A-E). The edge of the ulcer usually exhibits a bluish or violaceous color and demonstrates an undermined quality. Irregular expansion of the involved tissue may lead to a serpiginous configuration. The base of the ulcer is purulent and necrotic, and the depth of the ulcer often extends into subcutaneous fat and occasionally reaches the fascia [1].
Patients may have a single lesion or multiple lesions in various stages of development. Ulcers typically resolve with atrophic, cribriform scars.
●Bullous (atypical) pyoderma gangrenosum – Bullous PG is a less common, superficial variant of PG that is most commonly seen in patients with PG related to hematologic disease [6]. Unlike ulcerative PG, the arms and face are the most common sites of involvement [1,6]. Patients typically present with the rapid development of blue-gray, inflammatory bullae in the involved areas [6]. The bullae quickly erode, resulting in superficial ulcers (picture 3).
Due to the strong association between bullous PG and hematologic disease, patients who present without an associated hematologic disorder should be followed closely for the development of a hematologic disorder [21].
●Pustular pyoderma gangrenosum – Pustular PG usually occurs in patients with inflammatory bowel disease, and tends to arise during periods of acute exacerbations of bowel disease [18]. Affected patients exhibit the rapid development of painful pustules surrounded by erythema (picture 4). Concomitant fever and arthralgias are common [1]. Pyostomatitis vegetans, which presents with multiple small pustules and erosions on the oral mucosa, may be a variant of pustular PG [1,22].
●Vegetative pyoderma gangrenosum – Vegetative PG (also known as superficial granulomatous pyoderma) is a typically localized, solitary, superficial form of PG that presents as an indolent, mildly painful nodule, plaque, or ulcer (picture 5). A verrucous quality is often present. The undermined borders and purulent bases of ulcerative PG are absent. The head, neck, and trunk are the most common sites for vegetative PG [1].
Special sites — In addition to the morphologic subtypes reviewed above, other terms have been used to describe certain presentations of PG. Examples include peristomal PG, genital PG, and extracutaneous PG:
●Peristomal pyoderma gangrenosum – Peristomal PG is an uncommon manifestation of PG that is characterized by the development of lesions consistent with ulcerative PG adjacent to a stoma (picture 6). This typically occurs in patients with ulcerative colitis or Crohn’s disease and may develop months to a few decades after placement of a stoma. Trauma caused by maintenance of the stoma or irritation from stoma secretions may play a role in the development of peristomal PG [1].
●Genital pyoderma gangrenosum – Genital PG may involve the vulva, penis, or scrotum. Lesions resemble those of ulcerative PG (picture 7).
●Extracutaneous pyoderma gangrenosum – Rarely, PG involves extracutaneous sites. In such cases, sterile neutrophilic infiltration develops in sites such as the lungs, intestine, cornea, liver, spleen, heart, bones, muscle, and central nervous system [23-35].
●Postoperative pyoderma gangrenosum – Postoperative PG is the development of PG in a surgical site, usually within two weeks after surgery [36]. The initial symptoms are surgical-site erythema and extreme pain out of proportion to the physical examination followed by wound dehiscence or the development of punctate ulcerations that coalesce into larger ulcers. Postoperative PG appears to be more common in women than in men. Common sites of involvement are the breasts and abdomen [36].
ASSOCIATED DISORDERS — More than 50 percent of patients with PG have an associated systemic disease, most commonly inflammatory bowel disease, arthritis, and hematologic disease or hematologic malignancy [5-7]. The proportion of patients with specific comorbidities varies among studies [5-7,37]. In one of the largest studies, a retrospective cohort study of 356 adults with PG, 161 (45 percent) had associated comorbidities, including [37]:
●146 patients (41 percent) with inflammatory bowel disease
●73 patients (21 percent) with inflammatory arthritis
●23 patients (7 percent) with solid organ malignant neoplasms
●21 patients (6 percent) with hematologic malignant neoplasms
●17 patients (5 percent) with hematologic disorders (monoclonal gammopathy of undetermined significance, myelodysplastic syndrome, or polycythemia vera)
Additional findings of this study suggest that patient age influences risk for specific comorbidities. Patients aged 65 years or older were more likely to have associated rheumatoid arthritis, ankylosing spondylitis, solid organ malignant neoplasms, hematologic malignant neoplasms, and hematologic disorders than younger patients. Inflammatory bowel disease was more common in patients under the age of 65 years.
PG may precede or follow the diagnosis of an associated disorder and may or may not parallel the clinical course of the associated disease [21,38].
PG may occur as a feature of autoinflammatory syndromes, such as PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome, PAPASH (pyogenic arthritis, pyoderma gangrenosum, acne, and suppurative hidradenitis [hidradenitis suppurativa]) syndrome, and PASH (pyoderma gangrenosum, acne, and suppurative hidradenitis) syndrome [39-42]. PAPA syndrome is an autosomal dominant disorder and occurs secondary to a defect in the PSTPIP1/CD2BP1 gene. PAPASH syndrome has been described in an adolescent in whom a novel mutation in the PSTPIP1 gene was detected [39]. PG has also been described in a patient with dissecting cellulitis of the scalp, hidradenitis suppurativa, and inflammatory acne [43]. (See 'Pathogenesis' above and "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)", section on 'PAPA syndrome'.)
Examples of additional disorders that have been infrequently linked to PG include pulmonary disease, systemic lupus erythematosus, thyroid disease, solid organ cancers, viral and autoimmune hepatitis, sarcoidosis, major depression, and diabetes [7,38,44]. In addition, PG has also been reported in patients exposed to levamisole [45]. Further study is necessary to validate a relationship between these disorders and PG.
DIAGNOSIS — The clinical, histopathologic, and laboratory findings in PG are nonspecific, and a diagnosis of PG can only be made once other diagnostic possibilities have been excluded. At least a clinical history, physical examination, and skin biopsy should be performed in all patients [38]. In patients known to have diseases associated with PG, the development of an ulcer should raise suspicion for this diagnosis. In addition, once PG has been diagnosed, patients should be evaluated for the presence of an associated underlying disease. (See 'Associated disorders' above and 'Laboratory studies' below.)
Diagnostic criteria — Historically, universally accepted and validated diagnostic criteria for PG have been lacking. Diagnostic criteria published in 2004 require the exclusion of all other diagnoses, which can be challenging or impractical in the clinical setting (table 1) [46]. Newer diagnostic criteria for ulcerative PG developed through a Delphi consensus of international experts provide greater structure to the diagnostic process and are our preferred tool for diagnosis [47]. These criteria include a single major criterion and eight minor criteria, including histologic, history, clinical examination, and treatment findings (algorithm 1).
●Major criterion:
•Biopsy of ulcer edge demonstrating a neutrophilic infiltrate
●Minor criteria:
•Exclusion of infection
•Pathergy
•Personal history of inflammatory bowel disease or inflammatory arthritis
•History of papule, pustule, or vesicle that rapidly ulcerated
•Peripheral erythema, undermining border, and tenderness at site of ulceration
•Multiple ulcerations (at least one occurring on an anterior lower leg)
•Cribriform or "wrinkled paper" scar(s) at sites of healed ulcers
•Decrease in ulcer size within one month of initiating immunosuppressive medications
At least the major criterion and four minor criteria are necessary for diagnosis.
A third diagnostic criteria, the PARACELSUS score, utilizes a point system with slightly different major and minor criteria [48]. This system was designed specifically for the purpose of differentiating venous leg ulcers from PG.
Diagnostic criteria are used predominantly for clinical studies but may offer a framework for diagnosis in daily practice.
Clinical assessment — The clinical assessment of the patient with a lesion suspicious for PG should include a thorough history and physical examination. Patients should be questioned regarding the history of lesion development, associated symptoms, and personal medical history. Examples of findings attainable via a patient history that support a diagnosis of PG include:
●Rapid course of lesion development
●Initial lesion consistent with papule, pustule, or vesicle
●Pain out of proportion to lesion
●History of preceding trauma (pathergy)
●History of disorders associated with PG (see 'Associated disorders' above)
The physical examination is useful for identifying the extent of disease, narrowing the differential diagnosis, and detecting clinical signs of PG-associated disorders.
Biopsy — Since the histopathologic findings of PG are nonspecific, biopsies are most useful for excluding other disorders that may present with similar clinical findings. A biopsy is indicated in patients without a preceding history of PG and in patients with established PG who present with lesions with atypical features or lesions that fail to respond as expected to therapy. Although clinicians are often concerned about biopsy-induced pathergy, the need to rule out other disorders and ensure proper treatment supersedes concern for the induction of an exacerbation of PG.
Procedure — The optimal procedure for biopsy is an elliptical incisional biopsy that incorporates both the inflamed lesion border and ulcer edge and extends vertically into the subcutaneous fat [46]. A tissue specimen that includes the inflamed border should be sent for routine histopathologic examination and microbial stains. In addition, a specimen from the ulcer should be sent for culture to evaluate for bacterial, fungal, and atypical mycobacterial infections.
Pathology — Specimens taken from the earliest lesions of PG demonstrate perifollicular inflammation and intradermal abscess formation (picture 8A-B) [49]. Once lesions progress to ulceration, epidermal and superficial dermal necrosis with an underlying mixed inflammatory cell infiltrate and abscess formation are typically detected. Giant cells may be found, and tissue from the edge of the lesion may demonstrate vascular changes suggestive of lymphocytic vasculitis. Leukocytoclastic vasculitis may also be present [49].
Additional findings may be identified based upon the subtype of PG. Specimens from bullous PG demonstrate subepidermal bullae. Pseudoepitheliomatous hyperplasia, sinus tracts, and palisading granulomas are features consistent with vegetative PG.
Direct immunofluorescence studies yield nonspecific findings in PG. Deposition of IgM, C3, and fibrin in vessel walls may be detected [38]. Because of the nonspecific nature of the results, direct immunofluorescence is usually only conducted when additional clinical findings indicate a need to exclude autoimmune bullous disease, lupus, or vasculitis as a cause of ulceration [46]. (See "Approach to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)
Laboratory studies — Similar to tissue biopsies, there are no laboratory studies that provide a definitive diagnosis of PG. Nonspecific findings such as leukocytosis, elevation of the erythrocyte sedimentation rate, and elevation of C-reactive protein levels may be present [19].
Laboratory tests are most useful for narrowing the differential diagnosis and identifying the presence of PG-associated diseases. Recommendations for the work-up of these patients vary. We typically obtain the following studies in patients with clinical and histopathologic findings consistent with PG:
●Complete blood count (to evaluate for underlying hematologic disorders)
●Comprehensive metabolic panel (to evaluate for hepatic or renal dysfunction and glucose abnormalities prior to initiation of systemic glucocorticoids or immunosuppressive agents)
●Antinuclear antibody titer (to evaluate for the presence of systemic lupus erythematosus or collagen vascular disorders in association with PG)
●Antineutrophilic cytoplasmic antibodies (to evaluate for granulomatous vasculitis as a cause of ulceration)
●Hypercoagulability studies (antiphospholipid antibody screen to evaluate for antiphospholipid syndrome as a cause of ulceration; based upon clinical suspicion, other tests to evaluate for thrombotic states [eg, cryoglobulins, Factor V Leiden, methylene tetrahydrofolate reductase])
●Hepatitis panel (to evaluate for associated hepatitis B or C, particularly for patients in whom immunomodulatory therapy is considered)
●Rheumatoid factor (as a component of the evaluation for cryoglobulinemia and rheumatoid arthritis)
●Serum immunofixation electrophoresis (to evaluate for paraproteins)
●Chest radiography (to evaluate for presence of extracutaneous involvement and for possible infection prior to the initiation of immunosuppressive therapy)
●Colonoscopy (to evaluate for underlying inflammatory bowel disease unless another cause of PG is identified)
Additional tests to evaluate for associated disorders and disorders in the differential diagnosis are ordered based upon clinical suspicion for specific diseases.
Differential diagnosis — Due to the lack of a definitive test for PG, misdiagnosis can occur. In one retrospective study, 15 of 157 consecutive patients seen at an academic institution and given a diagnosis of PG (10 percent) were subsequently found to have an alternative diagnosis [50].
Vascular occlusion disorders, venous disease, vasculitis, malignancy, cutaneous infection, drugs, exogenous tissue injury, and ulcerative inflammatory disorders (eg, cutaneous Crohn’s disease and ulcerative necrobiosis lipoidica) may be mistaken for PG (table 2) [50]. Antiphospholipid-antibody syndrome is one of the most common disorders mistaken for PG; other more commonly confused disorders include venous stasis ulcers, granulomatosis with polyangiitis, factitial ulcers, sporotrichosis, polyarteritis nodosa, livedoid vasculopathy, angiocentric T cell lymphoma, and cryoglobulinemia [50]. Necrotizing fasciitis is an additional potential misdiagnosis [51]. Aggressive debridement for this presumed diagnosis can lead to significant morbidity and deformity [52-54]. (See "Neutrophilic dermatoses", section on 'Necrotizing neutrophilic dermatoses' and "Necrotizing soft tissue infections".)
The clinical history, biopsy, and directed laboratory studies attained during patient evaluation aid in distinguishing PG from other diseases. Reassessment of a diagnosis of PG is indicated if the disease fails to respond as expected to therapy. (See "Pyoderma gangrenosum: Treatment and prognosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pyoderma gangrenosum".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Pyoderma gangrenosum (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Pyoderma gangrenosum is an uncommon neutrophilic dermatosis that most commonly presents with inflammatory ulcers on the skin. Although PG may occur at any age, there is a predilection for young and middle-aged adults and women. (See 'Epidemiology' above.)
●Pathogenesis – The factors that contribute to the development of PG are not well understood. Factors that are postulated to contribute to PG include dysregulation of the immune system and genetic susceptibility. (See 'Pathogenesis' above.)
●Clinical manifestations – The clinical manifestations of PG vary. The most common presentation is ulcerative (classic) PG, which typically presents as a rapidly developing, painful purulent ulcer with a violaceous and undermined border (picture 1A-E). Other variants of PG include bullous, pustular, and vegetative presentations. PG may also develop in peristomal, genital, and extracutaneous locations. (See 'Clinical manifestations' above.)
●Associated disorders – More than 50 percent of patients with PG have an associated systemic disease. The strongest associations are between PG and inflammatory bowel disease, hematologic disorders, and arthritis. (See 'Associated disorders' above.)
●Diagnosis – Since the clinical and histologic findings of PG are nonspecific, PG is a diagnosis of exclusion (table 2). At a minimum, the patient evaluation should include a patient history, physical examination, and biopsy to detect findings consistent with PG and to rule out other diseases. (See 'Diagnosis' above.)
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