PRACTICE DEVELOPMENT Understanding pyoderma gangrenosum KEY WORDS Pyoderma gangrenosum (PG) is a rare immune-related chronic ulcerating skin Immunosuppression condition with a predilection for the lower limbs. It is more common in females, Pathergy with the average age of onset between 20 and 50 years. There are two stages of the Pyoderma gangrenosum disease process: an ulcerative phase and a healing phase. The latter occurs once the heightened and ongoing inflammatory response has subsided, although the exact pathophysiology of PG has yet to be elucidated. Half of the cases of PG are associated with other comorbidities, such as inflammatory bowel disease, arthritis or haematological malignancies. The skin condition pathergy can be a stimulus for the onset of the disease and is due to incidental or healthcare-related trauma. There is no definitive test to diagnose PG and the diagnosis is one of exclusion. The aim of the treatment is to reduce the inflammation and therefore immunosuppression is the basis of any therapy. Nevertheless, the disease can recur following completion of the healing phase. G is a chronic ulcerating skin condition INCIDENCE OF PG that appears to be immune-mediated. It Patel et al (2015) report incidence of PG as is characterised by deep skin ulcers with 3–10 patients per million worldwide. In Europe, Pundermined edges that occur most often on incidence is thought to be six million per year, with the lower limbs but may affect any skin surface children accounting for 4% of that number (Teagle (Brooklyn et al, 2006a). and Hargest, 2014). It is an overactive inflammatory response to There is a reported female predominance for traumatic, inflammatory or neoplastic process PG (Laun et al, 2016; Sasor et al, 2018) and the and is therefore classified as a systemic auto- condition is most common among 20–50 year olds inflammatory disease (Ratnagobal and Sinha, 2013; (Adusen et al, 2016). There is significant morbidity Adışen et al, 2016). due to pain and poor wound healing, and the mortality rate is three times higher in people with HISTORY PG than the general population — higher still when Brocq, a French dermatologist, first described PG in the patient also has inflammatory bowel disease 1908 as Phagedenisme Geometrique (Gameiro et (IBD) (Mehrtens and Crawley, 2015). al, 2015). In 1931 Brunsting renamed it Pyoderma gangrenosum, believing it to be a disseminated PATHOPHYSIOLOGY streptococcal infection causing cutaneous gangrene In the general population, there is a self-limiting (Teagle and Hargest, 2014). In the 1930s, patients inflammatory response, however, patients with with Rheumatoid Arthritis were treated with PG have a heightened and ongoing inflammatory cortisone and it was noted their co-existent PG response. The duration of this abnormal TRUDIE YOUNG ulcers started to heal: the theory of PG migrated inflammatory response may last weeks to many Director of Education and Training, from infective to autoimmune (Mehrtens and years (Ratnagobal and Sinha, 2013). There are two Welsh Wound Innovation Centre, Ynysmaerdy, Rhondda Cynon Taff, Crawley, 2015). The bullous variant of PG was first stages of the disease: the active, ulcerative stage and Wales described in 1972 (Ratnsglobal and Sinha, 2013). the wound healing stage (Gameiro et al, 2015). Wounds UK | Vol 14 | No 5 | 2018 87 PRACTICE DEVELOPMENT Unfortunately, the cause and exact pathophysiology The individual will present with pain that is Box 1. Proposed diagnostic criteria (Su et al, 2004) of PG is not well understood. However, there is often thought to be out of proportion to the size of the ulcer bed (Schotanus et al, 2014; Tay et al, Major criteria: thought to be an abnormal functioning of the neutrophils (Teagle and Hargest, 2014; Patel et al 2014) and should be screened for the underlying • a painful rapidly progressing 2015; Abtahi-naeini et al, 2016; Laun et al, 2016), associated diseases (Ratnagobal and Sinha, 2013). ulcer which is affected by alterations in chemotaxis and In 2004, Su et al proposed a framework to aid • exclusion of other causes of ulceration phagocytosis (Ratnaglobal and Sinah, 2013). the diagnosis of PG (Box 1). A positive diagnosis is Genetic factors and mutations have been made if the individual has two major and at least Minor criteria: identified in patients with PG, as demonstrated two minor diagnostic characteristics. • the presence of systemic diseases in PAPA syndrome (pyogenic arthritis, PG, acne) As is evident in Box 2, PG is often confused with associated with PG • history suggestive of pathergy and PASH syndrome (PG, acne, suppurative other skin conditions/diseases (Sasor et al, 2018). • characteristic histopathological hidradenitis) (Mehrtens and Crawley, 2015; Furthermore, inability to distinguish between sub- findings Braswell et al, 2015; Shavit et al, 2017). types of PG can delay diagnosis and have serious • response to systemic steroids or clinical consequences (Brooklyn et al, 2006a), immunosuppression ONSET including delayed treatment and negative effects The onset of PG is variable: some patients present on quality of life. with one or two slowly growing ulcers, others Box 2. Differential diagnosis experience the sudden appearance of multiple PATHERGY • Skin infection, skin malignancy, rapidly enlarging ulcers (Patel et al, 2015). In a Pathergy is defined as a pathological hyper- vascular ulceration, systemic retrospective study of 27 patients, the disease reactivity to normal stimuli (Teagle and Hargest, conditions — systemic lupus duration spanned between 15 and 14,600 days 2014). In PG, 25% of cases are triggered by erythematosus, rheumatoid (Adisen et al, 2016). pathergy due to incidental or healthcare-related arthritis, Behcet's disease, Around 50% of cases of PG are associated with trauma (Ormerod et al, 2015). Examples of Wegener's granulomatosis, and another underlying condition, the remaining 50% pathergy-induced PG include wound infection and Sweet's syndrome (Brooklyn et are idiopathic, having no known cause (Teagle and surgical procedures, e.g. caesarean section, breast al, 2006) • Drug reaction, insect bite, Hargest, 2014). reduction and central line insertion (Braswell et factitious disorder, dermatitis PG can also occur in patients with HIV, solid al, 2015; Patel et al, 2015, Abtahi-naeini et al, 2016, artefacta (Teagle and Hargest, tumours and during pregnancy (Gameiro et al, Pichler et al, 2016). Stoma formation can induce 2014; Schotanus et al, 2014; 2015; Shavit et al, 2017) and can be drug-induced, PG along with accompanying excoriation from Montero et al, 2016). with Isotretinoin reported as a causative agent bowel contents and skin stripping during removal • Necrotising fasciitis as can occur (Teagle and Hargest, 2014). of containment device (Wallace, 2017). in the vulva, groin and penis (Tay Litvinov and Sasseville (2014) report a case of et al, 2014; Bhaskaran et al, 2016). DIAGNOSIS PG hastened by red tattoo dye, which caused an • Allergic contact dermatitis in In the absence of a definitive test (serologic or allergic contact dermatitis — the pathergy trigger. peristomal PG (Afifi et al, 20180) histological), PG is diagnosed by exclusion of other diseases (Patel et al, 2015; Wallace, 2017). TYPES OF PG Nevertheless, a biopsy will be taken from the There are five subtypes of PG and an individual ulcer bed and the adjacent skin and sent for can suffer from more than one subtype at any one histological examination (Patel et al, 2015). A time (Gameiro et al, 2015) (Box 3). typical biopsy result will identify a neutrophil and Classic PG is associated with IBD, arthritis other inflammatory cell infiltration into the dermis and haematological malignancies, with 25–50% (Brooklyn et al, 2006b; Schotanus et al, 2014, associated with pathergy (Brooklyn et al, 2006b; Teagle and Hargest, 2014). If the PG inflammation Teagle and Hargest, 2014). is minimal, the biopsy result will identify non- The clinical presentation is of a deep ulcer specific histopathology (Shavit et al, 2017). that can extend into the subcutaneous fat In PG, the generic systemic inflammatory and fascia, with a purulent or haemorrhagic markers will be raised, e.g. C-reactive protein, and discharge (Schotanus et al, 2014). The ulcer has more so in the active ulcerative stage of the disease a well-defined undermined violaceous border (Tay et al, 2014). accompanied by erythema of the surrounding 88 Wounds UK | Vol 14 | No 5 | 2018 PRACTICE DEVELOPMENT Box 3. Five subtypes of pyoderma gangrenosum • Classic pyoderma gangrenosum • Peristomal pyoderma gangrenosum • Pustular pyoderma gangrenosum • Bullous pyoderma gangrenosum • Vegitative/superficial pyoderma gangrenosum Figure 1. Classic PG Figure 2. Healed PG skin (Figure 1). It often starts as a small papule or The clinical presentation is rapidly evolving collection of papules that break down to form painful concentric bullae and vesicles that spread small ulcers that coalesce and form a wound with swiftly in a concentric pattern with a violaceous a necrotic centre. The individual is systematically flare that can develop into superficial ulcers unwell with symptoms such as fever, malaise, (Ratnaglobal and Sinha, 2013; Schotanus et al, arthralgia and myalgia. The ulcers, commonly 2014). found on the legs, are excruciatingly painful and It affects the upper limbs and face and dorsum of form unsightly, cribriform scarring. the hands (Shavit et al, 2017). Peristomal PG is associated with IBD and Vegetative/superficial granulomatous PG occurs close to abdominal stomas,