Volume 24 Number 1

Overview

Pyoderma gangrenosum (PG) is an atypical neutrophilic dermatosis that appears as an inflammatory and ulcerative condition of the skin¹. First described by Brocq in 1916, as phagedenisme geometrique, a rare neutrophilic dermatosis². Brunstig, Goeckerman and O’Leary in 1930 named it pyoderma gangrenosum. This was based on a series of five case reports of patients with ulceration of the skin³. Initially they believed that the condition was related to streptococcal infection, leading to cutaneous gangrene. Four of the patients had chronic ulcerative colitis, hence the initial association with inflammatory bowel disease. Brunstig et al. describe the ulcers as enlarging, painful, necrotic with bluish edges and circumferential erythema. Contrary to its name, it is neither infectious or a gangrenous disorder. Although first described almost 100 years ago, the aetiology remains a mystery⁴.

Epidemiology

Epidemiology data for the condition is based predominantly on case reports, case series and cohort studies, mostly in patients with inflammatory bowel disease^2,5-10. A rare condition, the incidence is estimated at three to 10 cases per million per year^2,4. Based on a large population-based cohort study the incidence in the UK is estimated at six per million per year⁸. PG generally affects people between the ages of 20 and 50 years⁴; it has also been reported in approximately 4% of children^1,2,11-13. Data regarding gender is contradictory. According to some there is a higher incidence in females^2,4,8,9,14, although others have reported no gender preference^2,5.

Pathogenesis

PG is classified as a neutrophilic dermatoses, with neutrophil predominant infiltrates of the skin, without evidence of primary vasculitis¹⁵. The physiological process that leads to PG remains ambiguous. Early hypotheses included occult bacterial infection, circulating antibodies, or the Shwartzman reaction (an immune response to bacterial endotoxins leading to tissue necrosis). However, there is a lack of evidence to support these theories¹. Current postulations regarding the pathogenesis of PG include neutrophil dysfunction, genetic factors and dysregulation of the innate immune system.

In pathology specimens there is the presence of neutrophilic infiltrates; this combined with the clinical response to anti-neutrophil agents, such as colchicine and dapsone, which disrupts chemotaxis and phagocytosis, suggests that neutrophilic dysfunction plays a role in the pathophysiology of PG^16,17. One study suggests that there are abnormalities in neutrophil trafficking and signalling, related to intracellular metabolic oscillations in patients with PG¹⁸.

Genetic features that have been reported include familial cases of PG and also PG related to pyogenic sterile arthritis syndrome (PAPA) and acne^19-24. There is also a growing body of evidence to suggest that dysregulation of the innate immune system is associated with PG^25,26. This builds on the evidence of neutrophil dysfunction.

Clinical Presentation

The lesions commonly occur on the lower legs, classically the pre-tibial region, but can occur on any anatomical location including: trunk, head, neck, breasts, upper limbs, genitalia, mucous membranes and peristomal distribution^1,2,27-29. Lesions have been reported to occur concurrently on different anatomical locations². Characteristically, the lesions begin as a small nodule or sterile pustule³⁰ which enlarge into well-demarcated ulcers, which can extend to the fascia with violaceous margins (red-blue) undermined border, surrounding erythema and induration. Typically the lesions have necrosis at the base, friable granulation tissue with a purulent or haemoserous exudate². The ulcers are often described as “necrolytic”, a process whereby as the tissue is destroyed, the liquefactive necrosis reveals a red-blue undermined wound edge³⁰. Invariably the lesions are extremely painful. Atrophic cribriform pigmented scarring can occur as the lesions heal, particularly with delayed diagnosis and treatment^2,4. PG has also been described in association with pathergy, a process that occurs as a result of trauma. This has been reported in wounds ranging from minor trauma to surgical incision sites^10,31. In surgical wounds, PG has been erroneously diagnosed as infection leading to wound debridement, which has triggered pathergy, resulting in aggravation of the disease and on occasion leading to amputation^32,33. In a retrospective review of 103 patients, pathergy was documented in 31% of patients¹⁴.

Clinical Variants

According to Powell et al. there are four clinical subtypes: ulcerative or ‘classic’; bullous (atypical); pustular; and vegetative, all sharing similar characteristics⁶. Peristomal PG, genital PG, extracutaneous PG and infantile PG have also been described in the literature^1,2,4.

Ulcerative: Most common variant. Starts as a tender papule or vesicle that rapidly ulcerates, has a purulent base, with undermined, inflamed, violaceous borders. Painful lesions associated with systemic disease, requiring immunosuppressive treatment^6,29.

Bullous: Less common variant, associated in patients with haematological malignancy, an indicator of a poor prognosis. It is characterised by painful bullae, usually located on the upper limbs and face. The bullae may spread and progress to superficial lesions and ulcers. Systemic immunosuppression is required^2,4,6.

Pustular: This variant of PG is most often associated with inflammatory bowel disease (IBD) and may occur during exacerbations of bowel inflammation. Small painful pustules, with surrounding erythema, that usually improve with the treatment of IBD^4,6.

Vegetative: Also known as superficial granulomatous pyoderma, the least painful and aggressive of all the variants of PG. It is a superficial nodule, plague or ulcer that progresses slowly without undermined edges or a purulent wound bed. Responds well to less aggressive forms of treatment^4,6.

Peristomal: Development of lesions in the peristomal area following formation of an ileostomy or colostomy in patients with ulcerative colitis or Crohn’s disease. Possibly as a result of pathergy from the surgical procedure, leakage of faeces on to the skin, or irritation from adhesive stomal appliances^2,4,28,34.

Genital: Lesions occurring on the vulva, penis or scrotum. Behçet’s disease should be excluded⁴.

Extracutaneous: Rare form of PG, sterile neutrophilic infiltrates occurring in sites such as the lungs, spleen, central nervous system, gastrointestinal tract, intestine, liver, cornea, heart, and lymph nodes⁴.

Associated disorders (Table 1²⁹)

It has been estimated that approximately 40–50% cases of PG are associated with a systemic disease and the remainder are idiopathic^2,4. PG is the most common skin disorder associated in patients with IBD (Crohn’s disease and ulcerative colitis) and has been reported in approximately 2–12% of patients with IBD³⁵. Other common disorders include arthritis⁹, haematological malignancy¹⁴, PAPA syndrome², hidradenitis suppurativa, and HIV¹.

 

Table 1: Diseases associated with pyoderma gangrenosum²⁹

Wollina U. Clinical management of pyoderma gangrenosum. Am J Clin Dermatol 2002;3(3):149–58.

 

Diagnosis

Histopathology and laboratory findings in PG are non-specific; therefore, the diagnosis is based on clinical history, physical examination and confirmed through a process of elimination. There should be a high index of suspicion in patients with non-healing ulcers, especially in the presence of systemic diseases². The clinician must, however, err on the side of caution as many of the associated diseases may not be overtly obvious⁴. There are several differential diagnoses, and ulcerative cutaneous lesions that mimic PG (Table 2¹) including: malignancy, infectious disease, antiphospholipid antibody-associated occlusive disease, vasculitis, and drug reactions^2,4.

 

Table 2: Differential diagnosis of pyoderma gangrenosum¹ 

Ahronowitz I, Harp J, Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review. Am J Clin Dermatol 2012;13(3):191–211.

 

Laboratory investigations are not diagnostic for PG; patients often have neutrophil leukocytosis^30,36. The inflammatory process is reflected with elevated erythrocyte, C-reactive protein, and protein electrophoresis²⁹. It is important to target laboratory investigations for associated diseases, such as IBD or arthritis, and to exclude other ulcerating conditions; for example, other autoimmune connective tissue diseases, or anticardiolipin syndrome^29,30. Tissue biopsy for histopathology should be performed to exclude other conditions such as malignancy or vasculitis. A biopsy can also be performed for microbiology, culture and sensitivity (MC&S), particularly looking for atypical mycobacteria, fungi and parasites. Although performing a tissue biopsy can cause pathergy, the procedure should be performed, as this will assist in ruling out other aetiologies^1,2,4.

The important factor to take into consideration is that PG mimics many other conditions, leading to misdiagnosis^1,30,37. Delay in treatment can lead to extensive tissue loss, undue pain for the patient and potentially inappropriate therapies². Early referral to a physician or dermatologist is recommended if PG is suspected³⁰. Su et al. proposed a diagnostic criterion for classic ulcerative PG, to consider the essential features for diagnosing PG. Both of the major criteria must be met and two from the minor criteria³⁰.

Major criteria

1. Rapid progression of a painful, necrolytic cutaneous ulcer with an irregular, violaceous, and undermined border

2. Other causes of cutaneous ulceration have been excluded

Minor criteria

1. History suggestive of pathergy or clinical finding of cribriform scarring

2. Systemic diseases associated with PG

3. Histopathologic findings (sterile neutrophilia, +/– mixed inflammation, +/– lymphocytic vasculitis)

4. Treatment response (rapid response to systemic steroid treatment)

Treatment

There is a paucity of guidelines for the treatment of PG. This is due to a lack of clinical controlled trials. The disease process in poorly understood and treatment is based predominately on clinical experience⁴. Approach to treatment should be multidisciplinary, including dermatology, rheumatology, wound care specialists, pain specialists and pathologists³⁶. Treatment aim is to reduce the inflammation, minimise pain, promote wound healing, and control underlying disorders^1,2,4. If the patient has any underlying systemic disease, control of this often results in the control of skin lesions². As there are numerous approaches to treatment a comprehensive review is outside the scope of this article. The authors have provided a summary of treatment options. Response to treatment is considered one of the minor diagnostic criteria, as suggested by Su et al.

Wound care

At each presentation the lesions should have a comprehensive assessment of the wound bed and the wound border, paying attention in particular to the type of tissue at the wound bed, amount and type of exudate, evidence of violaceous wound margins and the level of pain the patient is experiencing. The wound(s) should be measured, including length, width, depth, and, if possible, clinical photography of the wound as this allows for accurate ongoing wound assessment³⁸. The TIME principle should be used as a guide for selecting the appropriate wound dressing^39,40. Dressing selection will depend on the wound assessment; however, the dressing should be non-adherent to the wound bed and removed easily to minimise pain and trauma. Dressings that adhere to the wound bed may increase pain on removal and trigger pathergy¹. Although PG is not infectious, having an open wound may increase the risk of infection; therefore, the wound and peri-wound must be monitored for clinical signs of infection such as: erythema, warmth, increased pain, increased exudate, lymphangitis and malodour¹. In the presence of infection appropriate treatment should be commenced, including antibiotics and topical antimicrobial dressings⁴⁰.

Topical agents

For small lesions, such as superficial pustules or shallow ulcers, treatment can include local application of high-potency corticosteroid lotion, ointment, cream or intralesional injections^1,21,29,38. Topical agents can also be used in conjunction with systemic therapy for patients with severe PG³⁸. Topical corticosteroids are more effective in patients with peristomal PG. Local injections of triamcinolone are preferred for non-peristomal PG²⁹. Tacrolimus (FK-506), cyclosporine solution and intralesional injection of cyclosporine have also been used on PG lesions^1,29,38. However, there is the need for larger clinical studies to prove their efficacy in the management of PG³⁸. These must be applied with caution due to the risk of systemic absorption³⁸. Other topical agents described in the literature include: topical application of 5-Aminosalicyclic acid¹, recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF)⁴¹. There are also reports of the application of nicotine transdermal delivery on the ulcers and use of nicotine gum^42,43.

Systemic treatment

Systemic therapy is required in patients with all but superficial lesions². Topical agents also do not address systemic disease and as the disease progresses a combination of topical and systemic agents may be required (Table 3⁴). Systemic treatments have many side effects and can dampen the patients’ immune response, leaving them more susceptible to infections. Systemic high-dose corticosteroids, such as prednisolone, are often used initially with a rapid response; however, there are well-documented adverse effects with long-term use^1,38. Another first-line treatment is cyclosporine; however, side-effects include renal toxicity, myelosuppression, hepatotoxicity and increased risk of infection^1,38. Patients with underlying IBD have gone into remission with the use of cyclosporine⁴⁴. Other modes of immunosuppression include mycophenolate, mofetil, methotrexate and azathioprine. These agents are considered more effective as adjunct therapy¹. Immune modulators such as thalidomide are an emergent treatment option. These suppress neutrophil chemotaxis and tumour necrosis factor alpha (TNF-α)². Thalidomide and methotrexate are considered more effective as adjunctive therapy³⁸. In patients with less severe forms of PG sulphur drugs are considered a second choice. Dapsone alone or in combination with corticosteroids is a common treatment. Neutrophil function and the production of reactive oxygen species is inhibited with dapsone²⁹. Patients must have normal levels of glucose-6-phosphate dehydrogenese for this line of therapy^29,38. Other immune modulation agents include infliximab and interferon-α^1,2,4,36.

 

Table 3: Topical and systemic treatment of pyoderma gangrenosum⁴

Rucco E, Sangiuliano AG, Miranda A, Nicoletti G. Pyoderma gangrenosum: an updated review. J Eur Dermatol Venerol 2009;23(9):1008–17.

 

Surgical intervention

Surgery is not generally recommended due to the risk of pathergy^1,45; as a result the ulcers could potentially worsen following surgery¹. However, there are a few reports in the literature of success following surgical intervention. There is one report of success with a free flap to cover a large lesion⁴⁶, and the use of split-skin grafts and keratinocyte autografts⁴⁷. Split-skin grafting has also been shown to reduce the patients’ pain⁴⁵. There is also a case report of debridement, vacuum-assisted closure (VAC^®) and hyperbaric oxygen therapy to promote wound healing⁴⁸. According to Teagle and Hargest², hyperbaric oxygen therapy can be helpful, even in recalcitrant cases. In general, surgery should be based on individual assessment of the patient and their wounds, weighing up the risk of pathergy.

Pain management

Pain associated with PG can be distressing for the patient. Patients report the pain as “stabbing” in nature. There are reports of severe pain leading to amputation of the affected limb³⁸ The source of pain associated with PG is multifactorial and is attributed to the inflammatory process in the dermis and subsequent ulceration³⁸. Pain levels should be monitored and as the ulcer improves pain levels should decrease. Although dressing changes are fundamental they may also be a source of pain; this must be considered when selecting a dressing and during dressing changes. Pain relief may be required and administered before dressing changes and during the procedure. Due to the chronicity of the wounds, narcotics should be avoided or limited to breakthrough pain³⁸. A multidisciplinary approach may be required for pain management¹

Case one

A 37-year-old female was referred to the wound clinic with a non-healing leg ulcer to the anterior aspect of her right lower leg, which was sustained four months earlier after knocking it on a wooden crate at work. Regular wound management was being performed by community nurses with a variety of dressings. On examination, the wound was 2.2 cm x 1.7 cm, had a sloughy base, and was extremely painful (Figures 1 and 2). Her only medical history was a right recurrent deep vein thrombosis (DVT) and a pulmonary embolus. A previous venous duplex scan revealed non-occlusive thrombus throughout much of the deep venous system of her right leg. Her only medication usage was warfarin. Ankle brachial indices were on the right: 0.9: left: 0.97. In view of her history of previous DVTs, a repeat venous duplex scan was ordered which revealed deep and superficial incompetence. Bacterial culture grew Pseudomonas aeruginosa and Staphylococcus aureus sensitive to ciprofloxacin. Based on the venous duplex scan and patient’s history, the wound was diagnosed as a venous leg ulcer and was initially treated with an appropriate primary dressing and compression bandaging 30–40 mmHg. Despite this, the wound increased in size, developed a violaceous margin, and became extremely painful (Figure 3). The patient was referred to a dermatologist, where a tissue biopsy was performed. This demonstrated non-specific ulceration; cultures for atypical mycobacteria and fungus were negative. Based on the clinical picture the patient was diagnosed with PG and commenced on a reducing dose of prednisolone starting at 50 mg per day along with a course of ciprofloxacin. Investigations were performed to rule out associated underlying medical conditions, such as IBD, autoimmune and haematological disease, all of which were negative. It was therefore deemed that the PG developed as a result of pathergy as a result of trauma rather than an associated medical condition. As the wound continued to display no signs of response to treatment a referral was made to the infectious diseases team who have requested another tissue biopsy to retest for atypical mycobacterial infection. The dermatology team were managing the patient at the time this paper was prepared.

 

 

 

 

Case two

A 79-year-old gentleman presented with a two-month history of non-healing leg ulcers bilaterally. His past medical history included chronic venous insufficiency, gastro-oesophageal reflux disease (GORD), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), and left total hip replacement. Initially the wounds measured 4 cm x 1 cm on the right lateral lower leg, and 2 cm x 2 cm, on the left medial lower leg. There was evidence of haemosiderin staining, pedal pulses were palpable, and the ulcers were painless. Originally the wounds were managed with local wound care and compression bandaging. However, over time, they gradually increased in size, and became infected and painful. The patient was admitted to hospital for intravenous antibiotics. During this admission the patient had a venous duplex scan, which demonstrated deep venous incompetence of the left leg, lesser saphenous vein, and incompetence of the saphenopopliteal junctions. He had varicose veins in the left calf draining into the lesser saphenous vein. The right lower leg demonstrated a competent deep system; varicose veins were identified draining into both greater and lesser saphenous veins with incompetent valves. Venous ablation was performed on the left short saphenous vein, and stenting of the left common iliac and left external iliac veins. The patient was discharged home and monitored as an outpatient with the support of community nurses for wound care. The wounds continued to deteriorate and the patient was admitted three months later with cellulitis. During this admission the patient underwent diagnostic angiogram and tibial peroneal trunk angioplasty and stent. Over time the ulcers continued to worsen (Figure 4). The patient was admitted for surgical debridement of his wounds. However, on the same day the dermatologists were consulted to review the patient. They diagnosed PG, and advised against any form of debridement due to the risk of pathergy. The patient was commenced on prednisolone 40 mg daily, methotrexate 30 mg weekly, and an increase in analgesic agents. The wounds were cleansed with Prontosan^® solution and dressed with PolyMem^® silver. The wounds responded well to wound care and systemic corticosteroids (Figure 5).

 

 

 

Case three

A 30-year-old gentleman was referred to the wound clinic for management of a venous leg ulcer. He had a past medical history of ulcerative colitis (currently in remission) and GORD, reoccurring ulcers to the right lower leg for three to four years, and he had recently undergone venous ablation. On examination, there was evidence of a healed ulcer over the anterior aspect of the right lower leg, haemosiderin staining (Figure 6), and an ulcer over the medial aspect of the same leg, small satellite ulcers, and there was also evidence of atrophic cribriform scarring proximal to this lesion (Figure 7). The patient was a fly-in, fly-out worker, five weeks on and five weeks off; therefore, it was difficult to have consistency with wound care. Initially the patient was managed with a silicone foam dressing and compression hosiery 30–40 mmHg, with the patient attending to his own wound care. At his next review the wounds had increased in size, demonstrated violaceous margins and were extremely painful (Figure 8.) An urgent referral was made to see a dermatologist. Biopsy was performed, which demonstrated ulceration associated with inflammation and vascular proliferation with associated small vessel neutrophilic vasculitis and small vessel micro-thrombi. Despite this, based on the clinical appearance of the wounds and the patient’s history of ulcerative colitis, a diagnosis of PG was made and he was commenced on prednisolone 50 mg daily. Over the coming month the wounds did not respond to the immunosuppression agent and the pain increased. A trial of prednisolone 1 mg crushed and applied topically to the wounds was initiated. However, the wounds increased significantly in size (Figure 9). The patient was then commenced on cyclosporine 200 mg and prednisolone 75 mg daily. During this period of time the patient had several admissions for wound infection and pain control. As there was very little response from the immunosuppressive agents, the patient was commenced on weekly infusions of Infliximab; an MRI was also performed to exclude osteomyelitis. There was gradual improvement in the wounds (Figure 10). As would be expected, pain has been an issue; this was managed in collaboration with the acute pain service, at our facility. Unfortunately, during the course of the treatment the patient lost his job.

 

 

 

 

 

Discussion

These three case studies illustrate the complexity of diagnosing PG. Two of the cases responded poorly to treatment. This is consistent with the literature where, despite appropriate therapy for PG, there can be a failure for the wounds to progress²⁷. Underlying conditions should be treated; however, PG can also occur when the underlying condition is in remission²⁷, as was the situation with case three. The second case did have underlying RA; however, he responded well to systemic treatment for PG.

When treating patients with suspected PG, one must always be open to the possibility of misdiagnosis. Indeed, many other ulcerating wounds can mimic PG^30,37. Weenig et al. reported that out of 157 patients being treated for PG, 10% (n=15) were found not to have PG³⁷. The consequences of misdiagnosis can be disastrous; particularly taking into account that the immunosuppressive agents used to treat PG may be contraindicated in other conditions³⁷. Systemic immunosuppression can also make the patient vulnerable to infection, as was the case with patient three who had several admissions to hospital with wound infection. In a study conducted by Weenig et al., they identified six broad disease categories that can mimic PG: vascular occlusive or venous disease; vasculitis; malignancy; exogenous tissue injury; infection; and other inflammatory disorders³⁷. All three of the patients had underlying venous disease and were managed according to best practice⁴⁹, with appropriate wound care, compression bandaging or compression hosiery and, where clinically indicated, surgical intervention. Treating the ulcer as venous in origin possibly delayed the diagnosis of PG.

The accurate diagnosis of PG is challenging. The proposed diagnostic criteria by Su et al. aids the clinician with the diagnosis of PG³⁰; this should not be used in isolation but as a guide. Independently, Von den Driesch had previously developed a diagnostic criteria for PG⁵⁰. The criteria are virtually the same as the one developed by Su et al. von den Driesch studied 44 patients with PG, where each patient was diagnosed using a standardised diagnostic criteria. There was long-term follow-up in 42 of the patients in the study cohort. Adopting a diagnostic criterion into clinical practice could potentially reduce the number of cases misdiagnosed with PG.

Treatment of PG remains challenging to the clinician. Treatment is typically based on the individual requirements of the patient, underlying medical conditions, the presence of diseases associated with PG, and the extent of the ulceration². The main goal of therapy is to reduce inflammation, control pain and promote healing¹. Recommended first-line treatment is appropriate wound care, with topical and/or systemic corticosteroids^1,2. In the three cases, patient two responded well to a combination of prednisolone, methotrexate, and simple wound care. However, the other two cases proved to be challenging.

Conclusion

Despite first being described almost a century ago, the diagnosis and management for patients with PG remains complex. Although three cases were presented, each of them proved challenging in diagnosis and treatment. Indeed, at the time of writing this paper two of the patients were still proving to be difficult to manage. Endless pain affects patients’ quality of life. Unfortunately one of the patients lost his job due to repeated hospital admissions, which put strain on his marriage and his ability to pay his mortgage.

Misdiagnosis of PG can have devastating consequences, using the diagnostic criteria proposed by Su et al. should aid the clinician with diagnosis of PG. As there is a lack of specific guidelines for the treatment of PG, we recommend referral to a dermatologist or physician. A multidisciplinary approach is essential in managing this complex condition.

Conflicts of interest

The authors do not have a conflict of interest to declare.

 

Author(s)

Donna Evealyne Angel*
RN, NP, BN, MSc, PGDip(Clin Spec), Royal Perth Hospital
Royal Perth Hospital
Wellington Street, GPO Box XX2213
Perth, WA 6847, Australia
Tel: (08) 9224 2244
Email: donna.angel@health.wa.gov.au

Johanna Lee van Rooyen
RN, BN, PGDip(Clin Nur)

* Corresponding author

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