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Pyoderma gangrenosum: a diagnosis not to be missed

Pyoderma gangrenosum (PG) is a rare, painful, non-infectious, ulcerative, inflammatory . Clinicians need to be aware of PG because if the condition is incorrectly managed, it can lead to extensive tissue damage. Diagnosis is made largely on clinical appearance, from the patient history and from the exclusion of other possible diagnoses. Management requires a multidisciplinary approach as systemic therapies are often required to avoid the spread of the disease and to achieve wound healing. PG is often associated with underlying systemic disease, but can also be found in isolation, as the case study in this article highlights. Martyn Butcher

When isolated, these have been It is believed that Interleukin-8 may found to initiate tissue necrosis when play a key role in the development KEY WORDS injected into the subject’s own skin of PG. It has been identified that in Pyoderma gangrenosum (Samitz, 1966; Ebringer et al, 1969). sufferers, there is an over-expression of this pro-inflammatory cytokine in Atypical skin ulceration Cell-mediated defects have been the skin. Inflammatory found to include altered production of Systemic co-factors macrophage inhibition by lymphocytes, On histological examination, decreased chemotaxis, tissue with PG shows necrosis of the and impaired monocyte phagocytosis superficial dermis and . the (Nerella et al, 1985). centre of the lesion exhibits necrosing suppurative inflammation which Von den Driesch (1997) reports subsequently leads to ulceration. The yoderma gangrenosum (PG) is that 50% of all sufferers also have co- advancing edge of the lesion shows a a rare, painful, non-infectious, existing systemic disease present. These lymphocytic vascular reaction (Magro Pulcerative, inflammatory skin are categorised into four main groups et al, 1997). This tissue shows a high condition that was first described by (Schwaegerle et al, 1988): number of invading . Brocq in 1916 but more completely 8Inflammatory bowel conditions studied in 1930 by Brunstring et al. It (including and There is marked oedema in the occurs typically in adults between Crohn’s disease) tissues with superficial vascular damage. 40 and 60 years of age and is 8Haematological disorders (including In some cases, the central point of commonly associated with underlying lymphoid and myeloid leukaemias the lesion originates from a pustular systemic diseases. and myeloma) necrosis of the hair follicle, with 8Rheumatoid conditions (including granulomatous inflammation. Aetiology , and systemic The aetiology of PG is not fully ) Presentation understood but it is believed to 8Hepatopathies (Callen, 1989) Generally PG is most common on be an immune-mediated process (including chronic active hepatitis, the lower extremities and the trunk. (Weedon, 2002). Both humoral and primary biliary cirrhosis and Although predominantly a condition cell-mediated abnormalities have sclerosing cholangitis). seen in adult life, occasionally it can be been associated with PG. Where seen in childhood and may be seen humoral abnormalities are suspected, In 50% of cases, the disease follows on the buttocks, perineum, and the antibodies against skin and bowel acute trauma or injury to the area head and neck (Graham et al, 1994). have been discovered along with the (including surgery), in a process known As already described, PG may initially production of dermonecrotic factors. as pathergy (Cairns et al, 1994; Esnault present following trauma including et al, 1995). It is felt that cell-mediated surgery. There are a number of clinical Martyn Butcher is TVCNS/Skin and Wound Care Service defects are responsible for this form of presentations of PG described in the Manager, Plymouth Hospitals NHS Trust, Plymouth PG presentation. texts, these being known as ulcerative,

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pustular, bullous, and vegetative. The Differential diagnoses include: while additionally altering neutrophil clinical signs of PG vary with each type 8Sweet’s syndrome (although this function (Chow and Ho, 1996). (Barham et al, 2004). rarely presents with peri-follicular Systemic immunosuppressant drugs inflammation and there is no such as cyclosporin have been used, Ulcerative PG destruction of the capillary bed) however, these are not without risk. The ulcerative form of PG is the 8Behçet’s disease Secondary infection can occur and easiest to recognise and is the one 8Rheumatoid the immuno-compromised individual most commonly associated with this 8Hepatic (Magro et al, 1997) may be at risk of catastrophic sepsis. diagnosis. Painful ulcers evolve from one 8Necrosing cutaneous infections such The recent development of biological or more tender papules or pustules, as necrotising fasciitis TNF-α inhibitors such as infliximab frequently around hair follicles. These 8Cutaneous anthrax and etanercept normally used in the characteristically have well demarcated 8Pustular drug reactions. management of severe rheumatoid purple (sometimes described as disease and psoriatic arthritis does violaceous) undermined borders and As the condition may be found in offer new options for PG sufferers surrounding . Ulcers may be association with a number of other who fail to respond to other therapies. singular or multiple and occur anywhere systemic disease processes it may be on the body (although most commonly necessary to undertake a wide variety There appears to be a lack of on the trunk and lower limbs) (Powell of tests including blood chemistry, renal consensus on the topical management and Su,1996). and hepatic function, colonoscopy, of pyoderma lesions. Samuel and radiography, and bone marrow biopsy Williams (1996) found in their Pustular PG (Trent and Kirsner, 2001). review of the condition a variety of Pustular PG develops as small painful topical strategies employed from pustules on otherwise healthy Treatment alginate dressings, hydrogels, topical skin during acute exacerbations of There have been a number of , antimicrobials inflammatory bowel disorders (Powell treatment regimes indicated for the and hydrocolloids. In some cases, and Su, 1996). management of PG. The choice of debridement has been suggested, therapy depends on the severity of the however, in view of the potential role Bullous PG presenting symptoms and the presence of pathergy in the development and Bullous PG arises from rapidly or absence of underlying systemic acceleration of this condition, this developing haemorrhagic blisters mainly disease. Where the condition is found option does not appear appropriate. located on the arms (Bennett et al, in association with systemic disease, the 2000) in patients with myloproliferative first priority should be the control of Barham et al (2004) suggested a disorders (Powell and Su, 1996). this condition (Barham et al, 2004). therapeutic ladder for the management of PG. This progresses from relatively Vegetative PG Where lesions are mild and there is simple topical steroid therapy to high- The vegetative form of the condition an absence of systemic disease it may cost, high-risk systemic interventions. is the least typical. This presents as a be possible to control the condition While these guidelines are of use, they non-painful superficial ulcer generally with topical preparations such as topical leave the clinician with little advice without the classic purple edge. It is corticosteroids and local dressings on how to manage the cutaneous often solitary and progresses slowly. It is (Callen, 1989). Topical , a drug manifestations of the condition. not usually associated with any systemic licensed for the management of atopic conditions (Powell and Su, 1996). eczema, has recently been shown to be Future developments effective in the management of early The future management of PG will rely Healing, when it does eventually PG lesions (Petering et al, 2001). heavily on our increased understanding occur, often leaves a characteristic of the disease process. The diversity cruciform (star or cross-like) . It Where the condition is more of its presentation and the failure of is thought this is due to anomalies widespread or aggressive in nature, clinicians to diagnose the condition in fibrin deposition caused by the a systemic approach is favoured. early, along with the failure to develop a abnormal inflammatory response. High-dose oral corticosteroids have reliable diagnostic tool, make systematic been the mainstay of treatment for a research into the condition difficult Diagnosis/differential diagnosis number of years (Barnham et al, 2004). to achieve. Newer systemic therapies No single test is diagnostic of PG, but Sulphones and other antileprotics designed for moderating the immune the diagnosis is normally made from the and antimicrobials have also been response appear to be the main thrust clinical presentation. However, a battery found to be useful. It is believed of research. Topical wound management of tests are normally undertaken to that these drugs act predominantly is designed at managing the symptoms exclude other causes of ulceration. as anti-inflammatory mediators, of pain, exudate management and,

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intravenous antibiotics. Wound swabs Table 1 were taken of the lesions to identify the Therapeutic ladder for pyoderma gangrenosum probable cause of the infection and to Drug Action ensure the administration of the most Topical or intralesional corticosteroids Local anti-inflammatory appropriate antibiotic. The diagnosis Topical cromolyn sodium Anti-inflammatory of necrotising fasciitis was considered Topical tarcrolimus Local immunosuppressant but was thought to be unlikely as the pyrexia was of low level (Barker et al, Minocycline Antimicrobial 1987). Instead it was thought that the Clofazimine Antileprotic causative organism was more likely Dapsone Antileprotic to be related to his work with cattle. Sulfasalazine Aminosalicylates Cross-species bacterial transfer is a potential risk and can be of major Antileprotic significance. Many species of Methotrexate: weekly pulse Anti-metabolite harmless to one species can be Anti-inflammatory pathogenic in others. Cyclosporin Immunosuppressant Jim was moved to a side room and Azathioprine Immunosuppressant barrier-nursed in order to prevent the Cyclophosphamide Alkylating chemotherapy spread of organisms to other patients Mycophenolate mofetil Immunosuppressant on the ward. Meanwhile his antibiotic Intravenous gammaglobulin Immunoglobulin regimen was supplemented with Etanercept TNF-α inhibitor metronidazole to provide cover against gram-negative organisms. Infliximab TNF-α inhibitor Following three days of intravenous (Barham et al, 2004) antibiotic therapy, there had been no improvement in Jim’s condition. He still exhibited a low pyrexia and the areas of tissue damage had extended following the successful implementation the physical nature of his work, thought to approximately 10x10cm at the of corrective medical treatment, healing. he must have scratched his skin while calf area and 15x15cm on the thigh working with the cattle. Over the wound. Blood culture had failed to A case study next few days these lesions rapidly reveal any septicaemia and wound Jim Penworthy (pseudonym) is a 58- grew in size and ulcerated. They were swabs had only grown Staphylococcus year-old farmer in the south-west of intensely painful, and thinking they were aureus and skin flora. The area remained England. He owns a large prize-winning , he decided to visit his GP. intensely painful with a distinct area dairy herd. During the past few of peri-wound . The surgeons years his work has been influenced On examination, his GP noted considered that further investigations first by concerns over BSE and by that the two areas had extended were required urgently to exclude the UK outbreak of foot and mouth very rapidly from approximately more unusual infections. Specifically, the disease. Although in both cases his 1cm to approximately 25cm each potential for a diagnosis of cutaneous livestock were not directly affected, within three days. Fearing a serious anthrax needed to be considered. this has increased the amount of destructive infection, he administered work required of him while reducing an intravenous bolus injection Jim was becoming increasingly his income from the herd. Despite of Augmentin 1.2g and made worried. He found the social isolation this, apart from mild hypertension, arrangements for Jim to be seen imposed on him, due to barrier he enjoys good health and is looking urgently by the surgeons at the district nursing, intolerable. Although not a forward to passing the farm on to his general hospital. very sociable man, he was used to son in the next few years. spending most of his days with his On admission, Jim’s medical history animals and walking in the fields. He While bathing, Jim noticed two small was taken and measurements taken was very worried about the speed at lesions on his skin. One was on his left of the lesions. Jim was found to have which his wounds had deteriorated inner thigh, the other on his right inner a mild pyrexia of 37.7ºc. Surrounding and was worried that the surgeons calf. Both of these areas appeared as each lesion was an area of distinct had been unable to find the cause small dark purple spots. He could not erythema. It was decided to admit Jim of the infection. If anthrax was recall injuring himself, but because of to facilitate further administration of the cause, not only would this be

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Figures 1 and 2. The florid red-purple edge of the lesions is clearly visible in these views. The central area of the lesions show ulceration to the dermal layers.

medically serious for him but would any other features of note. Jim’s past Meanwhile the care team was be disastrous for his herd. The Ministry medical history was also unremarkable. faced with the dilemma of managing of Food and Fisheries would have to Importantly he denied any rheumatoid his ulcers. Both ulcers were leaking be informed and his herd would be disease or bowel condition. moderate to high amounts of exudate. isolated and possibly destroyed. The wound beds were covered in a Both the dermatologist and the fine layer of necrotic slough, however, Due to the deterioration in his TVCNS had seen similar lesions and they remained exquisitely painful. wounds, the surgeons booked him in agreed that this was an inflammatory Samuel and Williams (1996) found for excision of the areas under general ulcer, most probably PG. the association of pain, inflammation, anaesthetic in theatre. However, before and exudate common in many case this procedure it was decided to refer Treatment studies of this condition. Wound him to the dermatologists and the Jim appeared to present with the classic management in Jim’s case was based nursing staff of the skin and wound ulcerative variant of PG but with no around the need for good symptom care service. A joint visit was arranged obvious underlying disease and so his control and the need to reduce with the tissue viability nurse and the planned surgery was cancelled (further inflammation until such time that the on-call dermatologist. pathergic stimuli could intensify the systemic corticosteroids took effect. ulceration and lead to an escalation There was also a need to minimise On examination, Jim was found of the condition) and was prescribed the risk of secondary infection. High to have two clearly defined regular high dose oral corticosteroids dose systemic corticosteroids reduce shaped ulcers to his legs (Figures 1 and (prednisolone 60mg daily). The aim the inflammatory response and so can 2) Both lesions appeared to extend of this treatment was to reduce the mask the signs of infection. Although into the lower levels of the dermis with abnormal inflammatory response Jim the antibiotic therapy initiated earlier extensive destruction of the tissues. was experiencing. provided cover, reducing bacterial The edges of the ulcers were clearly colonisation of the skin reduces the defined with a purple haemorrhagic In the absence of any atypical potential pool of . border. Jim explained that this colour bacterial colonisation, it was decided had been present throughout the to discontinue barrier nursing. Jim was It was decided to control Jim’s and had been the issue that finding segregation increasingly difficult flora with the regular application of had prompted him to go to his GP. to manage and welcomed this change Dermol 500® (Dermal Laboratories, Physical examination failed to reveal in treatment. Hitchin) as a skin and peri-wound

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Figures 3 and 4. The purple margins of the lesion have now resolved. Despite some superficial slough, granulation tissue is clearly visible and there are early signs of islands of re-epithelialisation.

emollient. Dermol lotion is an effective the surrounding erythema resolved. After three weeks of treatment emollient that is composed of liquid Further extension of the ulcers into the (Figures 3 and 4), Jim’s PG appeared paraffin, with benzalkonium chloride, surrounding skin ceased. Exudate levels under control and so he was isopropyl myristate, and chlorhexidine subsided and Jim stated that the pain commenced on a decreasing steroid hydrochloride (British National was noticeably reduced. regimen. High-dose corticosteroids Formulary, 2004) making it effective in Despite the reduction in exudate it administered for three weeks or more reducing normal skin pathogens. was decided to continue with Aquacel need to be reduced gradually to as a primary dressing for both ulcers. prevent adrenal insufficiency (British Both ulcers were dressed with This could now be left on for up to National Formulary, 2004). Initially his a hydrofibre dressing (Aquacel®). three days before saturation of the prednisolone was reduced to 50mgs (ConvaTec Ltd, Uxbridge). This product hydrofibre was achieved. As frequent daily, and then it was reduced by 10mg has a highly hydrophilic action that observation of the wound was less a day in weekly decrements until he enables it to absorb significant fluid imperative, an adhesive foam dressing was taking 10mg daily. At this point his levels. In so doing, the product changes was utilised as a secondary dressing dose was reduced by 2mg per day at to a gel. This prevents the product (Biatain adhesive) (Coloplast Ltd, weekly intervals. adhering to the wound bed, minimising Peterborough). This in turn permitted wound bed trauma and inflammation, less frequent dressing changes. Long-term use of corticosteroids and so reducing pain at dressing change. can have a detrimental effect on This dressing was initially retained Following 14 days of steroid therapy wound healing. Although Jim was with a simple wound pad held in place it was decided that Jim should be making good progress, it was felt he with an elasticated tubular bandage discharged. Plans were put in place had a significant risk of developing (Tubifast®) (SSL International plc, for him to return twice weekly to chronic ulceration. It was therefore Manchester) as it was essential to the clinic as an outpatient. This would decided to discontinue Aquacel monitor the progress of the wound enable ongoing management of his dressings (exudate levels had now closely. These were changed daily. ulcers and would allow the nursing reduced considerably) and commence staff to monitor for side effects of the the use of a matrix metalloproteinase Within a few days, the ulcers corticosteroids. Blood glucose levels (MMP) inhibiting therapy. Promogran® noticably changed. The purple wound were monitored to check for steroid- dressings (Johnson and Johnson edges began to fade in colour and induced . Medical, Ascot) were used on both

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Cairns BA, Herbst CA, Sartor BR et al (1994) ulcers as the primary wound contact Peristomal pyoderma gangrenosum and layer from week three of steroid Key Points inflammatory bowel disease. Arch Surgery 129: therapy. This product consists of a 769 mixture of collagen and cellulose 8 Pyoderma gangrenosum is a that is able to bind to excess MMPs Callen JP (1989) Pyoderma gangrenosum and rare, but potentially debilitating related disorders. Med Clin North Am 73: 1247 in the wound bed and exudate. condition which can cause Excess MMPs are believed to be one considerable skin damage. Chow RKP, Ho VC (1996) Treatment of of the major causes of chronicity pyoderma gangrenosum. J Am Acad Dermatol 34: 1047–60 in wound healing. In line with 8 In the absence of a reliable ® local protocol, Promogran was diagnostic test for PG, it is Ebringer A, Doyles AE, Harris GS (1969) used in conjunction with a topical necessary to rely on clinical Dermonecrotic factor I; nature and properties antimicrobial (Inadine®).(Johnson presentation and elimination of a dermonecrotic factor to guinea pig skin and Johnson, Peterborough, UK) found in human serum. Br J Exp Pathol 50: of other possible conditions 559–65 In our experience, failure to do when arriving at a formal so increases the risk of critical diagnosis of this condition. Esnault P, Dompartin A, Moreau A, Caraes colonisation and local wound B, Leroy D (1995) Recurring postoperative 34: infection. 8 The different forms of the pyoderma gangrenosum. Int J Dermatol 647–50 condition can make diagnosis Outcome even more difficult for the Graham JA, Hansen KK, Rabinowitz LG, Jim went on to heal completely, and clinician. Esterly NB (1994) Pyoderma gangrenosum in he has now stopped his systemic infants and children. Ped Dermatol 11: 10 therapy. Although he does have a risk 8 Treatment is targeted at Magro C, Crowson AN, Mihm M (1997) of recurrence of the PG, to date he moderating the immune Cutaneous manifestations of nutritional has had no signs of its reactivation. response and supportively deficiency states and gastrointestinal disease. Once stable Jim had extensive managing associated wound In: Elder et al, eds. Lever’s Histopathology investigations to find the underlying of the Skin. 8th edn. Lippincott-Raven problems. Publishers, Philadelphia: 357–9 cause of the problem including gastroscopy and colonoscopy. No Nerella P, Daniela A, Guido M, et al (1985) abnormalities were found. Leukocyte chemotaxis and pyoderma gangrenosum. Int J Dermatol 24: 45–7 It is recognised in patients Petering H, Kiehl P, Breuer C et al (2001) with PG that on healing, many Pyoderma gangrenosum: successful topical References therapy with Tacrolimus. Hautarzt 52: 47–50 demonstrate cruciform scarring Barham KL, Jorizzo JL, Grattan B, Cox NH Powell FC, Su WPD (1996) Pyoderma (Barham et al, 2004). Jim has been (2004) Vasculitis and neutrophilic vascular gangrenosum: classification and management. reactions. 49.38 In: Burns T, Breathnach S, advised to massage the scarred J Am Acad Dermatol 34: 395–409 area with a simple emollient daily to Cox N, Griffiths C, eds. Rook’s Textbook of maintain tissue health and keep the Dermatology. Blackwell Science, Oxford Samitz MH (1966) Cutaneous vasculitis in association with ulcerative colitis. Cutis 2: Barker FG, Leppard BJ, Seal DV (1987) scar tissue flexible. Jim is now back 383–7 working full time on the farm. Streptococcal . Comparison between histological and clinical features. J Samuel J, Williams C (1996) Pyoderma Clin Pathol 40: 335–41 gangrenosum: an inflammatory ulcer. J Wound Conclusion Care 5(7): 314–8 PG is an uncommon skin condition Bennett ML, Jackson JM, Jorizzo JL, et al but one that clinicians need to be (2000) Pyoderma gangrenosum: a comparison Schwaegerle SM, Bergfeld WF, Senitzer D et al of typical and atypical forms with an emphasis (1988) Pyoderma gangrenosum: a review. J Am aware of. Although linked to other on time to remission. Medicine 79: 37–46 Acad Dermatol 18: 559 autoimmune conditions it can, as British National Formulary (2004) British in this case, be found in isolation. Trent JT, Kirsner RS (2001) Diagnosing Medical Association and Royal Pharmaceutical pyoderma gangrenosum. Adv Skin Wound Care In such cases confirmation of the Society of Great Britain, Oxford 14(3): 151 diagnosis can be difficult. However, Brocq L (1916) Nouvelle contribution à l’étude failure to identify and treat it Von den Driesch P (1997) Pyoderma du phagedeniome geometrique. Ann Dermatol gangrenosum: a report of 44 cases with follow- promptly can lead to significant Syphiligr 6: 1–39 ups. Br J Dermatol 137: 1000–5 areas of tissue loss, or worse still, Brunstring LA, Goeckerman WH, O’Leary Weedon D (2002) The vasculopathic reaction surgical intervention which can PA (1930) Pyoderma gangrenosum: clinical pattern: pyoderma gangrenosum. In: Skin lead to significant escalation of the and experimental observations in five cases Pathology (2nd Edn). Curchill Livingstone, disease process. WUK occurring in adults. Arch Dermatol 22: 655–80 London: 251–2

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