Pyoderma gangrenosum: an updated review

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1 DOI: /j x JEADV Blackwell Publishing Ltd REVIEW ARTICLE Pyoderma gangrenosum: an updated review E Ruocco, S Sangiuliano,, * AG Gravina, A Miranda, G Nicoletti Departments of Dermatology, Plastic Surgery and Gastroenterology, Second University of Naples, Naples, Italy *Correspondence: S Sangiuliano. soniasang@tele2.it Abstract Pyoderma gangrenosum is a rare, ulcerative, cutaneous condition. First described in 1930, the pathogenesis of pyoderma gangrenosum remains unknown, but it is probably related to a hyperergic reaction. There are various clinical and histological variants of this disorder. Pyoderma gangrenosum often occurs in association with a systemic disease such as inflammatory bowel disease, rheumatologic disease, paraproteinaemia, or haematological malignancy. The diagnosis, mainly based on the clinical presentation and course, is confirmed through a process of elimination of other causes of cutaneous ulcers. Local treatment may be sufficient for mild disease, while for severe cases, systemic immunosuppressants are the mainstay. Long-term treatment with these agents is often required, but this can expose patients to adverse side-effects. Received: 2 October 2008; Accepted: 22 December 2008 DOI: /j @@@@.x Keywords Crohn s disease, hyperergic reaction, inflammatory bowel disease, pathergy, phagédenisme géométrique, pyoderma gangrenosum, ulcerative colitis Conflicts of interest None declared. Definition Pyoderma gangrenosum is a rare, chronic, often destructive, inflammatory skin disease in which a painful nodule or pustule breaks down to form a progressively enlarging ulcer with a raised, tender, undermined border. Lesions present either in the absence of any apparent underlying disorder or in association with a systemic disease, such as ulcerative colitis, Crohn s disease, polyarthritis, and gammopathy amongst others. 1 History Pyoderma gangrenosum was first described by Brocq in 1916 as phagédenisme géométrique. 2 In 1930, at the Department of Dermatology, Mayo Clinic, Brunsting, Goeckerman and O Leary coined the term pyoderma gangrenosum and advanced the theory that it had an infectious aetiology (streptococci and staphylococci). 3 They considered pyoderma gangrenosum to be the dissemination of a distant focus infection (i.e. the bowel in ulcerative colitis or the lungs in empyema). More than 70 years later, the aetiology of pyoderma gangrenosum is still unknown, but, in all likelihood, the disease is not directly caused by bacteria nor is it infectious in nature. Epidemiology The incidence of pyoderma gangrenosum is uncertain, but it is estimated to be 3 10 patients per million population per year, occurring at any age but most commonly between 20 and 50 years with a possible slight female predominance. Fifty per cent of cases are associated with an underlying systemic disease, most commonly inflammatory bowel disease (IBD), arthritis and lymphoproliferative disorders. Pulmonary and cardiac involvements are other possible underlying systemic diseases. 4 Aetiology and pathogenesis The aetiology of pyoderma gangrenosum is unknown and the pathogenesis is poorly understood. Although the disease is idiopathic in 25 50% of patients, an underlying immunologic abnormality may exist as suggested by its frequent association with systemic diseases with a suspected autoimmune pathogenesis. 4 The phenomenon of pathergy (i.e. the development of new lesions or aggravation of existing ones following trivial trauma and frequently present in pyoderma gangrenosum) would suggest altered, exaggerated, and uncontrolled inflammatory responses to non-specific stimuli. 1 Neutrophil dysfunction (i.e. defects in chemotaxis or hyperreactivity) has been suggested. Evidence of abnormal neutrophil trafficking and metabolic oscillations was described 5 as was a streaking leucocyte factor that enhances migration of leucocytes without altering their chemotactic activity, impairment of microbicidal activities of leucocytes, and impaired neutrophil functions associated with IgE hyperimmunoglobulinemia. IgA

2 Pyoderma gangrenosum: a review 1009 gammopathies, which can impair neutrophil chemotaxis in vitro, are not uncommon in pyoderma gangrenosum. Circulating immunoglobulins affecting neutrophil functions and monoclonal or polyclonal hyperglobulinemia frequently occur in pyoderma gangrenosum. There is insufficient evidence to support the theory that the disturbance of cellular immune functions in pyoderma gangrenosum is a common denominator in its pathogenesis. Thus, although evidence suggests that disturbances of immunoregulation and immunologic effector functions occur in some patients with pyoderma gangrenosum, they are not detectable in others, and it is unclear whether or not they are epiphenomena. Furthermore, interleukin-8 (IL-8), a potent leucocyte chemotactic agent, has been shown to be overexpressed in pyoderma gangrenosum ulcers and to induce similar ulceration in human skin xenografts transfected with recombinant human IL-8. The factors triggering or maintaining these abnormalities are unclear but are probably multifactorial (i.e. genetic predisposition, undefined infectious agents, or paraneoplastic or paraimmune phenomena). Rare familial forms of pyoderma gangrenosum have been reported. The recently described PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) is an autosomal-dominant disorder that maps to chromosome 15q. The IL-16 gene maps to 15q25 and may be overexpressed in this disorder because the IL-16 protein is chemotactic to neutrophils. 1,4 Clinical features Classic forms The salient feature of pyoderma gangrenosum is an ulcer with a raised inflammatory border and a boggy, necrotic base. Primary lesion starts as a deep-seated, painful nodule or as a superficial haemorrhagic pustule, either de novo or after minimal trauma. Both processes undergo necrosis leading to a deep or shallow, central ulceration, discharging a purulent and haemorrhagic exudate; the irregular, crenelate border is elevated and is dusky red or purplish; it is undermined, soggy, and often perforated so that pressure releases pus, both into the ulcer and through the openings. The actively advancing ulceration may expand rapidly in one direction and more slowly in another, resulting in a serpiginous pattern. The margins are often surrounded by an intense halo of bright erythema that extends up to 2 cm from the ulcer border into the neighbouring, apparently normal, skin. Peripheral growth results from the burrowing extension of the undermined margin or from fresh haemorrhagic pustules arising on the border. The base of such an ulcer is partially covered with necrotic material and studded with small abscesses. Superficial ulcers may be confined to the dermis, but more often extend into the fat and even down to the fascia. There may be a single or multiple ulcers and they can sometimes coalesce to form multicentric, irregular ulcerations (Fig. 1). Simultaneously or subsequently arising multiple lesions also occur in different parts of the body. Most frequently, pyoderma gangrenosum affects the Figure 1 Severe pyoderma gangrenosum: extensive ulcerative, bullous and crusting lesions on an upper limb. lower extremities or the trunk, though any area of the body may be affected. 1,6,7 Mucous membranes are usually spared, but aphthous lesions may occur in the oral cavity and vast ulceration of the oral mucosa, larynx and pharynx, vulva, and eyes has occasionally been observed. The clinical course may present two patterns: (1) explosive onset and rapid spread of lesions; clinically, this type of pyoderma gangrenosum is characterized by pain, toxicity and fever, haemorrhagic blisters and suppuration, extensive necrosis, and soggy ulcer margins with a highly inflammatory halo; (2) indolent and gradually spreading clinically exhibits massive granulation within the ulcer from the onset, crusting and even hyperkeratosis at the margins; it spreads slowly, over large areas of the body for months, and is characterized by spontaneous regression and healing in one area and progression in another. In both forms, reepithelialization occurs from the margins and the ulcers heal with thin, atrophic cribriform pigmented scars. 1 There is no lymphadenopathy or lymphangitis. Twenty percent of cases show a Koebner phenomenon (or isomorphic response or pathergy), so that injury to the skin from accidental trauma, surgical incision, and even venesections, or prick tests often initiate a new lesion. Considerable toxicity and fever are usually associated with the acute onset of pyoderma gangrenosum lesions, but systemic symptoms may also be absent. Lesions are, almost invariably, painful. Rarely, pyoderma gangrenosum may start in the subcutaneous fat, presenting as an extremely painful, suppurative panniculitis. Breakdown of the lesion and the centrifugal extension of the resulting ulcer eventually reveal the true nature of the process. Atypical cases may resemble purpura fulminans, neutrophilic dermatosis (see variants) or, in early abortive cases, erythema nodosum or nodular vasculitis. Features of Behçet s disease, such

3 1010 Ruocco et al. Table 1 Variants of pyoderma gangrenosum Ulcerative (classic form) Pustular Bullous Vegetative Peristomal Genital Infantile Extracutaneous Very painful, large ulceration with a purulent base and undermined borders surrounded by a halo of centrifugally enlarging erythema. Usually requires aggressive systemic immunosuppressive therapy for control. Discrete painful sterile pustules (0.5 2 cm in diameter) with a surrounding erythematous halo. Pustular eruption often improves with treatment of the underlying ibd. Rapidly evolving superficial painful vesicles and enlarging bullae, with central necrosis, erosion, and a surrounding halo of erythema. Systemic immunosuppressive therapy is required; the association with hematological malignancy is often indicator of poor prognosis. Superficial ulceration, with not undermined borders and a nonpurulent base, slowly progressive. Often responds to topical, intralesional or less aggressive systemic therapy. Skin lesions in the peristomal area in patients with ulcerative colitis or Crohn s disease who have ileostomy or colostomy. Vulvar, penile or scrotal localization. Perianal and genital areas are usually involved in infants. Lungs, heart, central nervous system or other internal organs can be affected in the absence of cutaneous lesions. as orogenital ulcers or superficial thrombophlebitis, have also been reported in isolated cases. 1 Variants (Table 1) Pustular pyoderma gangrenosum O Loughlin and Perry first described pustular pyoderma gangrenosum in association with active IBD. 8 This variant of pyoderma gangrenosum is characterized by multiple sterile pustules surrounded by an erythematous halo, often symmetrical, and associated with fever and arthralgias. Pustular eruption often improves on treatment of the underlying disease. Histopathologic features are subepidermal oedema with a dermal neutrophilic infiltrate and subcorneal neutrophil accumulation. Pyostomatitis vegetans is probably oral pustular pyoderma gangrenosum, a pustular, vegetative process of the mucous membranes, in particular the mouth, followed by superficial sloughing and snail track erosions. It is often associated with ulcerative and vegetating skin lesions and IBD. 5,6 Atypical or bullous pyoderma gangrenosum In 1972, Perry and Winkelmann 9 described another variant of pyoderma gangrenosum characterized by rapidly evolving painful vesicles and enlarging bullae with central necrosis and erosion surrounded by a halo of erythema. This central necrosis causes shallow erosion rather than a necrotic ulcer. Bullous pyoderma gangrenosum is most probably due to the more rapid superficial necrosis that occurs in this form of the disease. The blistering seems to develop in concentric rings around the edges. The superficial nature of the necrosis induces a grey hue in the surrounding tissue. The necrolytic tissue produces the characteristic blistering common in this variant of pyoderma gangrenosum. Arms and face are more commonly affected than legs. It has been reported with haematological disease, such as preleukaemic conditions (i.e. myeloid metaplasia) and acute myelogenous leukaemia. Another neutrophilic dermatosis (Sweet s syndrome or acute febrile neutrophilic dermatosis) can be difficult to distinguish from atypical pyoderma gangrenosum. Histology typically shows dermal neutrophilia and subepidermal bullae formation in the latter. 5,6 Vegetative pyoderma gangrenosum It is a localized, nonaggressive form of pyoderma gangrenosum with verrucous and ulcerative lesions, which was termed superficial granulomatous pyoderma in The condition originally described as malignant pyoderma and supposed to be a separate entity by Perry et al. 11 is now considered by most authors as a variant of pyoderma gangrenosum, although Gibson et al. 12 recently classified at least some of these cases as a atypical form of Wegener s granulomatosis. The ulceration is more superficial, the base is usually non-purulent, and there are no undermined borders or surrounding erythema. What is more, unlike typical ulcerative pyoderma gangrenosum, associated systemic diseases are absent and the lesions affect predominantly the head and neck. Histopathological features include the prominence of histiocytes within the neutrophilic infiltration, tissue eosinophilia, intra- and subepidermal granuloma formation. 6,7 Peristomal pyoderma gangrenosum A rare subset of pyoderma gangrenosum recently recognized in patients with ulcerative colitis or Crohn s disease who have had abdominal surgery and have an ileostomy or colostomy, peristomal pyoderma gangrenosum consists of the formation of skin lesions in the peristomal area occurring 2 months to 25 years after enterostomy/colonostomy. 13,14 As mentioned above, pathergy is a process whereby, in susceptible persons, trauma to the skin results in pustules and/or ulcers. Trauma to the peristomal skin related to irritation caused by leakage of faeces or caused by the adhesive of the stomal appliance may evoke pathergy, thus causing peristomal pyoderma gangrenosum. Alternatively, pathergy may ensue from debridement, grafting, and/or relocation of the stoma. 15 Genital pyoderma gangrenosum In this variant, which usually involves the vulva, the ulceration differs from typical pyoderma

4 Pyoderma gangrenosum: a review 1011 gangrenosum in its location alone. A similar process has been described on the penis or scrotum. When genital lesions are present, however, Behçet s disease should also be considered. Vulvar, penile, or scrotal pyoderma gangrenosum can be distinguished from the aphthous lesions of Behçet s by confirmation of other features of Behçet s disease. Pyoderma gangrenosum in infants and children This rare form (only 3 4% of all cases are in this age-group) is not a true variant since the clinical appearance and location resemble those of the classic lesions in adults. However, in infants, the perianal and genital areas tend to be involved. Associated processes are similar to those in adults. In most children, the outcome is favorable. Extracutaneous neutrophilic disease In this variant of pyoderma gangrenosum, culturenegative pulmonary neutrophilic infiltrates are the most commonly reported extracutaneous sign. Sterile neutrophilic infiltrates can also occur in the heart, central nervous system, gastrointestinal tract, eye, liver, spleen, and lymph nodes. 16 Clinical symptomatology reflects the localization of the lesions. Exacerbating factors Because of pathergy, biopsies, intradermal skin testing or injections (including the injection of saline), pricks, and even insect bites, can induce new lesions. However, pathergy occurs in only 20% of patients, and, since even major surgery is well tolerated by some individuals, its significance is difficult to assess. 17 Pathergy may also be the reason for the rejection of autologous skin grafts and the development of new lesions in donor sites, but again, the skin grafts are not always rejected. Potassium iodide can also induce an exacerbation of pyoderma gangrenosum as can granulocyte macrophage colony-stimulating factor, but, as with pathergy after trauma, this does not always occur. Pyoderma gangrenosum has also been reported as a complication of many kinds of surgery, such as hernioplasty, heart surgery, plastic surgery of the breasts (for breasts augmentation or reduction) and cervicofacial plastic surgery 1,18 and even as a side-effect of isotretinoin therapy for acne nodulocystic. 19 Histopathology Because the histopathologic findings are non-specific, the diagnosis of pyoderma gangrenosum rests primarily on clinical features. The primary objective of biopsy is to rule out other causes of ulceration (i.e. infection, vasculitis, malignancy). Skin biopsy specimens taken from the necrotic, undermined ulcer border of pyoderma gangrenosum reveal oedema and massive neutrophilic inflammation. There may also be engorgement and thrombosis of small- and medium-sized vessels, necrosis, and haemorrhage. The extremely dense infiltrate of polymorphonuclear leucocytes leads to abscess formation and liquefaction necrosis of the tissue with secondary thrombosis of venules. Lesions further evolve into suppurative granulomatous dermatitis and regress with prominent fibroplasia. The neutrophil is the cytologic hallmark of pyoderma gangrenosum. Neutrophilic infiltrates can be seen in active untreated expanding lesions. In fully developed ulcers, there is marked tissue necrosis with surrounding mononuclear cell infiltrates. The concomitant occurrence of pyoderma gangrenosum and necrotizing vasculitis, and patients with pyoderma gangrenosum developing Wegener s granulomatosis, has also been reported. However, the pathogenic role played by immune complex vasculitis has yet to be proved. 1,4 Associated diseases (Table 2) In 40 50% of cases, pyoderma gangrenosum involves only the skin ( idiopathic pyoderma gangrenosum). The remaining cases have an antecedent or coincident (or subsequently developed) associated condition. The most common associations are IBD (ulcerative colitis and Crohn s disease), arthritis (seronegative arthritis, spondylitis of IBD, and rheumatoid arthritis), and haematologic diseases (in particular, myelogenous leukaemia, hairy cell leukaemia, myelofibrosis, and monoclonal gammopathy). Other so-called neutrophilic dermatoses that have been reported in association with pyoderma gangrenosum are Behçet s disease, subcorneal pustular dermatosis and Sweet s syndrome. 1,4 IBD Together with erythema nodosum, pyoderma gangrenosum represents the most common dermatologic disorder accompanying IBD, which comprises ulcerative colitis and Crohn s disease (Fig. 2). Pyoderma gangrenosum has been reported to occur in 2 12% of IBD patients. 16 Pyoderma gangrenosum can precede colitis or may occur at any stage of the disease, even after the colon has been removed. 20,21 In most patients, symptoms of ulcerative colitis precede pyoderma gangrenosum, and exacerbations of the bowel disease frequently correlate with worsening of the skin lesions. However, pyoderma gangrenosum is not closely related to the activity of colitis and it may persist for long periods while bowel disease is quiescent. Pyoderma gangrenosum is also associated with Crohn s disease, but the prevalence of this association is lower than that observed in ulcerative colitis. 16 Arthritis Arthritis is frequently associated with pyoderma gangrenosum and usually precedes it. Some patients have classic seropositive rheumatoid arthritis; others have seronegative, acute, oligoarticular, and non-destructive arthritis associated with IBD; and some have a seronegative rheumatoid like arthritic syndrome. Still, other patients have spondylitis in conjunction with IBD-associated pyoderma gangrenosum. Felty s syndrome, osteoarthritis, and sacroileitis have been reported in patients with pyoderma gangrenosum. In some, the arthritis cleared after total

5 1012 Ruocco et al. Table 2 Pyoderma gangrenosum: associated diseases Diseases of the Ulcerative colitis gastrointestinal tract Crohn s disease Diverticulosis Gastritis Gastric and duodenal ulcers Intestinal polyps Primary biliary cirrhosis Chronic active hepatitis Disease of the joints Rheumatoid arthritis (seropositive without IBD, seronegative with IBD) Ankylosing spondylitis Osteoarthritis Polychondritis Haematologic diseases Collagen-vascular diseases Neoplasia Infectious diseases Miscellaneous Leukaemia (acute myeloid, lymphoblastic, chronic myeloid, lymphoid, hairy cell leukaemia) Myeloproliferative syndrome Hyperglobulinaemia Trombocythaemia Splenomegaly Myelodysplasia Dysglobulinaemia Congenital hypogammaglobulinaemia Monoclonal hypergammaglobulinaemia Myeloma Waldenström syndrome Lymphoma Takayasu s disease Wegener s granulomatosis Systemic lupus erythematosus Necrotizing vasculitis Rheumathoid uveitis and scleritis Cancer (colon, prostate, breast, bronchus) Carcinoid tumor Post-traumatic (postoperative, accidental trauma) Thyroid diseases Diabetes Diseases of the lung (pneumonitis, abscess) proctocolectomy. An association of pyoderma gangrenosum with the SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) and psoriatic arthritis has been described. 1,7 Monoclonal gammopathy Pyoderma gangrenosum is associated with paraproteinemia in up to 15% of patients, mostly of the IgA but also of the IgG and IgM types. 4 Although over the short-term patients with a monoclonal gammopathy do not show progression to malignancy, some patients with pyoderma gangrenosum have myeloma at presentation or develop it subsequently. Myeloma usually appears later than pyoderma gangrenosum. In view of the abnormalities in neutrophil function in pyoderma gangrenosum, it is interesting that IgA immunoglobulins have been shown to inhibit neutrophil function in vitro and may possibly render the host immunologically susceptible to the development of pyoderma gangrenosum. 1 Haematologic malignancy Pyoderma gangrenosum occurs in acute myeloblastic, myelomonocytic, and chronic myeloid leukaemia in both adults and children, and in myelodysplasia (15 25%). 4 It has been described in smouldering leukaemia and in hairy cell leukaemia. Pyoderma gangrenosum occurs in association with leukaemia in children and has been described in patients with polycythemia rubra vera, erythroid hypoplasia, myelofibrosis, and Hodgkin s disease. 1 Other conditions Pyoderma gangrenosum has been observed in association with active chronic hepatitis, primary biliary cirrhosis, paroxysmal nocturnal haemoglobinuria, systemic lupus erythematosus, the antiphospholipid antibody/lupus anticoagulant syndrome, and occasionally with gastric and duodenal ulcers, polyps, diverticulitis, and diabetes. Carcinoid tumour, metastatic adenocarcinoma of the colon and the adrenal cortex, andcarcinoma of the bladder, prostate, breast, bronchus, andovary have been described in patients with pyoderma gangrenosum; however, these latter associations are probably fortuitous. 1,7 Several studies have documented patients with pyoderma gangrenosum and Behçet s syndrome. Both diseases share certain features, such as arthritis, pustulation, aphthous lesions of the mucous membranes, and the phenomenon of pathergy. Pyoderma gangrenosum has been observed with vasculitis, erythema elevatum et diutinum (also a form of vasculitis), acne conglobata and fulminans and Wegener s granulomatosis. There is an increased frequency (up to 30%) of pyoderma gangrenosum in patients with Takayasu s disease in Japan but not in Europe (1 out of 80 cases). Reports mention severe pneumonitis and pulmonary abscess formation in patients with pyoderma gangrenosum, which may indicate pulmonary involvement in this condition. 1 Neutrophilic dermatoses The predominant cell type in pyoderma gangrenosum lesions is the neutrophil. This, together with the absence of any sign of infection and its response to sulfa drugs, places pyoderma gangrenosum in the group of neutrophilic dermatoses, which remain aetiologically poorly understood. These are reactive processes with non-infectious dermal neutrophilia in common. In addition to pyoderma gangrenosum, neutrophilic dermatoses include acute febrile neutrophilic dermatosis (Sweet syndrome), bowel-associated dermatosis arthritis syndrome, neutrophilic eccrine hidradenitis, subcorneal pustular dermatosis (Sneddon- Wilkinson disease) and rheumatoid neutrophilic dermatitis, as

6 Pyoderma gangrenosum: a review 1013 Figure 2 Severe pyoderma gangrenosum: (a) oedema, loss of vascularity, presence of abundant mucus and patchy subepithelial haemorrhage. (b) Inflammatory pseudopolyps result from inflamed, regenerating epithelium interposed among ulcerations. well as some primarily vasculitic disorders (such as Behçet s syndrome, pustular vasculitis, and erythema elevatum diutinum). 1 Laboratory findings A high erythrocyte sedimentation rate, leukocytosis, and elevated C-reactive protein are invariably present; there may be anaemia and low serum iron; hyper- or hypoglobulinemia may occur. Specific autoantibodies are not known to be formed, the complement system is not altered in pyoderma gangrenosum, and circulating immune complexes have not been detected regularly. HLA typing has also not revealed a consistent pattern. 1 Diagnosis and differential diagnosis The diagnostic evaluation of a patient presumed to have pyoderma gangrenosum has two objectives: first, to rule out other causes of cutaneous ulceration and, second, to determine whether there is a treatable systemic, associated disorder. Since there is no specific laboratory test, and the histopathology is indicative, but not diagnostic, the diagnosis of pyoderma gangrenosum rests entirely on the clinical presentation and course. Moreover, some of the associated disease processes may be clinically silent. The differential diagnosis of ulcerative cutaneous lesions includes infectious disease, malignancy, vasculitis, insect bites, venous or arterial insufficiency (comprising antiphospholipid antibody associated occlusive disease), and above all factitious (self-inflicted) ulcerations 22 (Table 3). Cultures should be taken from the exudate and, when possible, directly from the tissue. Biopsy, although not specific, is a means of excluding malignancy, vasculitis, and infections caused by deep fungi, mycobacteria, or parasites. Even though it can sometimes lead to extension of the ulceration (via pathergy), biopsy should be carried out in most cases. In order to test for any associated disorder and to help rule out other causes of cutaneous ulceration, a thorough history of all patients should be taken and the gastrointestinal tract should be examined in selected patients. Radiographic procedures may include an uppergastrointestinal series and a barium enema. Flexible sigmoidoscopy and/or colonoscopy may also be done, with biopsies. A complete blood count, evaluation of the peripheral smear, and, in selected individuals, a bone marrow aspirate or biopsy will help exclude haematological malignancy. Serum protein electrophoresis, serum immunodiffusion studies, and serum and urine immunoelectrophoresis can be useful in ruling out monoclonal gammopathy or myeloma. Pyoderma -gangrenosum like leg ulcers may occur in patients with antiphospholipid antibody syndrome or vasculitic conditions; thus, the Venereal Disease Research Laboratory, anticardiolipid antibody, partial thromboplastin time, and anti-neutrophil cytoplasmic antibody (ANCA) tests should be performed. Patients with pyoderma gangrenosum will frequently be panca (perinuclear) positive, especially if they have IBD. The presence of canca (cytoplasmic) would indicatewegener s granulomatosis. 16 Course and prognosis The disease behaves in an unpredictable way. Pyoderma gangrenosum may have a dramatic onset with pustular and bullous lesions rapidly turning into ulcers, which progressively enlarge until arrested by treatment; in these cases, there may be toxicity, fever, and considerable pain. More chronic forms show

7 1014 Ruocco et al. Table 3 Differential diagnosis of pyoderma gangrenosum (from Conrad and Trüeb) 6 General Ulcerative pyoderma gangrenosm Early lesions: Pustular pyoderma gangrenosum Bullous pyoderma gangrenosum Vegetative pyoderma gangrenosum Drug reaction Halogenoderma Factitial dermatosis Cutaneous neoplasms Systemic vasculitis: Wegener granulomatosis Mixed cryoglobulinemia Polyarteritis nodosa Antiphospholipid antibody syndrome Livedo vasculitis Infections: Sporotrichosis Amebiasis Syphilitic ulceration Ecthyma gangrenosum Others Insect/spider bites (necrotizing arachnidism) Neoplasms Ischemic ulceration Behçet disease Panniculitis Malignant processes: Primarily T-cell lymphomas Other cutaneous neoplasms Pustular vasculitis Various infections including gonococcal septicemia Folliculitis: Herpetic Others Pustular drug eruption Sweet syndrome Insect/spider bite (necrotizing arachnidism) Acute cellulitis Various bullous dermatoses Infections: Mycobacterial Sporotrichosis Cutaneous neoplasms ulcers that extend slowly in a creeping fashion, expanding in one direction and healing spontaneously in another or in the centre. In both forms, spontaneous healing can occur, but as old lesions resolve, new lesions may arise. The disease may come to a spontaneous halt without apparent reason; sometimes, it remains quiescent for months and even years, and exacerbates again after minimal trauma, surgery, or no apparent triggering cause. 1 Despite advances in therapy, the long-term outcome for patients with pyoderma gangrenosum remains unpredictable. pyoderma gangrenosum is a potentially lethal disease, with a mortality rate of up to 30% in some series. Poor prognostic indicators are male sex, old age at onset and bullous pyoderma gangrenosum specifically when associated with malignant haematological disorders. 6 The prognosis is more predictable in those patients in whom an identifiable underlying disease is recognizable and amenable to treatment. But even here, the prognosis is that of the associated disease and this may be unfavourable, especially if the immune system is involved. When associated with ulcerative colitis, the disease activity of pyoderma gangrenosum may parallel that of the bowel disease: the control of the intestinal condition can resolve the skin problem and recurrences may occur at periods of exacerbation of IBD. However, skin lesions may also have an evolution that is partially independent of the intestinal activity of IBD, and while some authors suggest a relationship between exacerbations of the colitis and the onset of skin disorder, 23,24 others have found no correlation. 25,26 In some patients with IBD and pyoderma gangrenosum, a trauma may be a common precipitating factor without any association with clinical exacerbation of disease. The overall prognosis of pyoderma gangrenosum without underlying disease is good, particularly in those patients who readily respond to treatment, but considerable scarring and disfigurement may eventually result. 1 Treatment (Table 4) There are very few controlled trials of treatment for pyoderma gangrenosum perhaps due to the relatively rare and sporadic occurrence of the disease. As the pathogenesis is not well understood, treatment has developed largely on an empirical basis. There is no specific and uniformly effective therapy for pyoderma gangrenosum. The therapeutic approach depends on lesion extension and depth, the associated disorder, the baseline status of the patient, risk and patient tolerance to prolonged therapy. The therapeutic goal is to reduce the inflammatory process of the wound in order to promote healing, to reduce pain, and to control the contributing underlying disease with minimum adverse side-effects. Local or topical treatment may be tried in milder forms and those not associated with systemic disease. The most tangible results are reported with systemic corticosteroids and cyclosporine, and these effective, but toxic, modalities can be employed when the severity of the disease justifies the risks (i.e. when there is facial involvement or very rapid progression). In patients with underlying disease, therapy should be directed not only to pyoderma gangrenosum but also and primarily to the systemic disorder. Effective management of an underlying pathology often seems to result in improvement of pyoderma gangrenosum. 1,4,27 When associated with IBD, pyoderma gangrenosum generally responds to treatment of the underlying IBD. Patients with pyoderma gangrenosum associated to severe chronic ulcerative colitis may best be served by total colectomy, although this is not a guaranteed cure for the associated pyoderma gangrenosum. 28,29

8 Pyoderma gangrenosum: a review 1015 Table 4 Management of pyoderma gangrenosum Corticosteroids Antimicrobial agents Steroid-sparing immunosuppressive agents Immune modulation Miscellaneous Topical Intralesional Systemic Benzoyl peroxide Clofazimine Diaminodiphenylsulfone (dapsone) Rifampicin Sulfapyridine Minocycline Vancomycin Mezlocillin 5-aminosalicylic acid (topical) 6-mercaptopurine Azathioprine Cyclophosphamide Cyclosporine (topical, systemic) Methotrexate Chlorambucil Mycophenolate mofetil Tacrolimus (topical, systemic) Infliximab Alefacept Interferon-α Intravenous immunoglobulin Plasmapheresis Thalidomide Colchicine Heparin Nicotine (topical) Disodium cromoglycate (topical) Hyperbaric oxygen Although measures directed at cleaning the ulcer and preventing bacterial overgrowth are important, more invasive surgical debridement should be discouraged as it may trigger new lesions. When surgery is unavoidable in patients with a history of pyoderma gangrenosum, the surgeon should be made aware of this risk (avoiding trauma to the skin). Surgical incisions should be kept as short as possible. Careful wound closure may be helpful. Prophylactic systemic corticosteroids or cyclosporine may be indicated perioperatively. 1,26 Topical treatment In mild cases, local measures such as dressings, limb elevation, rest, topical agents, or intralesional corticosteroid or cyclosporine injections can be sufficient to control the disease process. Compresses, wet-to-dry dressings, or the bioocclusive semipermeable dressings may be useful. Hyperbaric oxygen has been reported to be helpful in a small number of cases. 16 Other local therapies that may be used in controlling the inflammation or promoting wound healing include benzoyl peroxide 30 disodium cromoglycate 31 and nicotine. 32 Probably the most effective topical agent is triamcinolone diacetate (5 mg/ml), injected twice weekly into the border of ulceration. Care must be taken to avoid super-infection and to limit the potential systemic effects of corticosteroids that arise from injecting large doses intralesionally. Intralesional injection of cyclosporine has also proved beneficial in several cases. Topical agents designed to alter the immune response such as tacrolimus 0.1%, 5-aminosalicylic acid, or superpotent topical corticosteroids may be helpful. Topical human platelet-derived growth factor may be beneficial in patients with disease in remission but where re-epithelialization is slow. 6 Systemic treatment Glucocorticoids Systemic corticosteroids have generally been the most predictable, effective medication when delivered in adequate doses. They halt the progression of existing ulceration and prevent the development of new lesions. High doses such as mg/day of prednisone may be necessary initially; to be reduced as the inflammatory component of pyoderma gangrenosum disappears and gradually phased out only after complete resolution has occurred. Pulse therapy with suprapharmacologic doses of methylprednisolone (1 g/day for five consecutive days) most effectively halts progressive pyoderma gangrenosum, and it is now the first-line treatment for severe pyoderma gangrenosum in many departments. However, there is a continued need for suppression of the inflammatory process following pulse therapy by the use of oral prednisolone or sulfa drugs. Unfortunately, side-effects occur in up to 50% of the patients in long-term oral glucocorticoid therapy. The most resistant lesions require protracted therapy at a higher than desirable dosage, thus facilitating adverse side-effects. Such patients should be closely monitored and receive supplemental calcium, vitamin D and, if necessary, bisphosphonates. 1 Sulfa drugs Dapsone, sulfapyridine, and sulfasalazine are beneficial, but not all patients respond in the same way. In the authors experience, sulfasalazine is the most effective of the three, not only in patients with associated ulcerative colitis but also in some patients with pyoderma gangrenosum but no systemic disease. Initial daily doses range from 4 to 6 g and are gradually reduced to maintenance levels of g. Combining this with systemic glucocorticoids, particularly in the initial phases of therapy, may be necessary, but there have also been patients who failed to respond. An occasional patient can be maintained symptom free with sulfa drugs alone, but it has not been established beyond doubt that such suppression of disease activity is actually related to treatment. Up to 200 mg/day of dapsone has been used as

9 1016 Ruocco et al. monotherapy or as an adjunctive, steroid-sparing agent. Usually, the drug is administered at lower doses ( mg/day), and the standard precautions on a pretherapy evaluation are necessary. Dapsone is effective in a number of cutaneous disorders that are all characterized by the abnormal accumulation of polymorphonuclear leucocytes, such as erythema elevatum diutinum, dermatitis herpetiformis, Sneddon-Wilkinson disease, Sweet s syndrome, and pyoderma gangrenosum. The sulfa drug mechanism in pyoderma gangrenosum is unknown, but it may be related to a stabilizing effect on the lysosomes, to their interference with the myeloperoxidase-halide system of polymorphonuclear leucocytes, or to a decrease of glycosaminoglycan viscosity in this condition. 1 Cyclosporine Cyclosporine has proved to be a very helpful substitute therapy for patients whose pyoderma gangrenosum is resistant to corticosteroid therapy or who have had serious side-effects. Significant improvement occurs within weeks of oral cyclosporine therapy in doses that range from 6 to 10 mg/kg per day, and healing can be expected within 1 3 months. Some patients require low-dose maintenance therapy, but in others, the drug can be completely withdrawn. Patients may require concomitant medium-to-lowdose glucocorticoid therapy. As with other immunosuppressive treatments, patients have to be monitored carefully for side-effects. 1 Other immunosuppressive agents 6-Mercaptopurine, azathioprine, and methotrexate have been reported to be beneficial but are not universally successful. Cyclophosphamide induced remissions in some patients; however, the risk of infertility, haemorrhagic cystitis, hair loss, and secondary malignancies must be taken into account. Chlorambucil (4 mg/day) has demonstrated a remarkable glucocorticoid-sparing effect. 1,6 Clofazimine Reports have stressed the dramatic efficacy of clofazimine (Lamprene ) in pyoderma gangrenosum. Doses of mg/ day apparently stop progression of lesions within 1 2 weeks and lead to complete or partial healing within 2 5 months. However, some patients do not respond to clofazimine, which generally has fewer side-effects than those of glucocorticoids, but splenic infarction was observed in one patient. 1 Miscellaneous treatments Pyoderma gangrenosum responds to minocycline, colchicine, heparin, and intravenous vancomycin and mezlocillin (although, as indicated by worldwide experience, the disease is usually unresponsive to any kind of antibiotic); it has been reported to improve with salazosulfapyridine and isotretinoin combination therapy in one patient and to respond to interferon alpha. Plasmapheresis has been successfully used in the treatment of some patients with pyoderma gangrenosum as have intravenous immunoglobulin and thalidomide in cases of pyoderma gangrenosum associated with Behçet s disease. 1 Infliximab, a chimeric (mouse/human) monoclonal antibody that targets the membrane-bound precursor of tumour necrosis factor (TNF)-alpha and exerts its biological activity by preventing the binding of TNF-α to its receptor, has been reported to be effective in patients with pyoderma gangrenosum refractory to systemic corticosteroid and cyclosporine therapy. The onset of clinical response is fast and improvement often dramatic. In many instances, specifically in those associated with IBD, infliximab helps both pyoderma gangrenosum and the underlying disorder. Lately, it has been applied to refractory pyoderma gangrenosum associated to concomitant IBD as first-line therapy. 6,33 36 One aspect that remains unclear concerning infliximab therapy in refractory pyoderma gangrenosum is the optimal number of doses for the induction and maintenance of skin lesion response. In some cases, three doses (at 0, 2, and 6 weeks) infused at 5 mg/ kg bodyweight were administered with adequate tolerance and response, demonstrating a rapid improvement in the skin lesions and intestinal activity. To maintain remission, azathioprine was administered, permitting the discontinuation of steroids and the interruption of infliximab therapy. 34,35 A randomized, doubleblind, placebo-controlled trial has demonstrated that infliximab at a dose of 5 mg/kg is superior to placebo in the treatment of pyoderma gangrenosum. Since open-label treatment with infliximab has produced promising results, it should be considered in patients with pyoderma gangrenosum, irrespective of whether or not they have coexistent IBD. 36 The benefits of infliximab outweigh the risk of its use, especially when administrated to patients with pyoderma gangrenosum that have not responded to standard therapies. Nevertheless, appropriate caution is important in the selection and monitoring of patients treated with this drug. All patients should be screened for latent tuberculosis. Individuals who may have recently been in contact with tuberculous patients are not candidates for this drug. While using infliximab, monitoring patients for symptoms of infection is recommended and therapy should be discontinued if symptoms develop. 6 Alefacept is a recombinant protein that blocks the LFA-3/CD2 interaction both in vitro and in vivo, resulting in interference with T-lymphocyte activation and subsequent modification of the inflammatory process. An open-label pilot study showed that alefacept treatment may significantly reduce pyoderma gangrenosum severity levels, making it a safe and effective alternative to current systemic immunosuppressants. 37 References 1 Wolff K, Stingl G. Pyoderma gangrenosum. In: Freedberg IM, Eisen AZ, Wolff K et al., eds. Fitzpatrick s Dermatology in General Medicine, 5th edn. New York, NY: Mc Graw-Hill, 1999; 2: Brocq L. Nouvelle contribution a l étude du phagédénisme géométrique. Ann Dermatol Syphiligr 1916; 6: 1 39.

10 Pyoderma gangrenosum: a review Brunsting AL, Goeckerman WH, O Leary PA. Pyoderma gangrenosum: clinical and experimental observation in five cases occurring in adults. Arch Dermatol Syphilol, 1930; 22: Bolognia JL, Jorizzo JL, Rapini RP, eds. Pyoderma gangrenosum. Dermatology. London, UK: Mosby, 2003; 1: Su WP, Davis MD, Weenig RH, Powell FC, Perry HO. Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria. Int J Dermatol 2004; 43: Conrad C, Trüeb RM. Pyoderma gangrenosum. J Dtsch Dermatol Ges 2005; 3: Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol, 1996; 34: O Loughlin S, Perry HO. A diffuse pustular eruption associated with ulcerative colitis. Arch Dermatol 1978; 114: Perry HO, Winkelmann RK. Bullous pyoderma gangrenosum and leukemia. Arch Dermatol 1972; 106: Wilson-Jones E, Winkelmann RK. Superficial granulomatous pyoderma: a localized vegetative form of pyoderma gangrenosum. J Am Acad Dermatol 1988; 18: Perry HO, Winkelmann RK, Muller SA, Kierland RR. Malignant pyodermas. Arch Dermatol 1968; 98: Gibson LE, Daoud MS, Muller SA, Perry HO. Malignant pyodermas revisited. Mayo Clin Proc 1997; 72: Lyon CC, Smith AJ, Beck MH et al. Parastomal pyoderma gangrenosum: clinical features and management. J Am Acad Dermatol 2000; 42: Tjandra JJ, Hughes LE. Parastomal pyoderma gangrenosum in inflammatory bowel disease. Dis Colon Rectum, 1994; 37: Hughes AP, Jackson JM, Callen JP. Clinical features and treatment of peristomal pyoderma gangrenosum. J Am Med Assoc 2000; 284: Callen JP. Pyoderma gangrenosum. Lancet 1998; 351: Van der Sluis I. Two cases of pyoderma (ecthyma) gangrenosum associated with the presence of an abnormal serum protein (beta2a-paraprotein): with a review of the literature. Dermatologica 1966; 132: Bonamigo RR, Behar PR, Beller C, Bonfá R. Pyoderma gangrenosum after silicone prosthesis implant in the breasts and facial plastic surgery. Int J Dermatol 2008; 47: Tinoco MP, Tamler C, Maciel G, Soares D, Avelleria JC, Azulay D. Pyoderma gangrenosum following isotretinoin therapy for acne nodulocystic. Int J Dermatol 2008; 47: Cook TJ, Lorincz AL. Pyoderma gangrenosum appearing 10 years after colectomy and apparent cure of chronic ulcerative colitis. Arch Dernatol, 1962; 55: Holmlund DEW, Wahlby L. Pyoderma gangrenosum after colectomy for inflammatory bowel disease. Acta Chir Scand 1987; 53: Ilter N, Adi4en E, Gürer MA, Kevlekçi C, Tekin Ö, Sayin A. Dermatitis artefacta masquerading as pyoderma gangrenosum. Int J Dermatol 2008; 47: Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis, part Ill, complications. Gut 1964; 5: Russell B. Phagedenic and gangrenous ulceration of the skin complicating ulcerative colitis. (Phagedena Geometricum). Br J Dermatol 1950; 62: Johnson ML, Wilson HTH. Skin lesions in ulcerative colitis. Gut 1969; 10: Thornton JR, Teague RH, Lon-Beer TS, Read AE. Pyoderma gangrenosum and ulcerative colitis. Gut 1979; 21: John B-J. Pyoderma gangrenosum. In: Lebwohl M, Heymann WR, Berth-Jones J, Coulson I, eds. Treatment of Skin Disease. London, UK: Mosby, 2002: Levitt MD, Ritchie JK, Lennard-Jones JE, Phillips RKS. Pyoderma gangrenosum in inflammatory bowel disease. Br J Surg 1991; 78: Hamblin TJ. Pyoderma gangrenosum. Lancet 1998; 351: Nguyen LQ, Weiner J. Treatment of pyoderma gangrenosum with benzoyl peroxide. Cutis 1977; 19: Tamir A, Landau M, Brenner S. Topical treatment with 1% sodium cromoglycate in pyoderma gangrenosum. Dermatology 1996; 192: Wolf R, Ruocco V. Nicotine for pyoderma gangrenosum. Arch Dermatol 1998; 134: Mimouni D, Anhalt GJ, Kouba DJ, Nousari HC. Infliximab for peristomal pyoderma gangrenosum. Br J Dermatol 2003; 148: Romero-Gomez M, Sanchez-Munoz D. Infliximab induces remission of pyoderma gangrenosum. Eur J Gastroenterol Hepatol 2002; 14: Regueiro M, Valentine J, Plevy S et al. Infliximab for treatment of pyoderma gangrenosum associated with inflammatory bowel disease. Am J Gastroenterol 2003; 98: Brooklyn TN, Dunnill MG, Shetty A et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut 2006; 55: Foss CE, Clark AR, Inabinet R, Camacho F, Jorizzo JL. An open-label pilot study of alefacept for the treatment of pyoderma gangrenosum. J Eur Acad Dermatol Venereol 2008; 22: