Etiology and Management of Pyoderma Gangrenosum

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by painful, necrotic ulceration. It typically affects patients in the third to sixth decades of life, with almost equal incidence in men and women. PG occurs most frequently on the lower extremities. Five clinical variants are currently recognized: classic, bullous, pustular, vegetative, and peristomal types. Half of PG cases are seen in association with systemic disease. Mimickers include infection, vascular insufficiency ulcers, systemic vasculitides, autoimmune disease, cancer, and exogenous tissue injury, among others. PG is often a diagnosis of exclusion, as there are no specific laboratory or histopathologic findings to confirm the diagnosis. PG thus presents many clinical challenges: it is difficult to diagnose, is frequently misdiagnosed, and often requires a work-up for underlying systemic disease. Successful management of PG typically requires multiple modalities to reduce inflammation and optimize wound healing, in addition to treatment of any underlying diseases. Prednisone and cyclosporine have been mainstays of systemic treatment for PG, although increasing evidence supports the use of biologic therapies, such as tumor necrosis factor-α inhibitors, for refractory cases of PG. Here, we review the clinical presentation and pathophysiology of PG, as well as its associated conditions, diagnostic work-up, and management.     

Bullous pyoderma gangrenosum: A case report and review of the published work

Pyoderma gangrenosum (PG) is an ulcerative skin disorder characterized by neutrophilic infiltrations. PG is generally classified into four types: (i) ulcerative; (ii) pustular; (iii) bullous; and (iv) vegetative. Among them, bullous PG is known as a rare type. Herein, we report a case of bullous PG together with a summary of the 12 PG cases treated in our department over the previous 15 years, and we review 38 well‐documented bullous PG cases (65.8% female; aged 18–80 years [mean ± standard deviation, 51.6 ± 16.8]) in the published work, including the present case, from 1972–2011. Although the disease most frequently associated with PG is inflammatory bowel disease, bullous PG is most commonly associated with hematological disorders (25/38, 65.8%), which indicates the characteristic pathophysiology specific to bullous PG.     

PARANEOPLASTIC PYODERMA GANGRENOSUM

Pyoderma Gangrenosum (PG) is often associated with an underlying disease. PG as a paraneoplastic disease is illustrated by the presentation of four patients with malignancy of myeloproliferative origin and PG. An associated malignancy isfound in approximately 7% of patients with PG, most commonly haematologic in nature and in particular leukaemia. Clinically the PG is often of the superficial bullous variant and is associated with a poor prognosis.     

Successful treatment with doxycycline and nicotinamide of two cases of persistent pemphigoid gestationis

Pemphigoid gestationis (PG) is a rare dermal-epidermal autoimmune bullous disease of pregnancy and postpartum, which relapses more seriously and earlier during following pregnancies. PG also occurs in association with trophoblastic tumours or oral contraceptive treatment. The term 'persistent PG' represents the cases where active disease persists for months to many years after delivery. Four cases of persistent PG have been reported to date in the literature. So far, systemic cortico-steroids have been the main PG therapy and the use of cyclophosphamide, dapsone, pyridoxine, methotrexate, plasmapheresis or ritodrine has also been reported, with contradictory results. In this paper are described two patients with persistent PG who were successfully treated with doxycycline (200 mg/day) and nicotinamide (500 mg/day), a treatment that was demonstrated to be safe and efficacious in bullous pemphigoid.     

Clinicopathological features and HLA tissue typing in pemphigoid gestationis patients in Kuwait

Pemphigoid gestationis (PG) is a rare autoimmune disease of pregnancy. We report a series of 22 cases of PG in Kuwait. They constituted 18% of all the autoimmune bullous diseases registered in our centre over a span of 11 years. PG was observed to be the third most common bullous disease in our region. Ninety-five per cent of the patients were of Arab ethnicity. The clinical features observed in our patients were comparable to those reported elsewhere. Systemic steroids (prednisolone 20-60 mg daily) remained the mainstay of treatment to control the active disease and an optimal dose of 20 mg of prednisolone was maintained throughout the pregnancy and immediate postpartum period. We observed a favourable outcome of pregnancies complicated by PG without any associated maternal or foetal morbidity. Kuwaiti patients with PG were observed to have a predominance of HLA-DR3 and DQ2 antigens. No predominance of HLA-DR4 antigen was observed.     

Pyoderma gangrenosum in a patient with bullous systemic lupus erythematosus

We report a 55-year-old woman with bullous systemic lupus erythematosus, who later developed pyoderma gangrenosum (PG). Dapsone was effective for the eruption of bullous bullous systemic lupus erythematosus but not for pyoderma gangrenosum. Cyclosporine was effective for the skin lesions of pyoderma gangrenosum. This is the first reported case of PG associated with bullous systemic lupus erythematosus.     

Widespread idiopathic pyoderma gangrenosum evolved from ulcerative to vegetative type: a 10-year history with a recent response to infliximab

Pyoderma gangrenosum (PG) is an infrequent neutrophilic dermatosis, which commonly presents with a limited number of ulcerative, pustular, bullous or vegetative lesions associated with an underlying systemic disorder. We report a 34-year-old man with ulcerative PG that was exceptionally widespread and not associated with any other condition. Moreover, it was resistant to steroid treatment and, after prolonged use of ciclosporin, it unexpectedly developed a vegetative pattern, further supporting the hypothesis that the different forms of PG are part of a single clinical spectrum. Finally, dramatic improvement of the condition occurred after treatment with infliximab, an antitumour necrosis factor-alpha monoclonal antibody; however, this produced circulating autoantibodies. Although this has not had any clinical consequence to date, accurate follow-up in patients treated with infliximab is essential to monitor the onset of a possible autoimmune disorder induced by the drug.     

Successful treatment of one case of pemphigoid gestationis complicating with polycystic ovary syndrome

Pemphigoid gestationis (PG) is a rare, autoimmune, subepidermal bullous dermatosis associated with pregnancy. It is mainly caused by autoantibodies against hemidesmosomal proteins‐bullous pemphigoid 180, and usually presents in the second or third trimester of pregnancy sometimes exacerbates spontaneously after delivery. Here we reported a case of PG with polycystic ovary syndrome (PCOS). This patient received assisted reproduction technology and suffered PG in her third trimester of pregnancy. To the best of our knowledge, there is no similar case has been reported.     

Pemphigoid gestationis ohne Blasenbildung

BACKGROUND AND OBJECTIVE: Pemphigoid gestationis (PG) is a rare pregnancy-associated autoimmune bullous disease characterized by autoantibodies to the 180 kD bullous pemphigoid antigen (BP180). The clinical spectrum of PG is polymorphic and for diagnostic purposes, a skin biopsy is usually taken demonstrating the deposition of autoantibodies. PATIENTS AND METHODS: From 2 patients, skin biopsies were obtained for histopathologic and immunofluorescence studies. Circulating autoantibodies were characterized by immunoblotting and ELISA using a recombinant form of the immunodominant BP180 NC16 A domain. RESULTS: The 2 PG patients described here did not show blisters but complained about severe itching. In the first case, PG presented in the first trimester of the second pregnancy as an erythema-multiforme-like disease. The second patient developed urticarial plaques a few days after delivery. PG was diagnosed by the detection of autoantibodies against recombinant BP180 NC16 A by immunoblot and ELISA analysis and confirmed by linear deposits of C3 at the cutaneous basement membrane zone on direct immunofluorescence microscopy. Skin lesions healed with oral prednisolone. CONCLUSIONS: In our two patients, non-bullous PG could be diagnosed by serological tests. Immunoblotting and ELISA might be sensitive and specific tools when screening sera of patients with pruritic skin lesions in pregnancy for the presence of autoantibodies to BP180. In some cases, these newer techniques may make a skin biopsy unnecessary.     

Pyoderma gangrenosum occurring near an arteriovenous dialysis shunt

Pyoderma gangrenosum (PG) is an uncommon cutaneous disease of unknown etiology. In 50 percent of affected patients, PG is associated with systemic disease including inflammatory bowel disease, arthritis, and hematologic malignancies.(1) Diagnosis of PG is based on clinical presentation, histopathology and on the exclusion of other diseases that can produce clinically similar lesions, e.g. infection, vasculitis, malignancy, collagen vascular diseases, diabetes, and trauma. Four variants of PG have been described: ulcerative, pustular, bullous, and vegetative.(2) We report a woman with renal failure who developed PG in the absence of any obvious triggering trauma in a distinctive unilateral crop just distal to an arteriovenous dialysis shunt.     

Immunopathology of the placenta in pemphigoid gestationis and linear IgA disease

We have investigated the immunopathology of the placenta in bullous diseases by studying the deposition of immune complexes and expression of MHC class II subregion products by immunohistological methods. Placentae from seven patients with pemphigoid gestationis (PG) and two patients with linear IgA disease were studied. In PG immune complexes containing IgGI and C3 were identified in six cases. In linear IgA disease IgAI containing immune complexes were found in both cases. Placentae from patients with PG showed aberrant expression of MHC Class II products. This was not seen in the placentae from patients with linear IgA disease. In PG there was incoordinate expression of the subregion products, DP and DR being more extensively and consistently expressed than DQ. These results and previous immunogenetic studies suggest that PG may be unique among organ specific autoimmune disease, the autoantibodies forming during an allogenic response rather than target cells behaving as antigen presenting cells.     

The role of T lymphocytes and cytokines in the pathogenesis of pemphigoid gestationis

BACKGROUND: Pemphigoid gestationis (PG), also known as herpes gestationis, is a rare autoantibody-mediated bullous disease, usually associated with pregnancy and the postpartum period. However, infiltrating cells have recently been suggested to also contribute to the pathogenesis of cutaneous lesions. OBJECTIVES: To evaluate the immunophenotype of T cells infiltrating the PG lesional skin and their prevalent cutaneous cytokine expression, as well as the presence and distribution of mast cells, eosinophils and neutrophils. Methods We performed an immunohistochemical study with a large panel of monoclonal antibodies to CD3, CD4, CD8, HLA-DR, CD25, myeloperoxidase, tryptase, eosinophil cationic protein EG2, human interleukin (IL)-2, -4, -5, -8, interferon (IFN)-gamma, and granulocyte-macrophage colony-stimulating factor using the alkaline phosphatase-antialkaline phosphatase procedure on lesional skin of seven patients with PG. Skin from four subjects with pruritic urticarial papules and plaques of pregnancy and three additional healthy donors were used as controls. RESULTS: The findings indicate that there is a T-cell population with a prevalent T-helper (Th) 2 phenotype in the lesional skin of PG subjects. We also found a number of eosinophils and neutrophils with clear signs of activation. CONCLUSIONS: These data suggest that an inflammatory infiltrate is involved in the production of PG bullous lesions. In particular, we assume that the Th2 cells might be implicated in the very early stages of autoimmune response and may exercise a broad influence in blister formation in this disease.     

Pyoderma gangrenosum: a report of 21 cases

BACKGROUND: Pyoderma gangrenosum (PG) is an uncommon, destructive, cutaneous ulceration, belonging to the neutrophilic disease spectrum. It is associated with systemic disease in 50% of cases. METHODS: We report a retrospective study of 21 cases of PG. All cases studied fulfilled the following criteria: (i) clinical features of PG; (ii) histopathology consistent with a diagnosis of PG, and excluding other specific dermatoses. RESULTS: The average age of our patients was 41.8 years. The male to female ratio was 1.1. The typical ulcerative variant was found in 17 patients, bullous PG in two patients, and the granulomatous variant in two patients. Sixty-two per cent of our patients had lesions on their lower legs. Two patients had neutrophilic pulmonary involvement concurrent with the ulcers. An association with other internal diseases was noted in 12 patients. Histopathologic study showed vasculitis in 13 patients. Of these, 11 were leukocytoclastic and the others predominantly lymphocytic. CONCLUSIONS: PG is a rare disease, with the ulcerative variant being most frequent. The lower legs are the most commonly affected sites. The recurrence rate in our study was about 46% regardless of the treatment prescribed. Pulmonary involvement was fatal in two patients.     

Pustular pyoderma gangrenosum

Pyoderma gangrenosum (PG) is an idiopathic inflammatory disease of unknown aetiology, frequently associated with an underlying systemic condition such as inflammatory bowel disease or haematological malignancy. Its occurrence tends to parallel exacerbations of the underlying disease. Four clinical variants of PG have been described and these include ulcerative, pustular, bullous and vegetative types. We report two cases of the pustular form, which is an uncommon variant of PG, where the pustules do not progress to form ulcers. Both our patients suffered with inflammatory bowel disease which remained quiescent as the pustular PG developed.     

Pemphigoid gestationis: a case report and review of the literature

Pemphigoid gestationis (PG) is an uncommon autoimmune bullous disease that almost exclusively presents during pregnancy. Patients typically present with a diffuse blistering and intensely pruritic eruption that begins periumbilically and spreads to involve the rest of the body. Direct immunofluorescence demonstrating C3 in a linear pattern along the dermoepidermal junction confirms the diagnosis of PG. Corticosteroids remain the choice of therapy and early intervention is essential because of possible adverse effects of PG on the fetus. We report a case of PG and review the literature.     

Neutrophilic dermatosis of myeloproliferative disorders: Atypical forms of pyoderma gangrenosum and Sweet's syndrome associated with myeloproliferative disorders

Atypical forms of pyoderma gangrenosum (PG) and Sweet's syndrome (SS) (acute febrile neutrophilic dermatosis) have been separately reported in association with various forms of leukemia over the past decade. A case in which both atypical bullous PG and atypical SS occurred in a patient with myeloid metaplasia is presented, and the literature is reviewed concerning the association of these dermatoses with neoplasias of myeloid origin. The current case and review support the thesis that these dermatoses, when associated with myeloproliferative disorders, represent points on a continuum of noninfectious, nonmetastatic, inflammatory neutrophilic dermatoses that may occur in patients with derangements in myeloid cell proliferation.     

Conjunctival involvement in the autoimmune blistering dermatoses: a clinical and histopathological study

The conjunctiva was examined by slit lamp microscopy and biopsy for direct immunofluorescence (IF) in patients with cicatricial pemphigoid (CP), bullous pemphigoid (BP), pemphigoid gestationes (PG), linear IgA dermatosis (LAD), pemphigus and dermatitis herpetiformis (DH).
In CP, five of 13 patients had definite scarring, seven equivocal, and one no signs. IF showed linear deposition of IgG and/or C₃ along the BMZ in 45%.
In BP, six of 18 patients had fine conjunctival scarring. IF showed linear IgG IgA and/or C₃ in 73 %. Scarring was not observed in one PG patient.
In LAD, three of seven patients had conjunctival scarring, one with marked symblepharon. IF in five patients showed linear IgG without IgA in three.
In pemphigus, neither of two patients had scarring. IF in both showed IgG and/or C3 between epithelial cells.
In DH, one of three patients had fine scarring.
These findings demonstrate that conjunctival involvement may occur in autoimmune bullous dermatoses other than CP and LAD.     

The intracellular and extracellular domains of BP180 antigen comprise novel epitopes targeted by pemphigoid gestationis autoantibodies

Pemphigoid gestationis (PG) is an autoimmune sub-epidermal bullous dermatosis of pregnancy associated with circulating autoantibodies targeting the extracellular non-collagenous (NC) 16A domain of bullous pemphigoid (BP) 180 antigen. In order to determine whether BP180 regions other than NC16A are recognized by PG autoantibodies, we have analyzed the reactivity of 15 PG patient sera against several BP180 antigenic sites by sensitive methods such as immunological screening and ELISA. Most PG sera tested (13 of 15) reacted with an epitope (amino acid 508-541) mapped in the NC16A domain. Of note, nine of 15 PG patient sera reacted with at least one additional antigenic site other than NC16A. Specifically, two epitopes in the BP180 extracellular domain and five epitopes in the intracellular one were recognized by three and seven PG sera, respectively. In addition, a representative intracellular epitope was recognized by PG autoantibodies as a portion of BP180 antigen both in denaturating and native conditions. Finally, reactivity against epitopes additional to NC16A was also detected at an early stage of the disease. The identification and characterization of hitherto unrecognized epitopes targeted by PG patient autoantibodies provide novel insights into the pathophysiology of humoral immune response to BP180 in PG.     

IgG4 as the predominant IgG subclass in pemphigoides gestationis

BACKGROUND: Pemphigoides gestationis (PG) is a blistering disorder of pregnancy caused by antibodies against basement membrane proteins. They are directed against the 180 kD bullous pemphigoid antigen (BPAg2), towards the epitopes within the NC 16A domain. There are many similarities between pemphigoid gestationis and bullous pemphigoid (BP), but the literature so far indicated different immunofluorescence results in regards with C3 and IgG, and IgG subclasses (IgG4 vs. IgG1). METHODS: We evaluated staining patterns and IgG subclasses, as well as C5b-9 membrane attack complex (MAC) in 10 pregnant patients with PG, using sandwich double antibody immunofluorescence (SDAI) and direct immunofluorescence (DIF). RESULTS: All ten specimens stained with C3 by DIF, but only five had trace amount of IgG reactants by this method. By SDAI, 100% were positive for the IgG4 and C5b-9 MAC, 70% for IgG2, 50% for IgG1, and 40% for IgG3. CONCLUSION: IgG4 was the predominant IgG subtype identified. This finding has not been reported for PG, but it mimics results reported for BP. One explanation is prolonged disease course, as well as blocking of antigenic domains by IgG4. Understanding this completely will help develop therapies and prevention strategies for immunobullous and other autoimmune diseases, and perhaps aid in an exact classification.     

Pemphigoid gestationis with predominant involvement of oral mucous membranes and IgA autoantibodies targeting the C-terminus of BP180

Pemphigoid gestationis (PG) is an autoimmune pregnancy-associated subepidermal blistering disease. It usually affects skin and, rarely, mucous membranes. In the vast majority of patients with PG, the autoimmune response is directed to the membrane-proximal NC16A domain of the 180-kd bullous pemphigoid (BP) antigen (BP180) and is mediated by IgG1 and IgG3 autoantibodies. We report the case of a patient with PG associated with extensive lesions on oral mucous membranes. Immunoblotting studies demonstrated the presence of circulating IgA autoantibodies in the patient's serum that were exclusively directed to a 49 amino acid stretch on the C-terminal portion of the BP180 ectodomain located 800 amino acids downstream from NC16A. This C-terminal stretch of BP180 has previously been demonstrated to localize to the lamina lucida/lamina densa interface and to be recognized by IgG and IgA antibodies in a subgroup of patients with cicatricial pemphigoid as well as by IgG autoantibodies in some BP sera. Our patient's lesions healed without scarring within 6 weeks after delivery of a healthy child. The findings in this patient extend the clinical and immunopathologic spectrum of PG.