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Clinical Updates

Lindy P. Fox, MD

Pyoderma Gangrenosum (PG)

Lindy Fox

Tuesday, April 03, 2007

Pyoderma gangrenosum (PG), first described by Brocq1 in 1916 and later characterized by Brunsting et al.2 in 1930, is an uncommon, neutrophilic, ulcerative skin disease.3,4 The incidence of PG has not been precisely determined; several accounts, however, have reported a range of 15 cases seen over 10 years, to 21 cases over 19 years, to 180 cases seen over 53 years.5-8 Pyoderma gangrenosum occurs with equal frequency in both sexes;6,8 although, some report an increased frequency in females.9 It can present at any age, but PG most commonly presents in young to middle aged adults, aged 25 to 54 years.3,6,8 Most patients have multiple lesions.3,8 The lower extremities are the most common sites of involvement in classic PG, while bullous PG is more common on the upper extremities.3,8,10 However, other organ system involvement by PG (occasionally with fatal outcomes8) has been reported and include the pulmonary musculoskeletal, cardiac, nervous, gastrointestinal, splenic, hepatic, and renal systems.3

Lesions typically begin as tender papules, papulopustules, or vesicles that spontaneously ulcerate and progress to painful ulcers with a purulent base and undermined, ragged, violaceous borders.3,5 Active lesions often show a gunmetal gray border surrounded by an erythematous to halo.6 Partially treated lesions may retain the advancing erythematous border while healing from the center. Atrophic cribriform scarring is characteristic of healed lesions of PG, especially in cases that begin with multifocal pustules that ulcerate and coalesce into the larger, fully formed ulcer. Pathergy, a phenomenon characterized by exacerbation of the disease after trauma, is observed in 20-30% of cases and can initiate or aggravate PG.3

Based on the clinical morphology, behavior, and associations of particular lesions, PG has been classified into 4 distinct clinical variants: ulcerative, pustular, bullous, and vegetative.6 Although unusual, more than one variant can be present in an individual patient.6 The ulcerative variant, the most common form of PG, presents as a rapidly enlarging ulcer with a purulent base, undermined border, and surrounding erythematous halo.6,8 Pustular PG presents as discrete painful pustules with erythematous halos on clinically intact skin.6 Vegetative PG, also known as superficial granulomatous pyoderma, presents as a single slowly progressive, relatively painless, superficial, vegetative ulcer without an undermined border6. Bullous PG typically presents as a painful erythematous papule, plaque, or superficial bulla that evolves into a superficial ulceration with blue-gray bullous borders.6 Variations on these general clinical categories include peristomal PG in patients with Crohn's disease and pyostomatitis vegetans, among others.

Associated Conditions

Associated with an underlying systemic disease in 50-78% of patients, PG can present before, concurrently with, or after the development of an associated underlying condition.3 Diseases associated with PG can broadly be categorized into inflammatory bowel disease (either ulcerative colitis or Crohn's disease), rheumatoid arthritis, seronegative arthritis (asymmetrical, monoarticular arthritis of the large joints), and a hematologic disease or malignancy (see Table 1).3,5,6 While many other diseases have been reported in association with PG, some argue that the laundry list of other possible associations are unlikely to be clinically relevant, as they do not appear to occur with greater prevalence in patients with PG than they do in the general population.3 PG is idiopathic (ie, not associated with any underlying disease) in approximately 50% of cases.3,6,9

Table 1. Underlying Disorders Associated With PG3
 
Disorders likely to be
truly associated
with PG
 Less common (possible
 true association
 with PG)
  • Ulcerative colitis
  • Crohn's disease
  • Seronegative arthritis
  • Rheumatoid arthritis
  • Hematologic disease
    (paraproteinemia, other)
    or malignancy (leukemia,
    myeloma, other)
  • Takayasu's arteritis
  • Chronic active and
    chronicpersistent hepatitis

Although the initial presentation of PG should prompt an evaluation for possible underlying associated diseases, recognition of specific clinical variants can increase suspicion for a particular underlying disease entity. For example, the ulcerative variant of PG is most commonly associated with arthritis, inflammatory bowel disease, and monoclonal gammopathy (usually IgA11); pustular PG is most commonly associated with acute inflammatory bowel disease; vegetative PG is often not associated with any specific disease; and bullous PG is most closely associated with an underlying hematologic malignancy.6

Potentially fatal disorders such as underlying malignancies associated with PG are essential to detect. The percentage of patients with any type of PG that is found to have an associated malignancy is approximately 7%, with acute myelogenous leukemia representing the most commonly linked malignancy.12 Approximately 50-67% of the patients with malignancy associated PG have lesions clinically consistent with bullous PG.12,13 Bullous PG found in association with a hematologic malignancy usually portends a poor prognosis.6,14

Histology and Laboratory Findings

There are no pathognomonic histologic findings for PG. Biopsies of early lesions demonstrate neutrophilic abscesses in the dermis, some of which might be folliculocentric.3,9 In later lesions, necrosis, ulceration, superficial dermal edema, and a dense dermal infiltrate predominate.15 Biopsy of the erythematous border shows a nonspecific perivascular mononuclear (lymphocytic) infiltrate.15 Some authors report the possible finding of vasculitis within lesions of PG3. The histology of bullous PG typically demonstrates a dense neutrophilic infiltrate throughout the papillary and reticular dermis.16-18 Correlating with the bullae observed clinically is intra- or sub-epidermal edema.12 Vasculitis, although rare, has been observed in some biopsy specimens of bullous PG.17,19

While there are no diagnostic laboratory findings of PG, a neutrophilic leukocytosis and an elevated erythrocyte sedimentation rate might be present.15 When PG is associated with an underlying condition, laboratory abnormalities associated with that underlying condition may be found.

Diagnosis and Differential Diagnosis

As the laboratory evaluation and histologic features of PG are nonspecific, definitive diagnosis requires recognition of the clinical morphology, clinicopathologic correlation, and the exclusion of other disorders that mimic pyoderma gangrenosum (see Table 2).20

Table 2. Differential Diagnosis of PG* (with the most common misdiagnoses in bold)

  • Vascular occlusive or venous disease
    • Antiphospholipid antibody syndrome
    • Livedoid vasculopathy
    • Venous stasis
    • Small vessel occlusive arterial disease
    • Type I cryoglobulinemia
  • Vasculitis
    • Wegener's granulomatosis
    • Polyarteritis nodosa
    • Mixed cryoglobulinemic vasculitis
    • Takayasu's arteritis
    • Leukocytoclastic vasculitis with secondary infection
    • Other syndromes with vasculitis
      • Systemic lupus erythematosus
      • Rheumatoid arthritis
      • Behçet's disease
  • Cutaneous lymphoma or leukemia
    • Lymphoma
      • Angiocentric T cell lymphoma
      • Anaplastic large-cell T cell lymphoma
      • Bullous mycosis fungoides
      • Other lymphoma involving the skin
    • Leukemia cutis
    • Langerhans'-cell histiocytosis
  • Drug induced or exogenous tissue injury
    • Factitial disease
    • Brown recluse spider bite
    • Hydroxyurea
    • Bromoderma/iododerma
    • Contact vulvitis
  • Infection
    • Deep fungal infection
      • Sporotrichosis
      • Aspergillosis
      • Cryptococcosis
      • Zygomycosis
      • Penicillium marnefei infection
    • Bacterial infection
    • Mycobacterial infection
    • Herpes simplex
    • Parasitic infection
      • Amebiasis
      • Leishmaniasis
    • Syphilis (gumma)
  • Inflammatory disease involving the skin
    • Cutaneous Crohn's disease
    • Sweets syndrome
    • Necrobiosis lipoidica diabeticorum
    • Pemphigus vegetans

*Revised and adapted from Weenig RH, Davis MD, Dahl PR, et al. Skin ulcers misdiagnosed as pyoderma gangrenosum. N Engl J Med. 2002 Oct 31;347(18):1412-8 and Bennett ML, Jackson JM, Jorizzo JL, et al. Pyoderma gangrenosum. A comparison of typical and atypical forms with an emphasis on time to remission. Case review of 86 patients from 2 institutions. Medicine. 2000 Jan;79(1):37-46.

An excellent chart and literature review, published by Weenig et al. in the New England Journal of Medicine, found that 95 of 240 patients were misdiagnosed as having PG; i.e., patients presented with ulcers that clinically resembled PG but were ultimately determined to have an alternative diagnosis.15 The most common (in decreasing order with the most important diseases to exclude in parentheses) were vascular occlusive or venous disease (antiphospholipid antibody syndrome, livedoid vasculopathy, and venous stasis), vasculitis (Wegener's granulomatosis, polyarteritis nodosa, mixed cryoglobulinemic vasculitis), a malignancy that involved the skin (lymphoma or leukemia), infection (deep fungal infection), drug-induced or exogenous tissue injury (factitial disease), or another inflammatory disease involving the skin (cutaneous Crohn's disease).15 Clinical features that suggest the diagnosis of PG include severe pain, a history of rapid progression of the primary lesion to ulceration, the presence of pathergy, symptoms of disorders typically associated with PG, and/or the history of ingestion of a medication known to trigger the onset of PG.15 Importantly, 64 of the 95 patients in Weenig's report had been treated for PG (although the ultimate diagnosis was not PG); 23 of these 64 patients (36%) were refractory to standard therapy for PG (including high dose corticosteroids) implying that failure to respond to standard therapeutic regimens should be reason to consider a diagnosis other than PG.15 Furthermore, "more than half" of the patients in the study who had undergone biopsies had histopathologic evidence of another disorder, suggesting that although the histopathology of PG is nonspecific, performing a skin biopsy in patients with suspected PG is important in excluding other diagnoses that mimic PG.15 Interestingly, the same study found that 39% of patients who received the incorrect diagnosis of PG had underlying disorders typically associated with PG.15

In general, histologic evaluations and laboratory tests are more useful for excluding entities in the differential diagnosis of PG and for determining the presence of underling diseases that are typically associated with PG than in directly affirming the diagnosis of PG. As such, a list of suggested evaluations for patients presenting with skin lesions reminiscent of PG is presented in Table 3.

Table 3. Suggested Evaluation for Patients With Skin Lesions Suggestive of PG**

  • History
    • Symptoms of pain
    • Rapid progression of initial lesion to ulceration
    • Pathergy
    • Symptoms of diseases typically associated with PG
    • History of ingestion of substances known to trigger PG
  • Physical exam
    • Ulcerative PG: ulcer with a purulent base, undermined border, and surrounding erythematous halo
    • Pustular PG: discrete pustules with erythematous halos on clinically intact skin
    • Vegetative PG: single slowly progressive, relatively painless, superficial, vegetative ulcer without an undermined border
    • Bullous PG: erythematous papule, plaque, or superficial bulla that evolves into a superficial ulceration with blue-gray bullous borders
  • Skin biopsy from inflamed peripheral border for:
    • Routine histology/lymphatic invasion
    • Special stains of the tissue to exclude infection (fungal, bacterial, viral, mycobacterial) and/or neoplastic process (immunohistochemical stains)
    • Tissue culture to exclude infection (fungal, bacterial, viral, mycobacterial)
  • Laboratory and investigative tests
    • Suggested for all patients
      • Complete blood count with differential
      • Erythrocyte sedimentation rate
      • Serum chemistry (renal and liver panels)
    • To consider based on the history, clinical presentation, associated symptoms, and histology
      • Chest X-ray
      • Gastrointestinal evaluation
        • Endoscopy, colonoscopy, etc.
      • Hematologic laboratory tests and evaluation
        • Serum and urine protein electrophoresis
        • Serum immunofixation or immunoelectrophoresis
        • Hypercoagulability panel (especially antiphospholipid antibody)
        • Bone marrow biopsy
      • Rheumatologic laboratory tests
        • Rheumatoid factor
        • Antinuclear antibody
        • Antineutrophilic cytoplasmic antibodies
    • Cryoglobulins
    • Venous and arterial flow studies
    • Other
      • Serum iodine levels
      • Serum bromide levels

**Revised and adapted from Weenig RH, Davis MD, Dahl PR, et al. Skin ulcers misdiagnosed as pyoderma gangrenosum. N Engl J Med. 2002 Oct 31;347(18):1412-8 and Bennett ML, Jackson JM, Jorizzo JL, et al. Pyoderma gangrenosum. A comparison of typical and atypical forms with an emphasis on time to remission. Case review of 86 patients from 2 institutions. Medicine. 2000 Jan;79(1):37-46.

Prognosis and Treatment

Treatment of PG is largely empiric, as there are almost no randomized clinical trials evaluating therapies. A recent paper presented treatment recommendations for PG derived from an evidence-based literature review of over 350 patients.21 These authors reported several important conclusions. Firstly, improvement or remission of PG was often achieved through successful management of the underlying associated disease, thereby emphasizing the utility of looking for and treating any conditions felt to be truly related to PG. In addition, this finding corroborates other reports; ie, that ulcerative PG (often associated with inflammatory bowel disease and rheumatoid arthritis) often requires aggressive immunosuppression (also used to treat inflammatory bowel disease and rheumatoid arthritis) to achieve therapeutic control; vegetative PG (usually not associated with an underlying disease) is usually responsive to topical or intralesional steroids; pustular PG often resolves after treatment for the associated inflammatory bowel disease; and bullous PG typically responds to treatment for the underlying malignancy.6, 22 Importantly, these authors noted that it was often not possible to determine whether successful treatment was due to the direct effect of a specific therapy on PG or on the underlying disease associated with it. A second significant finding was that failure of the underlying associated disease to respond to therapy implied a worse prognosis with regard to the treatment of PG.21

In general, the treatment approach to PG includes the following broad categories, often used in combination: local therapy, nonimmunosuppressant systemic treatments, systemic immunosuppressants (including prednisone), and biologic therapies. A reasonable approach to the treatment of PG, and one that seems to correlate best with the findings of Reichrath et al. is to take into account the extent of disease burden of PG as well as the underlying disorders associated with PG (see Tables 4 and 5).

Table 4: Indications for systemic therapy for PG21


  • Failure of localized lesion to respond to topical treatment
  • Progression of localized lesions of PG to involve deep structures
  • Localized PG occurring in conjunction with an underlying disorder known to respond to certain systemic agents
  • PG involving the eyes, genitalia, or extracutaneous organ systems
  • Disseminated PG

 

Table 5: Options for Pyoderma Gangrenosum Requiring Systemic Therapy***

Underlying
disorder
associated
with PG
Suggested
first-line
therapy
Second-line
agents
Other
therapies
to consider
None or no
response of
PG to
treatment for
underlying
associated
disease
(e.g. rheumatoid
arthritis,
hematologic
malignancy,
etc)
Corticosteroids
(prednisone
1-2g/kg/d)
or cyclosporine
(5mg/kg/d),
alone or
in combination;
can consider
pulse-dose
corticosteroids
(methylpred-
nisolone
1 g/d (IV)
for 1-5 days)
Thalidomide,
azathioprine,
methotrexate,
mycophenolate
mofetil, dapsone,
infliximab,
etanercept,
adalimumab,
cyclophos-
phamide,
tacrolimus,
colchicine,
clofazamine
Plasmapheresis,
granulocyte and
monocyte
adsorption
apheresis,
intravenous
immunoglobulin,
systemic
antibiotics
Inflammatory bowel disease Corticosteroids (prednisone 1-2g/kg/d) Infliximab 5mg/kg given at weeks 0,2,4,6 is also first line for Crohn's disease TNF-α inhibitor, thalidomide, mycophenolate mofetil, tacrolimus, dapsone, colchicine, azathioprine  

***Revised and adapted from Reichrath J, Bens G, Bonowitz A. Treatment recommendations for pyoderma gangrenosum: An evidence-based review of the literature based on more than 350 patients. J Am Acad Dermatol. 2005;53:273-83.

Topical therapy may be sufficient for patients with localized lesions, especially when treating superficial PG or peristomal PG. The best evidence for topical therapy exists for potent or superpotent topical corticosteroids, applied under occlusion or by intralesional injection, or topical immunomodulators (tacrolimus ointment or pimecrolimus cream).21 For localized lesions that fail to respond, continue to progress, or involve deeper structures (underlying muscle or tendon) or for localized PG occurring in conjunction with an underlying disorder known to respond to certain systemic agents, systemic therapy should be considered. PG involving the eyes, genitalia, or extracutaneous organ systems should also be treated with systemic therapy.21 Topical therapy for PG in patients already on systemic immunosuppression for an underlying disease should focus primarily on promoting wound healing (hydrocolloid dressings) and preventing infection (topical antiseptics).21 Surgical therapy, although reported to be helpful in some, should be performed on a case-by-case basis and primarily during periods of disease quiescence, especially because of the risk of inducing pathergy in response to surgical manipulation.21 Indeed, many patients are initially incorrectly treated (most often by non-dermatologists) with incision and drainage or debridement for what is thought to be an abscess or necrotic infection, interventions that typically result in disease exacerbation.

Based on their review, Reichrath et al. determined that for disseminated PG, especially when no associated disease could be found or treatment of the associated disease did not result in remission of PG, first line therapy should include systemic treatment with corticosteroids (methylprednisolone 0.5-1mg/k/d or prednisone 1-2g/kg/d) or cyclosporine (5 mg/kg/d), either alone or in combination.21

For patients with PG associated with Crohn's disease, including peristomal PG resistant to topical therapy, first line treatment should include the TNF-α inhibitor infliximab21. Interestingly, there are at least 2 reports (4 patients) of PG responding to treatment with etanercept;23, 24 one patient treated with etanercept had rheumatoid arthritis, but none had documented inflammatory bowel disease. An additional report documented successful therapy of idiopathic systemic PG with infliximab and adalimumab (a fully humanized anti-TNF-α antibody) given as separate treatment regimens to the same patient.25

Other systemic therapies that have been reported to be efficacious in PG, although the pooled data is not as good as for cyclosporine and/or systemic corticosteroids, include thalidomide (400 mg/d), mycophenolate mofetil (e.g. 2 g/d), azathioprine, methotrexate, tacrolimus, and dapsone.21 There is relatively good data to support cyclophosphamide as a steroid sparing agent21. Other therapies to consider include clofazamine, interferon alfa (particularly in patients with underlying interferon responsive diseases), plasmapheresis, granulocyte and monocyte adsorption apheresis, intravenous immunoglobulin, and systemic antibiotics.21

With any treatment method, nearly 70% of patients with PG will heal their lesions within 1 year of treatment, with approximately two-thirds of these patients noting clearing within the first 6 months, and 95% achieving remission at 3 years.3 Despite appropriate therapy, relapse of PG occurs in up to 46% of cases.8

References

  1. Brocq L. Nouvelle contribution à l'étude du phagedenisme geometrique. Ann Dermatol Syphiligr (Paris). 1916;6:1-39.
  2. Brunsting LA GW, O'Leary PA. Pyoderma (echthyma) gangrenosum- clinical and experimental observations in five cases occurring in adults. Archives of Dermatology 1930;22:655-80.
  3. Bennett ML, Jackson JM, Jorizzo JL, Fleischer AB, Jr., White WL, Callen JP. Pyoderma gangrenosum. A comparison of typical and atypical forms with an emphasis on time to remission. Case review of 86 patients from 2 institutions. Medicine (Baltimore). 2000;79(1):37-46.
  4. Blitz NM, Rudikoff D. Pyoderma gangrenosum. Mt Sinai J Med 2001;68(4-5):287-97.
  5. Srivastava M, Rencic A, Nousari HC. A rapidly expanding ulcer. Myelodysplastic syndrome-associated (paraneoplastic) pyoderma gangrenosum. Arch Dermatol. 2003;139(4):531-6.
  6. Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. AJ Am Acad Dermatol.  1996;34(3):395-409; quiz 10-2.
  7. Powell FC, Perry HO. Pyoderma gangrenosum in childhood. AArch Dermatol. 1984;120(6):757-61.
  8. Mlika RB, Riahi I, Fenniche S, et al. Pyoderma gangrenosum: a report of 21 cases. Int J Dermatol. 2002;41(2):65-8.
  9. Jorizzo JL, Solomon AR, Zanolli MD, Leshin B. Neutrophilic vascular reactions. J Am Acad Dermatol. 1988;19(6):983-1005.
  10. von den Driesch P. Pyoderma gangrenosum: a report of 44 cases with follow-up. Br J Dermatol. 1997;137(6):1000-5.
  11. Horton JJ, Trounce JR, MacDonald DM. Bullous pyoderma gangrenosum and multiple myeloma. Br J Dermatol.  1984;111(2):227-30.
  12. Duguid CM, O'Loughlin S, Otridge B, Powell FC. Paraneoplastic pyoderma gangrenosum. Australas J Dermatol.  1993;34(1):17-22.
  13. Ho KK, Otridge BW, Vandenberg E, Powell FC. Pyoderma gangrenosum, polycythemia rubra vera, and the development of leukemia. AJ Am Acad Dermatol. 1992;27(5 Pt 2):804-8.
  14. Koester G, Tarnower A, Levisohn D, Burgdorf W. Bullous pyoderma gangrenosum. J Am Acad Dermatol. 1993;29(5 Pt 2):875-8.
  15. Weenig RH, Davis MD, Dahl PR, Su WP. Skin ulcers misdiagnosed as pyoderma gangrenosum. N Engl J Med.  2002;347(18):1412-8.
  16. Suzuki Y, Kuroda K, Kojima T, Fujita M, Iseki T, Shinkai H. Unusual cutaneous manifestations of myelodysplastic syndrome. Br J Dermatol 1995;133(3):483-6.
  17. Hay CR, Messenger AG, Cotton DW, Bleehen SS, Winfield DA. Atypical bullous pyoderma gangrenosum associated with myeloid malignancies. J Clin Pathol. 1987;40(4):387-92.
  18. Fox LP, Geyer AS, Husain S, Grossman ME. Bullous pyoderma gangrenosum as the presenting sign of fatal acute myelogenous leukemia. Leuk Lymphoma 2006;41(1):147-50.
  19. Cramers M. Bullous pyoderma gangrenosum in association with myeloid leukaemia. Acta Derm Venereol. 1976;56(4):311-2.
  20. Callen JP, Dubin HV, Gehrke CF. Recurrent pyoderma gangrenosum and agnogenic myeloid metaplasia. Arch Dermatol. 1977;113(11):1585-6.
  21. Reichrath J, Bens G, Bonowitz A, Tilgen W. Treatment recommendations for pyoderma gangrenosum: An evidence-based review of the literature based on more than 350 patients. .J Am Acad Dermatol.  2005;53:273-83.
  22. Rogalski C, Paasch U, Glander HJ, Haustein UF. Bullous pyoderma gangrenosum complicated by disseminated intravascular coagulation with subsequent myelodysplastic syndrome (chronic myelomonocytic leukemia). J Dermatol.  2003;30(1):59-63.
  23. Roy DB, Conte ET, Cohen DJ. The treatment of pyodermal gangrenosum using etanercept. J Am Acad Dermatol.  2006;54(3):S128-34.
  24. Pastor N, Betloch I, Pascual JC, Blanes M, Banuls J, Silvestre JF. Pyoderma gangrenosum treated with anti-TNF alpha therapy (etanercept). Clin Exp Dermatol.  2005;31:129-56.
  25. Hubbard VG, Friedmann AC, Goldsmith P. Systemic pyoderma gangrenosum responding to infliximab and adalimumab. Br J Dermatol. 2005;152(5):1059-61.
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