Are You Confident of the Diagnosis?
Pyoderma gangrenosum (PG) is a rare, inflammatory, ulcerative disease. The clinical appearance of the ulceration is usually the first clue to this diagnosis. PG is a diagnosis of exclusion. The biopsy is not diagnostic and there are no biological markers of the disorder. Before establishing a diagnosis of PG, one must rule out other ulcerative conditions, incuding vascular, infectious, proliferative diseases.
PG is part of the spectrum of the neutrophilic dermatoses (ND), which includes Sweet syndrome and other conditions. In about 80% of cases, PG is associated with a systemic disease, mainly hematologic, digestive (inflammatory bowel disease), and rheumatologic. In addition, some PG patients may suffer from aseptic neutrophilic infiltrates in internal organs.
There is some current evidence that PG and other ND are linked to autoinflammatory syndromes.
Characteristic findings on physical examinatiion
In the typical ulcerative PG form, the lesion starts as a pustule or nodule, which may have been provoked by a minor trauma (pathergy phenomenon). This lesion becomes ulcerated and slowly enlarges centrifugally, with a typical pattern: the periphery is elevated, erythematous or violaceous, and its inner part is undermined by purulent exudates (Figure 1). The center is an eroding ulcer, with a necrotic (gangrenous) appearance. Exposure of muscle or tendon may occur. Pain is variable, sometimes severe. The diameter of PG ulcers may reach 20 cm or more. PG ulcers are solitary or multiple. Any part of the body may be involved. In addition to the typical, classic ulcerative form, three additional PG clinical variants are recognized: bullous, pustular, and vegetative.
Expected results of diagnostic studies
Histopathology is nonspecific but a biopsy is warranted to rule out infections (special stains must be performed), malignancies, and vasculitis. The histopathologic changes depend on the PG clinical type and the timing of the biopsy. Biopsies taken from the center of established PG ulcerations show marked neutrophilic, abscess-like infiltration. Experienced pathologists will not exclude the diagnosis of PG in instances where there is a mixed, or predominantly lymphocytic inflammatory infiltrate. There may be some leukocytoclasis and vascular damage, but no true vasculitis. Histologic overlap occurs with the other, more superficial neutrophilic dermatoses, such as subcorneal pustular dermatosis and Sweet syndrome.
A general, simple workup is performed, but as there is no biological nor immunological marker for PG, it is a diagnosis of exclusion. PG may be erroneously underdiagnosed, which leads to potentially harmful surgical interventions, or overdiagnosed, which may lead to unnecessary anti-inflammatory / immunosuppressive therapy with its attendant risks. The differential includes vascular conditions, infections, malignancies, and artefactual dermatoses.
Who is at Risk for Developing this Disease?
Pyoderma gangrenosum occurs in three main circumstances:
Without any pathological context
In patients with one of the associated diseases
Postoperatively, an ulceration on a surgical scar is highly suspicious of PG.
What is the Cause of the Disease?
The etiology of PG is unknown, and its pathogenesis is poorly understood. Current hypotheses about the etiology of PG include:
The mechanism of neutrophil recruitment and activation by some lymphocytic subpopulations
Possible abnormalities in adhesion molecules governing neutrophilic extravasation
The involvement of autoinflammatory mechanisms, which result in an overproduction of IL-1. PG is part of some inherited monogenic autoinflammatory syndromes, such as the PAPA syndrome, (pyogenic arthritis, PG and acne). Evidence indicates that autoinflammation and IL-1 most likely play an important role in the pathophysiology of classic, non inherited PG.
Systemic Implications and Complications
PG must be considered as a systemic disease, from two points of view: (1) some PG patients have extracutaneous neutrophilic infiltrates (the neutrophilic disease), and (2) PG is often associated with a mulstisystemic disorder.
Aseptic neutrophilic abscesses similar to PG may occur in extracutaneous sites. The main localizations of the neutrophilic disease are the lungs and the joints, but all organs may be involved (Figure 2, Table I). The diagnostic difficulties are diverse and depend on the localization of internal PG lesions. If the diagnosis of PG is not known, aggressive investigative procedures and surgery may be unavoidable. In a few instances, internal (pulmonary) PG precedes cutaneous PG.
|LungBoneJointsLymph NodesLiver, spleen, other intra-abdominal visceraCentral nervous systemMuscleHeart, blood vesselsEyeKidney|
Multisystemic diseases assoasiated with pyoderma gangrenosum
PG patients suffer from an associated disease. The main diseases associated with PG are shown in Table II. In the majority of cases, the associated disease is already known, but the occurrence of PG may be revelatory. A complete clinical workup is mandatory.
Digestive diseases IBD (Ulcerative colitis, Crohn’s disease)Liver disease (Chronic active hepatitis, primary cirrhosis, sclerosing cholangiitis)Blood disordersBenign monoclonal gammopathies (IgA) and myelomaChronic myeloproliferative disordersAcute leukemias MyelodysplasiasJoint disordersRheumatoid arthritis SpondylarthropathiesOther chronic rheumatic diseasesBehçet’s diseaseTakayasu’s diseaseWegener diseaseSarcoidosisAcne conglobataCancer (anecdotal)Endocrine disorders (anecdotal)IBD, inflammatory bowel disease.
Wound management and topical care are important, but a systemic antiinflammatory / immunosuppressive drug is the main focus of PG management.
Corticosteroids are the initial treatment of choice. It is reasonable to begin with 1-2mg/kg prednisone daily in divided doses to halt the progression of the disease and induce healing. A rapid improvement of pain and other discomfort is often recorded early, but high-dose steroids must be continued until lesions show evidence of healing, after which gradual tapering is possible. Measures to prevent and control steroids side effects (bone demineralisation) must be started early. Some authors advocate the use of intravenous steroids.
In chronic, paucilesional PG, steroid-sparing antiinflammatory drugs can be useful. These are dapsone, clofazimine, minocycline. In recurrrent cases, prompt treatment with intra-lesional injections of triamcinolone acetonide (10-40mg/ml) can be effective in aborting development of large ulcerated lesions.
In severe, recalcitrant PG, or in cases with contraindications or intolerance to steroids, cyclosporine (3-5mg/kg/day) is probably the best option. Other immunosuppressive drugs such as methotrexate, mycophenolate mofetil, and azathioprine have given good results, usually in association with oral steroids.
Anti-tumor necrosis factor (TNF)-alpha agents have recently been used with success, in PG associated with inflammatory bowel disease (IBD) and also in PG itself. Whether anti-TNF agents or anti-IL-1 agents, such as anakinra, become standard therapy for all PG patients awaits additional clinical research.
Optimal Therapeutic Approach for this Disease
A patient with PG must be evaluated for the following:
search for extracutaneous disease
evaluation of associated diseases (co-morbidities)
general workup, including drug safety issues
initiation of professional topical care
Topical wound care requires experienced health professionals. Treatments must reduce pain and avoid superinfection. It is also important to minimize any physical trauma, including physical wound debridement, as pathergy is a cause of initiation or aggravation of PG lesions.
Antiseptic solutions must be used for cleansing. Nonadhesive dressings should be applied over the lesions and held in place with elasticized bandages. Hydrocolloid dressings are useful.
Potent topical corticosteroids (clobetasol), and/or topical tacrolimus may be useful to heal small, superficial PG ulcers.
Systemic antiimmflamatory/immunosuppressive therapy should be intiated promptly after diagnosis confirmation. As mentioned in treatment options, corticosteroids are the treatment of choice for inital therapy to suppress the inflammatory process. After an initial suppression period of at least 6 weeks (depending on the size and number of lesions), a steroid-sparing agent is typically added and steroid/steroid-sparing therapies are consolidated so that corticosteroids can be weaned and the patient can be maintained on a steroid-sparing agent. After a peroid of stability without active and ulcerated leasions (3-6 months), maintenance therapy can be tapered to the lowest effective suppressive dose. The use of inhibitors of IL-1, anti-TNF inhibitors, and other important mediators is under investigation.
Patients with PG must be managed by dermatologists with experience treating internal medicine patients, or in cooperation with an internist. Patients must be informed of the expected healing time of the ulcers, the importance of topical care, and the careful monitoring of the efficacy and side effects of the drugs used.
Nurses and other health professionals must work in close contact with the physicians. It is important to emphasize to the patient the fact that the ulcerations, even the most dramatic ones, will heal, usually only leaving a slightly atrophic, depressed scar. In patients with recurrent PG, maintenance therapy with low-dose steroids and/or immunosuppressives will help prevent new lesions.
Unusual Clinical Scenarios to Consider in Patient Management
PG variants are usually less severe, and more often associated with multisystemic diseases.
Bullous PG (a form which overlaps with Sweet syndrome and is commonly associated with hematologic disease) presents as rapidly expanding blister or erosion, which do not end as deep ulcerations (Figure 3).
Pustular PG (often associated with IBD) consists of multiple, large painful pustules (Figure 4).
Vegetative PG (or superficial granulomatous PG) usually presents as a single nodule or plaque. It evolves slowly and may be responsive to topical therapy (Figure 5).
Pyoderma gangrenosum overlapping with or existing with other neutrophilic dermatoses
In recent years, numerous case reports and clinical publications suggested that some neutrophilic dermatoses (NDs) must be considered as a single group. This group includes PG, Sweet syndrome, subcorneal pustular dermatosis (Sneddon-Wilkinson disease), erythema elevatum diutinum, and other conditions. In this continuous spectrum of inflammatory conditions, overlapping symptoms are common. Patients with overlapping ND may have a blood disorder, a gammopathy, an inflammatory bowel disease, a chronic rheumatic disease, or no associated disease.
Postoperative pyoderma gangrenosum
Postoperative PG (Figure 6) may be considered as a consequence of pathergy. It is often unrecognized by surgeons because this enlarging purulent ulceration of a surgical scar is usually attributed to superinfection, leading to inefficient antibiotic therapy and aggressive surgical debridement. The initial surgery may have been motivated by an internal manifestation of pyoderma gangrenosum, misdiagnosed as an infection or malignancy. Peristomal PG is another manifestation of cutaneous pathergy in patients with inflammatory bowel disease who have an ileostomy or colostomy.
PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome is a rare autosomal dominant disease described in 1997. It belongs to the group of the monogenic autoinflammatory diseases. Successful treatment of PG in PAPA syndrome by anakinra has recently been reported. Such exceptional patients may give insights to pathophysiological considerations and therapeutic progress in non genetic PG.
What is the Evidence?
Brocq, L. “Nouvelle contribution à l’étude du phagédénisme géométrique”. Ann Dermatol Syph. vol. 9. 1908. pp. 1-39. (For French-reading lovers of beautiful texts of clinical dermatology, the description of the typical PG ulcer.)
Brooklyn, TN, Dunnill, GS, Shetty, A. “Infliximab for the treatment of pyoderma gangrenosum: a randomised, double-blind placebo-controlled trial”. Gut. vol. 55. 2006. pp. 505-9. (First clinical trial of infliximab in PG.)
Brunsting, LA, Goeckerman, WH, O’ Leary, PH. “Pyoderma (ecthyma) gangrenosum : clinical and experimental observations in five cases occurring in adults”. Arch Dermatol. vol. 22. 1930. pp. 655-80. (The initial description of PG by the Mayo Clinic Team. Four of these five patients had ulcerative colitis.)
Butler, D, Shinkai, K. “What do autoinflammatory syndromes teach about common cutaneous diseases such as phoderma gangrenosum? A commentary”. Dermatol Clin. vol. 31. 2013. pp. 427-35. (The current view of the pathophysiology of PG and other ND.)
Caughman, W, Stern, R, Haynes, H. “Neutrophilic dermatosis of myeloproliferative disorders”. J Am Acad Dermatol. vol. 9. 1983. pp. 751-8. (First description of a condition overlapping PG and Sweet syndrome, in patients with hematologic disorders.)
Field, S, Powell, FC, Young, V, Barnes, L. “Pyoderma gangrenosum manifesting as a cavitating lung lesion”. Clin Exp Dermatol. vol. 33. 2008. pp. 418-21. (This patient’s PG started in the lung, and involved the skin secondarily.)
Lindor, NM, Arsenault, TM, Solomon, H, Seidman, CE, McEvoy, MT. “A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome”. Mayo Clin Proc. vol. 72. 1997. pp. 611-5. (First description of this monogenic autoinflammatory disorder, which could be an example for future research on pathophysiology and treatment of PG.)
Powell, FC, Collins, S. “Pyoderma gangrenosum”. Clin Dermatol. vol. 18. 2000. pp. 283-93. (An excellent review of PG including classification, associated conditions, and management. The whole issue of this journal is about the neutrophilic dermatoses.)
Vignon-Pennamen, MD, Wallach, D. “The cutaneous manifestations of neutrophilic disease”. Dermatologica. vol. 183. 1991. pp. 255-64. (First indication that the neutrophilic dermatoses are not limited to the skin.)
Vignon-Pennamen, MD. “The extracutaneous involvement in the neutrophilic dermatoses”. Clin Dermatol. vol. 18. 2000. pp. 339-47. (Describes all the noncutaneous neutrophilic lesions.)
von den Driesch, P. “Pyoderma gangrenosum: a report of 44 cases with follow-up”. Br J Dermatol. vol. 137. 1997. pp. 1000-5. (Good clinical review, including the proposal of diagnostic criteria.)
Weenig, RH, Davis, MD, Dahl, PR, Su, WP. “Skin ulcers misdiagnosed as pyoderma gangrenosum”. N Engl J Med. vol. 347. 2002. pp. 1412-18. (Important clinical study focusing on ulcers that mimic PG. Insists on the necessary evaluation of al patients with suspected PG.)
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- Are You Confident of the Diagnosis?
- Who is at Risk for Developing this Disease?
- What is the Cause of the Disease?
- Systemic Implications and Complications
- Treatment Options
- Optimal Therapeutic Approach for this Disease
- Patient Management
- Unusual Clinical Scenarios to Consider in Patient Management
- What is the Evidence?