BMJ 2014;348:g3255 doi: 10.1136/bmj.g3255 (Published 27 May 2014)
Page 1 of 3
Endgames
ENDGAMES PICTURE QUIZ
A woman with a sore spot on her leg Jenny Caesar foundation year 2 doctor, Periasamy Balasubramaniam consultant dermatologist Wrexham Maelor Hospital, Wrexham LL1 3TD, UK
A 41 year old civil servant, with a background of poorly controlled Crohn’s disease, presented to her general practitioner with a skin lesion on her left shin that had been there for eight weeks (fig 1).
Answers
1. How would you describe the skin lesion? Short answer
Irregular plaque with cribriform (uneven) scarring and purplish discoloration, multiple tiny ulcerations, and pustules at the edge.
Long answer
The lesion had started as a small red blemish, “like a burn,” that appeared acutely and rapidly grew in size. She could not recall any injuries to this area. It was painful to touch and she had noticed some purplish discoloration around the edges of the wound. Although it started to heal in some areas it was also enlarging at the periphery.
The lesion consisted of an inflammatory plaque measuring 7 cm in diameter, with cribriform (uneven) scarring and tiny ulcerations with pustules at the periphery (fig 2). Although multiple clinical variants are noted (see long answer 2) the classic description of this lesion would be a painful ulcerative lesion, with a purulent base and well defined violaceous border.1 The border of the ulcer is often described as overhanging or undermined. This feature is caused by the spread of inflammation throughout the dermis, which leaves the overlying epidermis protruding over the edge of the lesion.2 Typical cribriform scarring is noted in most evolving lesions.
She was worried about “passing it on” to her children and had covered it with a bandage. She had no known allergies and was taking sulfasalazine for her inflammatory bowel disease.
Questions
1. How would you describe the skin lesion? 2. What is the most likely diagnosis? 3. What are the differential diagnoses? 4. What conditions are associated with this diagnosis?
Fig 2 Lesion consisting of an inflammatory plaque measuring 7 cm in diameter, with cribriform scarring (bottom arrowhead) and tiny ulcerations with pustules at the periphery (top arrow)
5. What are the treatment options?
Correspondence to: J Caesar [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
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BMJ 2014;348:g3255 doi: 10.1136/bmj.g3255 (Published 27 May 2014)
Page 2 of 3
ENDGAMES
2. What is the most likely diagnosis? Short answer
and liver function tests as baseline investigations. Bacterial cultures, skin biopsy for histopathology and microbiology, and autoimmune antibodies may be needed in unresponsive or atypical cases.
Long answer
4. What conditions are associated with this diagnosis? Short answer
Pyoderma gangrenosum.
The most likely diagnosis is pyoderma gangrenosum. First described in the 1930s,2 this is a cutaneous ulcerative condition classified as a neutrophilic dermatosis.3 Affecting 3-10 people per 1 000 000 per year, it is a rare condition that can present in any age group.4 However, classically, it presents in women aged 40-60 years.5 6 The diagnosis of pyoderma gangrenosum is mainly clinical. Patients in whom the diagnosis is suspected should be urgently referred to a dermatologist for assessment and further management. Histological features are often non-specific. In doubtful cases, skin biopsy and swabs should be performed to rule out other causes of ulcer, such as squamous cell carcinoma and infection. Pyoderma gangrenosum can be split into several subtypes:2 • Classic: most cases. Classic lesions (described in long answer 1) usually present on the trunk and lower limb.4 These lesions often leave an atrophic scar after resolution. Our case is an example of evolving classic type
• Atypical or bullous: usually associated with haematological disease, this variant is often seen as bluish bullae on the face and arms, which quickly erode to leave superficial ulcers7 • Pustular: often associated with acute exacerbations of inflammatory bowel disease8 and associated with fever and arthralgia,4 these painful, pustular lesions can affect any part of the body. They can be multiple and discrete • Superficial: also known as vegetative. This variant may have a verrucous quality, without the undermined border and erythematous border. Typically found on the head and neck.4
Pyoderma gangrenosum is characterised by a neutrophilic infiltration of the affected skin. However, its cause is unclear and there are currently no universally recognised criteria for diagnosis.
Some patients have associated symptoms of fever, malaise, and myalgia.1 Pathergy (disease occurring at sites of skin trauma) is also seen in about 30% of cases,5 with parastomal and genital cases being well documented. Rarely, extracutaneous pyoderma gangrenosum can develop, with sterile neutrophilic infiltrates developing in the intestine, cornea, spleen, heart, and bones.9
3. What are the differential diagnoses? Short answer
Differential diagnoses include squamous cell carcinoma, venous stasis ulcers, factitial (self inflicted) ulcers, antiphospholipid syndrome, and bacterial infection.
Long answer
A large number of differential diagnoses exist. The most common are squamous cell carcinoma, antiphospholipid syndrome, venous stasis ulcers, factitial ulcers (self inflicted—for example, by excessive scratching), bacterial infections (echthyma), and vasculitides (including granulomatosis with polyangiitis and polyarteritis nodosa).1
No definitive tests are available for pyoderma gangrenosum. All patients need a full blood count, urine analysis, and renal For personal use only: See rights and reprints http://www.bmj.com/permissions
About half of all cases of pyoderma gangrenosum are associated with inflammatory bowel disease; rheumatoid arthritis; myeloma, lymphoma, or leukaemia; and primary biliary cirrhosis. No clear cause is identified in the other half of cases.
Long answer
About half of cases are associated with underlying conditions, these include: • Inflammatory bowel disease (14-34%)
• Haematological cancer (20%), particularly IgA monoclonal gammopathy but also myeloma, leukaemia, myelodysplasia, lymphoma, and polycythaemia vera1 • Arthropathies (11-25%). Rheumatoid arthritis, ankylosing spondylitis, and seronegative arthritis have all been linked to pyoderma gangrenosum.10
A thorough history, systemic examination, and relevant investigations are important to rule out possible underlying systemic conditions because pyoderma gangrenosum can precede these disorders.
5. What are the treatment options? Short answer
Local and systemic treatments are available. In mild disease, super potent topical steroids or tacrolimus should be applied. In more widespread disease, the use of oral steroids should be considered as first line. However, in refractory disease, depending on severity and other comorbidities, oral antibiotics (such as minocycline), systemic immunosuppressants (such as ciclosporin, azathioprine, and mycophenolate mofetil), and biological agents such as anti-tumour necrosis factor should be considered. Surgical options are not appropriate in active disease and may cause the ulcer to enlarge.
Long answer
Patients should be treated holistically, with attention being paid to the biological, social, and psychological aspects of the condition. Patient education is also vital to aid understanding of the condition and treatment options. Patients should be informed that unsightly cribriform scarring is a common complication and, unfortunately, flat scar tissue is unlikely.
Medical treatment options depend on disease severity, associated disorders, and the overall health of the patient. If disease is localised or superficial, topical treatment applied to the active lesion may be appropriate.11 Super potent topical corticosteroids (for example, clobetasol propionate 0.05%) or calcineurin inhibitors (for example, tacrolimus 0.1%) are often used. However, no randomised control trials have been conducted on this topic to date.
Systemic treatment may be needed in more severe disease. Systemic corticosteroids reduce the inflammatory response and disease progression in many cases.11 Oral antibiotics (for example, minocycline) show a positive outcome in some cases.12 If disease is still progressing, systemic immunosuppressive Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g3255 doi: 10.1136/bmj.g3255 (Published 27 May 2014)
Page 3 of 3
ENDGAMES
agents (for example, ciclosporin, azathioprine, methotrexate, or mycophenolate mofetil) or biological agents (for example, adalimumab or infliximab) should be considered and local guidelines followed.
Wound care and dressings that promote a moist environment to optimise wound healing are also an essential aspect of patient care. Because pathergy is a recognised feature of the disease, it is important to prevent unnecessary damage to the surrounding skin, and barrier creams may help to prevent the spread of the ulcer. It is also important to optimise pain management in these patients.13 14 Surgical management is controversial in active disease owing to the risk of pathergy.
Treatment should be stopped only when the lesion has completely resolved. It is advisable to taper treatment gradually rather than stop abruptly, to prevent relapse or adverse effects from rapid cessation of immunosuppressant treatment.11
Patient outcome A short course of oral steroids initially improved our patient’s skin, but she then had to be started on adalimumab after rapid deterioration of her Crohn’s disease and pyoderma gangrenosum. Unfortunately, she has not responded to this treatment and is due to start additional azathioprine therapy soon. Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: None. Provenance and peer review: Not commissioned; externally peer reviewed.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Patient consent obtained. 1
2 3 4 5 6 7 8 9 10 11
12 13 14
Schadt C, Callen J, Ofori A. Pyoderma gangrenosum: pathogenesis, clinical features, and diagnosis. Up to Date 2013. www.uptodate.com/contents/pyoderma-gangrenosumpathogenesis-clinical-features-and-diagnosis?source=search_result& search=pyoderma+gangrenosum&selectedTitle=1%7E53. Callen J. Pyoderma gangrensoum. Lancet 1998;351:581-5. Moschella S, Callen J, Ofori A. Neutrophilic dermatoses. Up to Date 2013. www.uptodate. com/contents/neutrophilic-dermatoses?source=search_result& search=neutrophilic+dermatosis&selectedTitle=1%7E34. Ruocco E, Sangiuliano S, Gravina AG, et al. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol 2009;23:1008-17. Binus AM, Qureshi AA, Li VW, Winterfield LS. Pyoderma gangrenosum: a retrospective review of patient characteristics, comorbidities and therapy in 103 patients. Br J Dermatol 2011;165:1244-50. Saracino A, Kelly R, Liew D, Chong A. Pyoderma gangrenosum requiring inpatient management: a report of 26 cases with follow up. Australas J Dermatol 2011;52:218-21. Bennett ML, Jackson JM, Jorizzo JL 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;79:37-46. Powell FC, Hackett BC, Wallach D. Pyoderma gangrenosum. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s dermatology in general medicine. 8th ed. Vol 1. McGraw-Hill, 2012:371. Fukuhara K, Urano Y, Kimura S, Hori K, Arase S. Pyoderma gangrenosum with rheumatoid arthritis and pulmonary aseptic abscess responding to treatment with dapsone. Br J Dermatol 1998;139:556-8. Ahronowitz I, Harp J, Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review. Am J Clin Dermatol 2012;13:191-211. Schadt C. Callen J, O Ofori A. Pyoderma gangrenosum: treatment and prognosis. Up to Date 2013. www.uptodate.com/contents/pyoderma-gangrenosum-treatment-andprognosis?source=search_result&search=pyoderma+gangrenosum&selectedTitle=2% 7E53. 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. Alam M, Grossman ME, Schneiderman PI, Blume RS, Benvenisty AI. Surgical management of pyoderma gangrenosum: case report and review. Dermatol Surg 2000;26:1063-6. Barańska-Rybak W, Kakol M, Naesstrom M, Komorowska O, Sokołowska-Wojdyło M, Roszkiewicz J. A retrospective study of 12 cases of pyoderma gangrenosum: why we should avoid surgical intervention and what therapy to apply. Am Surg 2011;77:1644-9.
Cite this as: BMJ 2014;348:g3255 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
Page 1 of 3
Endgames
ENDGAMES PICTURE QUIZ
A woman with a sore spot on her leg Jenny Caesar foundation year 2 doctor, Periasamy Balasubramaniam consultant dermatologist Wrexham Maelor Hospital, Wrexham LL1 3TD, UK
A 41 year old civil servant, with a background of poorly controlled Crohn’s disease, presented to her general practitioner with a skin lesion on her left shin that had been there for eight weeks (fig 1).
Answers
1. How would you describe the skin lesion? Short answer
Irregular plaque with cribriform (uneven) scarring and purplish discoloration, multiple tiny ulcerations, and pustules at the edge.
Long answer
The lesion had started as a small red blemish, “like a burn,” that appeared acutely and rapidly grew in size. She could not recall any injuries to this area. It was painful to touch and she had noticed some purplish discoloration around the edges of the wound. Although it started to heal in some areas it was also enlarging at the periphery.
The lesion consisted of an inflammatory plaque measuring 7 cm in diameter, with cribriform (uneven) scarring and tiny ulcerations with pustules at the periphery (fig 2). Although multiple clinical variants are noted (see long answer 2) the classic description of this lesion would be a painful ulcerative lesion, with a purulent base and well defined violaceous border.1 The border of the ulcer is often described as overhanging or undermined. This feature is caused by the spread of inflammation throughout the dermis, which leaves the overlying epidermis protruding over the edge of the lesion.2 Typical cribriform scarring is noted in most evolving lesions.
She was worried about “passing it on” to her children and had covered it with a bandage. She had no known allergies and was taking sulfasalazine for her inflammatory bowel disease.
Questions
1. How would you describe the skin lesion? 2. What is the most likely diagnosis? 3. What are the differential diagnoses? 4. What conditions are associated with this diagnosis?
Fig 2 Lesion consisting of an inflammatory plaque measuring 7 cm in diameter, with cribriform scarring (bottom arrowhead) and tiny ulcerations with pustules at the periphery (top arrow)
5. What are the treatment options?
Correspondence to: J Caesar [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g3255 doi: 10.1136/bmj.g3255 (Published 27 May 2014)
Page 2 of 3
ENDGAMES
2. What is the most likely diagnosis? Short answer
and liver function tests as baseline investigations. Bacterial cultures, skin biopsy for histopathology and microbiology, and autoimmune antibodies may be needed in unresponsive or atypical cases.
Long answer
4. What conditions are associated with this diagnosis? Short answer
Pyoderma gangrenosum.
The most likely diagnosis is pyoderma gangrenosum. First described in the 1930s,2 this is a cutaneous ulcerative condition classified as a neutrophilic dermatosis.3 Affecting 3-10 people per 1 000 000 per year, it is a rare condition that can present in any age group.4 However, classically, it presents in women aged 40-60 years.5 6 The diagnosis of pyoderma gangrenosum is mainly clinical. Patients in whom the diagnosis is suspected should be urgently referred to a dermatologist for assessment and further management. Histological features are often non-specific. In doubtful cases, skin biopsy and swabs should be performed to rule out other causes of ulcer, such as squamous cell carcinoma and infection. Pyoderma gangrenosum can be split into several subtypes:2 • Classic: most cases. Classic lesions (described in long answer 1) usually present on the trunk and lower limb.4 These lesions often leave an atrophic scar after resolution. Our case is an example of evolving classic type
• Atypical or bullous: usually associated with haematological disease, this variant is often seen as bluish bullae on the face and arms, which quickly erode to leave superficial ulcers7 • Pustular: often associated with acute exacerbations of inflammatory bowel disease8 and associated with fever and arthralgia,4 these painful, pustular lesions can affect any part of the body. They can be multiple and discrete • Superficial: also known as vegetative. This variant may have a verrucous quality, without the undermined border and erythematous border. Typically found on the head and neck.4
Pyoderma gangrenosum is characterised by a neutrophilic infiltration of the affected skin. However, its cause is unclear and there are currently no universally recognised criteria for diagnosis.
Some patients have associated symptoms of fever, malaise, and myalgia.1 Pathergy (disease occurring at sites of skin trauma) is also seen in about 30% of cases,5 with parastomal and genital cases being well documented. Rarely, extracutaneous pyoderma gangrenosum can develop, with sterile neutrophilic infiltrates developing in the intestine, cornea, spleen, heart, and bones.9
3. What are the differential diagnoses? Short answer
Differential diagnoses include squamous cell carcinoma, venous stasis ulcers, factitial (self inflicted) ulcers, antiphospholipid syndrome, and bacterial infection.
Long answer
A large number of differential diagnoses exist. The most common are squamous cell carcinoma, antiphospholipid syndrome, venous stasis ulcers, factitial ulcers (self inflicted—for example, by excessive scratching), bacterial infections (echthyma), and vasculitides (including granulomatosis with polyangiitis and polyarteritis nodosa).1
No definitive tests are available for pyoderma gangrenosum. All patients need a full blood count, urine analysis, and renal For personal use only: See rights and reprints http://www.bmj.com/permissions
About half of all cases of pyoderma gangrenosum are associated with inflammatory bowel disease; rheumatoid arthritis; myeloma, lymphoma, or leukaemia; and primary biliary cirrhosis. No clear cause is identified in the other half of cases.
Long answer
About half of cases are associated with underlying conditions, these include: • Inflammatory bowel disease (14-34%)
• Haematological cancer (20%), particularly IgA monoclonal gammopathy but also myeloma, leukaemia, myelodysplasia, lymphoma, and polycythaemia vera1 • Arthropathies (11-25%). Rheumatoid arthritis, ankylosing spondylitis, and seronegative arthritis have all been linked to pyoderma gangrenosum.10
A thorough history, systemic examination, and relevant investigations are important to rule out possible underlying systemic conditions because pyoderma gangrenosum can precede these disorders.
5. What are the treatment options? Short answer
Local and systemic treatments are available. In mild disease, super potent topical steroids or tacrolimus should be applied. In more widespread disease, the use of oral steroids should be considered as first line. However, in refractory disease, depending on severity and other comorbidities, oral antibiotics (such as minocycline), systemic immunosuppressants (such as ciclosporin, azathioprine, and mycophenolate mofetil), and biological agents such as anti-tumour necrosis factor should be considered. Surgical options are not appropriate in active disease and may cause the ulcer to enlarge.
Long answer
Patients should be treated holistically, with attention being paid to the biological, social, and psychological aspects of the condition. Patient education is also vital to aid understanding of the condition and treatment options. Patients should be informed that unsightly cribriform scarring is a common complication and, unfortunately, flat scar tissue is unlikely.
Medical treatment options depend on disease severity, associated disorders, and the overall health of the patient. If disease is localised or superficial, topical treatment applied to the active lesion may be appropriate.11 Super potent topical corticosteroids (for example, clobetasol propionate 0.05%) or calcineurin inhibitors (for example, tacrolimus 0.1%) are often used. However, no randomised control trials have been conducted on this topic to date.
Systemic treatment may be needed in more severe disease. Systemic corticosteroids reduce the inflammatory response and disease progression in many cases.11 Oral antibiotics (for example, minocycline) show a positive outcome in some cases.12 If disease is still progressing, systemic immunosuppressive Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g3255 doi: 10.1136/bmj.g3255 (Published 27 May 2014)
Page 3 of 3
ENDGAMES
agents (for example, ciclosporin, azathioprine, methotrexate, or mycophenolate mofetil) or biological agents (for example, adalimumab or infliximab) should be considered and local guidelines followed.
Wound care and dressings that promote a moist environment to optimise wound healing are also an essential aspect of patient care. Because pathergy is a recognised feature of the disease, it is important to prevent unnecessary damage to the surrounding skin, and barrier creams may help to prevent the spread of the ulcer. It is also important to optimise pain management in these patients.13 14 Surgical management is controversial in active disease owing to the risk of pathergy.
Treatment should be stopped only when the lesion has completely resolved. It is advisable to taper treatment gradually rather than stop abruptly, to prevent relapse or adverse effects from rapid cessation of immunosuppressant treatment.11
Patient outcome A short course of oral steroids initially improved our patient’s skin, but she then had to be started on adalimumab after rapid deterioration of her Crohn’s disease and pyoderma gangrenosum. Unfortunately, she has not responded to this treatment and is due to start additional azathioprine therapy soon. Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: None. Provenance and peer review: Not commissioned; externally peer reviewed.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Patient consent obtained. 1
2 3 4 5 6 7 8 9 10 11
12 13 14
Schadt C, Callen J, Ofori A. Pyoderma gangrenosum: pathogenesis, clinical features, and diagnosis. Up to Date 2013. www.uptodate.com/contents/pyoderma-gangrenosumpathogenesis-clinical-features-and-diagnosis?source=search_result& search=pyoderma+gangrenosum&selectedTitle=1%7E53. Callen J. Pyoderma gangrensoum. Lancet 1998;351:581-5. Moschella S, Callen J, Ofori A. Neutrophilic dermatoses. Up to Date 2013. www.uptodate. com/contents/neutrophilic-dermatoses?source=search_result& search=neutrophilic+dermatosis&selectedTitle=1%7E34. Ruocco E, Sangiuliano S, Gravina AG, et al. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol 2009;23:1008-17. Binus AM, Qureshi AA, Li VW, Winterfield LS. Pyoderma gangrenosum: a retrospective review of patient characteristics, comorbidities and therapy in 103 patients. Br J Dermatol 2011;165:1244-50. Saracino A, Kelly R, Liew D, Chong A. Pyoderma gangrenosum requiring inpatient management: a report of 26 cases with follow up. Australas J Dermatol 2011;52:218-21. Bennett ML, Jackson JM, Jorizzo JL 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;79:37-46. Powell FC, Hackett BC, Wallach D. Pyoderma gangrenosum. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s dermatology in general medicine. 8th ed. Vol 1. McGraw-Hill, 2012:371. Fukuhara K, Urano Y, Kimura S, Hori K, Arase S. Pyoderma gangrenosum with rheumatoid arthritis and pulmonary aseptic abscess responding to treatment with dapsone. Br J Dermatol 1998;139:556-8. Ahronowitz I, Harp J, Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review. Am J Clin Dermatol 2012;13:191-211. Schadt C. Callen J, O Ofori A. Pyoderma gangrenosum: treatment and prognosis. Up to Date 2013. www.uptodate.com/contents/pyoderma-gangrenosum-treatment-andprognosis?source=search_result&search=pyoderma+gangrenosum&selectedTitle=2% 7E53. 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. Alam M, Grossman ME, Schneiderman PI, Blume RS, Benvenisty AI. Surgical management of pyoderma gangrenosum: case report and review. Dermatol Surg 2000;26:1063-6. Barańska-Rybak W, Kakol M, Naesstrom M, Komorowska O, Sokołowska-Wojdyło M, Roszkiewicz J. A retrospective study of 12 cases of pyoderma gangrenosum: why we should avoid surgical intervention and what therapy to apply. Am Surg 2011;77:1644-9.
Cite this as: BMJ 2014;348:g3255 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
