Clinical Review & Education
JAMA Clinical Challenge
Rapidly Progressing Leg Ulcer With Fever in a Woman With Chronic Diarrhea Hai Long, MD, PhD; Yuwen Su, MD, PhD; Qianjin Lu, MD, PhD A Day 7
B
Day 8
C
Day 12
Figure. Skin lesion progression and histopathological changes (hematoxylin-eosin, original magnification ×200).
A 27-year-old woman presents with a rapidly progressing painful ulceration on the left leg (Figure) with intermittent high fevers. The lesion began as 2 sesame seed–sized violaceous, papulovesicular rashes with an erythematous halo on her left medial malleolus 12 days prior to presentation. Within 1 week, more papulovesicles appeared, merged, and ulcerated spontaneously (Figure, A and B). The ulceration expanded outwardly at a rapid pace, with Quiz at jama.com increasing pain and a hemorrhagic exudative discharge (Figure, C [left panel]). The lesion did not respond to treatment with systemic antibiotics, including vancomycin and meropenem. During the prior 5 months, she experienced mild diarrhea, which was ultimately diagnosed as Crohn disease by colonoscopy with biopsy. Physical examination reveals a pale, febrile patient with left leg edema and a rounded, swollen, and tender 10 × 10-cm ulceration on her left medial malleolus. The ulceration has a raised rugged surface with thick hemorrhagic exudates and a surrounding violaceousgreyish necrotic border (Figure, C [left panel]). Laboratory tests show moderate anemia, hypoalbuminemia, and fecal occult blood. Histopathology of skin lesions shows dermal edema with dense infiltration of neutrophils and vascular fibrinoid necrosis (Figure, C [right panel]). Results of acid-fast staining, periodic acid–Schiff staining, bacterial and mycological cultures of skin biopsy specimens, and blood cultures are negative. Doppler studies of lower-limb arteries and deep veins are unremarkable, and serum autoantibodies, including antiphospholipid autoantibodies, antineutrophil cytoplasmic antibodies, antinuclear antibodies, and extractable nuclear antigen antibodies, are not detected.
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WHAT WOULD YOU DO NEXT?
A. Change dressings daily and implement hyperbaric oxygen therapy B. Prescribe systemic corticosteroids C. Surgically excise the lesion, followed by skin grafting D. Continue with broad-spectrum antibiotics
JAMA November 26, 2014 Volume 312, Number 20
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
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JAMA Clinical Challenge Clinical Review & Education
Diagnosis Pyoderma gangrenosum
What To Do Next B. Prescribe systemic corticosteroids The key clinical feature is a rapidly progressing, large, painful leg ulcer with fever in a young woman with Crohn disease. The clinical manifestations and histopathology findings are consistent with the features of pyoderma gangrenosum. Skin biopsy and other laboratory tests help to rule out other diagnoses such as infections, malignancies, arterial occlusive or venous disorders, and autoimmune diseases such as antiphospholipid syndrome, antineutrophil cytoplasmic antibodies–related vasculitis, and lupus. Systemic corticosteroids are the first-line treatment for pyoderma gangrenosum.
Discussion Pyoderma gangrenosum is a rare sterile inflammatory skin disorder characterized by progressive, painful, noninfectious skin ulceration.1 About half of pyoderma gangrenosum cases are associated with underlying systemic diseases such as inflammatory bowel diseases, rheumatoid arthritis, and hematologic malignancies.1-3 Although the etiology and pathogenesis remain unclear, immunological factors and neutrophil dysfunction are believed to play a role.1 Classic pyoderma gangrenosum begins as a pustule or vesicle that quickly ruptures, necrotizes, and progresses to ulceration within several days.1,2 The ulceration may have a necrotic, hemorrhagic base with a violaceous overhanging edge. The skin lesion is typically extremely painful. It may affect any part of the skin but has a predilection for the lower extremities. Pathergy, the development of new skin ulceration at sites of trauma such as cuts or punctures, is a common feature.1,2,4 Systemic symptoms such as fever, malaise, arthralgia, and myalgia may occur.4 Thehistopathologyofpyodermagangrenosumisnonspecific2,4 and varies depending on the timing and the site of the biopsy. Massive dermalinfiltratesofinflammatorycells,mainlyneutrophils,aretypical.2,4 The diagnosis of pyoderma gangrenosum should be based on a comprehensive review of clinical manifestations and exclusion ARTICLE INFORMATION Author Affiliations: Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China. Corresponding Author: Qianjin Lu, MD, PhD, Department of Dermatology, Second Xiangya Hospital, Central South University, 139 Middle Renmin Rd, Changsha, Hunan 410011, China ([email protected]). Author Contributions: Drs Long and Su contributed equally to this work.
of other causes of severe cutaneous ulceration.1,4 The differential diagnosis includes infections (eg, fungal or mycobacterial infection, ecthyma gangrenosum, syphilis, amebiasis cutis), malignancies (eg, primary skin cancers, leukemia cutis), vasculitides (eg, lupus vasculitis, Wegener granulomatosis, polyarteritis nodosa), other vascular disorders (eg, antiphospholipid syndrome, venous stasis ulceration, peripheral artery disease), diabetic foot ulcer, calciphylaxis, which is a skin necrosis associated with arteriole calcification and thrombosis, and traumatic ulcers such as factitial dermatitis.1,2,4,5 Skin biopsy is helpful in excluding these conditions. Systemic corticosteroids are a first-line therapy for pyoderma gangrenosum and usually achieve rapid response.1,4 This characteristic is also helpful for diagnosis.2 For cases resistant to corticosteroids, other immunomodulating treatments such as cyclosporine, mycophenolate mofetil, and intravenous immunoglobulin may be used.4,6-8 Anti–tumor necrosis factor α agents, including infliximab and adalimumab, are alternative first-line therapies.9 Because of the risk of pathergy, aggressive debridement and grafting are generally contraindicated,4 although successful wound debridements with skin grafting and potent immunosuppressive treatment have been reported.6 For wound care, nonstick dressings and hyperbaric oxygen therapy are beneficial.6 Antibiotics provide no benefit except in the setting of a secondary bacterial infection.
Patient Outcome Treatment with methylprednisolone (80 mg/d) was initiated. The fever and the rapid expansion of the ulceration ceased the next day. Exudates decreased and black eschars formed. Mesalazine was added to treat Crohn disease. The skin lesion and the pain gradually resolved, and the diarrhea improved. The patient was discharged after a 3-week inpatient stay, when methylprednisolone was reduced to 40 mg/d. She continued with oral prednisone and mesalazine for an additional 20 weeks. Her skin lesion completely healed, leaving an atrophic scar. No recurrence was reported at a 3-month follow-up.
Additional Contributions: We thank Haiquan Wen, MD, Ying Zhou, MD, PhD, Yunsheng Liang, MD, and Jing Zhang, MD, from our department for helpful discussion of the case. We thank the staff from Department of Pathology and the staff from Department of Gastroenterology in our hospital for their critical review of histopathology and helpful consultation, respectively. We thank Christopher Chang, MD, PhD, of Thomas Jefferson University for his critical reading and suggestions for the manuscript. We also thank the patient for providing permission to publish her information.
Conflict of Interest Disclosures:All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Correction: This article was corrected online on December 2, 2014, to correct an error in the text.
Funding/Support: This work was supported by the National Key Clinical Speciality Construction Project of National Health and Family Planning Commission, China.
1. Ruocco E, Sangiuliano S, Gravina AG, et al. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol. 2009;23(9):1008-1017.
Role of the Funder/Sponsor: The National Health and Family Planning Commission had no role in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication.
REFERENCES
2. Callen JP, Jackson JM. Pyoderma gangrenosum. Rheum Dis Clin North Am. 2007;33(4):787-802. 3. Marzano AV, Borghi A, Stadnicki A, Crosti C, Cugno M. Cutaneous manifestations in patients with inflammatory bowel diseases. Inflamm Bowel Dis. 2014;20(1):213-227.
jama.com
4. Brooklyn T, Dunnill G, Probert C. Diagnosis and treatment of pyoderma gangrenosum. BMJ. 2006; 333(7560):181-184. 5. Weenig RH, Davis MD, Dahl PR, Su WP. Skin ulcers misdiagnosed as pyoderma gangrenosum. N Engl J Med. 2002;347(18):1412-1418. 6. Cabalag MS, Wasiak J, Lim SW, Raiola FB. Inpatient management of pyoderma gangrenosum [published online July 29, 2013]. Ann Plast Surg. doi:10.1097/SAP.0b013e31829565f3. 7. Li J, Kelly R. Treatment of pyoderma gangrenosum with mycophenolate mofetil as a steroid-sparing agent. J Am Acad Dermatol. 2013; 69(4):565-569. 8. Cummins DL, Anhalt GJ, Monahan T, Meyerle JH. Treatment of pyoderma gangrenosum with intravenous immunoglobulin. Br J Dermatol. 2007; 157(6):1235-1239. 9. Agarwal A, Andrews JM. Systematic review: IBD-associated pyoderma gangrenosum in the biologic era, the response to therapy. Aliment Pharmacol Ther. 2013;38(6):563-572.
JAMA November 26, 2014 Volume 312, Number 20
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
2159
JAMA Clinical Challenge
Rapidly Progressing Leg Ulcer With Fever in a Woman With Chronic Diarrhea Hai Long, MD, PhD; Yuwen Su, MD, PhD; Qianjin Lu, MD, PhD A Day 7
B
Day 8
C
Day 12
Figure. Skin lesion progression and histopathological changes (hematoxylin-eosin, original magnification ×200).
A 27-year-old woman presents with a rapidly progressing painful ulceration on the left leg (Figure) with intermittent high fevers. The lesion began as 2 sesame seed–sized violaceous, papulovesicular rashes with an erythematous halo on her left medial malleolus 12 days prior to presentation. Within 1 week, more papulovesicles appeared, merged, and ulcerated spontaneously (Figure, A and B). The ulceration expanded outwardly at a rapid pace, with Quiz at jama.com increasing pain and a hemorrhagic exudative discharge (Figure, C [left panel]). The lesion did not respond to treatment with systemic antibiotics, including vancomycin and meropenem. During the prior 5 months, she experienced mild diarrhea, which was ultimately diagnosed as Crohn disease by colonoscopy with biopsy. Physical examination reveals a pale, febrile patient with left leg edema and a rounded, swollen, and tender 10 × 10-cm ulceration on her left medial malleolus. The ulceration has a raised rugged surface with thick hemorrhagic exudates and a surrounding violaceousgreyish necrotic border (Figure, C [left panel]). Laboratory tests show moderate anemia, hypoalbuminemia, and fecal occult blood. Histopathology of skin lesions shows dermal edema with dense infiltration of neutrophils and vascular fibrinoid necrosis (Figure, C [right panel]). Results of acid-fast staining, periodic acid–Schiff staining, bacterial and mycological cultures of skin biopsy specimens, and blood cultures are negative. Doppler studies of lower-limb arteries and deep veins are unremarkable, and serum autoantibodies, including antiphospholipid autoantibodies, antineutrophil cytoplasmic antibodies, antinuclear antibodies, and extractable nuclear antigen antibodies, are not detected.
2158
WHAT WOULD YOU DO NEXT?
A. Change dressings daily and implement hyperbaric oxygen therapy B. Prescribe systemic corticosteroids C. Surgically excise the lesion, followed by skin grafting D. Continue with broad-spectrum antibiotics
JAMA November 26, 2014 Volume 312, Number 20
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
jama.com
JAMA Clinical Challenge Clinical Review & Education
Diagnosis Pyoderma gangrenosum
What To Do Next B. Prescribe systemic corticosteroids The key clinical feature is a rapidly progressing, large, painful leg ulcer with fever in a young woman with Crohn disease. The clinical manifestations and histopathology findings are consistent with the features of pyoderma gangrenosum. Skin biopsy and other laboratory tests help to rule out other diagnoses such as infections, malignancies, arterial occlusive or venous disorders, and autoimmune diseases such as antiphospholipid syndrome, antineutrophil cytoplasmic antibodies–related vasculitis, and lupus. Systemic corticosteroids are the first-line treatment for pyoderma gangrenosum.
Discussion Pyoderma gangrenosum is a rare sterile inflammatory skin disorder characterized by progressive, painful, noninfectious skin ulceration.1 About half of pyoderma gangrenosum cases are associated with underlying systemic diseases such as inflammatory bowel diseases, rheumatoid arthritis, and hematologic malignancies.1-3 Although the etiology and pathogenesis remain unclear, immunological factors and neutrophil dysfunction are believed to play a role.1 Classic pyoderma gangrenosum begins as a pustule or vesicle that quickly ruptures, necrotizes, and progresses to ulceration within several days.1,2 The ulceration may have a necrotic, hemorrhagic base with a violaceous overhanging edge. The skin lesion is typically extremely painful. It may affect any part of the skin but has a predilection for the lower extremities. Pathergy, the development of new skin ulceration at sites of trauma such as cuts or punctures, is a common feature.1,2,4 Systemic symptoms such as fever, malaise, arthralgia, and myalgia may occur.4 Thehistopathologyofpyodermagangrenosumisnonspecific2,4 and varies depending on the timing and the site of the biopsy. Massive dermalinfiltratesofinflammatorycells,mainlyneutrophils,aretypical.2,4 The diagnosis of pyoderma gangrenosum should be based on a comprehensive review of clinical manifestations and exclusion ARTICLE INFORMATION Author Affiliations: Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, China. Corresponding Author: Qianjin Lu, MD, PhD, Department of Dermatology, Second Xiangya Hospital, Central South University, 139 Middle Renmin Rd, Changsha, Hunan 410011, China ([email protected]). Author Contributions: Drs Long and Su contributed equally to this work.
of other causes of severe cutaneous ulceration.1,4 The differential diagnosis includes infections (eg, fungal or mycobacterial infection, ecthyma gangrenosum, syphilis, amebiasis cutis), malignancies (eg, primary skin cancers, leukemia cutis), vasculitides (eg, lupus vasculitis, Wegener granulomatosis, polyarteritis nodosa), other vascular disorders (eg, antiphospholipid syndrome, venous stasis ulceration, peripheral artery disease), diabetic foot ulcer, calciphylaxis, which is a skin necrosis associated with arteriole calcification and thrombosis, and traumatic ulcers such as factitial dermatitis.1,2,4,5 Skin biopsy is helpful in excluding these conditions. Systemic corticosteroids are a first-line therapy for pyoderma gangrenosum and usually achieve rapid response.1,4 This characteristic is also helpful for diagnosis.2 For cases resistant to corticosteroids, other immunomodulating treatments such as cyclosporine, mycophenolate mofetil, and intravenous immunoglobulin may be used.4,6-8 Anti–tumor necrosis factor α agents, including infliximab and adalimumab, are alternative first-line therapies.9 Because of the risk of pathergy, aggressive debridement and grafting are generally contraindicated,4 although successful wound debridements with skin grafting and potent immunosuppressive treatment have been reported.6 For wound care, nonstick dressings and hyperbaric oxygen therapy are beneficial.6 Antibiotics provide no benefit except in the setting of a secondary bacterial infection.
Patient Outcome Treatment with methylprednisolone (80 mg/d) was initiated. The fever and the rapid expansion of the ulceration ceased the next day. Exudates decreased and black eschars formed. Mesalazine was added to treat Crohn disease. The skin lesion and the pain gradually resolved, and the diarrhea improved. The patient was discharged after a 3-week inpatient stay, when methylprednisolone was reduced to 40 mg/d. She continued with oral prednisone and mesalazine for an additional 20 weeks. Her skin lesion completely healed, leaving an atrophic scar. No recurrence was reported at a 3-month follow-up.
Additional Contributions: We thank Haiquan Wen, MD, Ying Zhou, MD, PhD, Yunsheng Liang, MD, and Jing Zhang, MD, from our department for helpful discussion of the case. We thank the staff from Department of Pathology and the staff from Department of Gastroenterology in our hospital for their critical review of histopathology and helpful consultation, respectively. We thank Christopher Chang, MD, PhD, of Thomas Jefferson University for his critical reading and suggestions for the manuscript. We also thank the patient for providing permission to publish her information.
Conflict of Interest Disclosures:All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Correction: This article was corrected online on December 2, 2014, to correct an error in the text.
Funding/Support: This work was supported by the National Key Clinical Speciality Construction Project of National Health and Family Planning Commission, China.
1. Ruocco E, Sangiuliano S, Gravina AG, et al. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol. 2009;23(9):1008-1017.
Role of the Funder/Sponsor: The National Health and Family Planning Commission had no role in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication.
REFERENCES
2. Callen JP, Jackson JM. Pyoderma gangrenosum. Rheum Dis Clin North Am. 2007;33(4):787-802. 3. Marzano AV, Borghi A, Stadnicki A, Crosti C, Cugno M. Cutaneous manifestations in patients with inflammatory bowel diseases. Inflamm Bowel Dis. 2014;20(1):213-227.
jama.com
4. Brooklyn T, Dunnill G, Probert C. Diagnosis and treatment of pyoderma gangrenosum. BMJ. 2006; 333(7560):181-184. 5. Weenig RH, Davis MD, Dahl PR, Su WP. Skin ulcers misdiagnosed as pyoderma gangrenosum. N Engl J Med. 2002;347(18):1412-1418. 6. Cabalag MS, Wasiak J, Lim SW, Raiola FB. Inpatient management of pyoderma gangrenosum [published online July 29, 2013]. Ann Plast Surg. doi:10.1097/SAP.0b013e31829565f3. 7. Li J, Kelly R. Treatment of pyoderma gangrenosum with mycophenolate mofetil as a steroid-sparing agent. J Am Acad Dermatol. 2013; 69(4):565-569. 8. Cummins DL, Anhalt GJ, Monahan T, Meyerle JH. Treatment of pyoderma gangrenosum with intravenous immunoglobulin. Br J Dermatol. 2007; 157(6):1235-1239. 9. Agarwal A, Andrews JM. Systematic review: IBD-associated pyoderma gangrenosum in the biologic era, the response to therapy. Aliment Pharmacol Ther. 2013;38(6):563-572.
JAMA November 26, 2014 Volume 312, Number 20
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/11/2015
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