When a Patient Presents With Multiple Ulcerations on the Lower Extremity
A 73-year-old male with well-controlled rheumatoid arthritis and hyperlipidemia presented to the office for evaluation and management of multiple ulcers located on the right lower extremity. The lesions started 2 to 3 months prior as small, painful erythematous papules that began to enlarge and ulcerate. The patient denied any lower extremity swelling, related no new medications, and no changes to his current medications. He denied any trauma to the area, as well as recent illness or vaccination. The patient previously treated the lesions with silver sulfadiazine cream and hydrogen peroxide. The patient’s medications included leflunomide, methotrexate, folic acid, and simvastatin. He denied any fevers, chills, cough, or sweats. His family and social history were unremarkable.
Physical exam demonstrated well-demarcated ulcerations with jagged, undermined, violaceous borders distributed on the right posterior thigh (multiple lesions), and right calf. There was no drainage from the ulcerations and the bases consisted of a combination of granular and fibrous tissue. There was surrounding erythema and some eschar within the ulcerations. There was 1+ pitting edema on exam.
Key Questions to Consider
1. What conditions are part of the differential diagnosis?
2. What is the most likely diagnosis of this patient’s ulcerations?
3. What are the key characteristics of this condition?
4. What are the treatment recommendations for this condition?
Solving the Differential Diagnosis
The differential diagnosis for this patient includes pyoderma gangrenosum, rheumatoid vasculitis, infectious ulceration, venous ulceration, and methotrexate-induced ulceration.
Rheumatoid vasculitis is an inflammatory process that affects small-to-medium-sized blood vessels. Involvement in the skin can present with purpura, nail fold infarctions, digital gangrene or ischemia, and cutaneous ulcers. Rheumatoid vasculitis often demonstrates multi-system involvement, affecting the central nervous system, peripheral nervous system, eyes, heart, lungs, kidneys, and gastrointestinal tract. The exact pathogenesis is not well understood, but rheumatoid factor autoantibodies, anticitrullinated peptide antibodies, and circulating immune complexes are believed to play a role. TNF-alpha is a possible trigger for rheumatoid vasculitis.1 Diagnosis involves histologic evidence of small or medium vessel vasculitis. Skin biopsy is effective and the least invasive option.2
Another possible differential diagnosis is infectious ulceration. Sources of contamination for infectious ulcers include the environment, the surrounding skin, and endogenous patient sources. The delay in wound healing for infectious ulcers commonly results from aerobic or facultative bacteria species, such as Staphylococcus aureus or Pseudomonas aeruginosa.3 Clinicians should also rule out acid-fast bacilli and fungal species. Infectious fungal species range from endemic species in the patient’s geographic region or opportunistic fungi that are part of the normal flora. Candida albicans inhabits many healthy humans; therefore, it is a common infectious agent.4 Similarly, acid-fast bacilli, or mycobacteria, are found in various soils and waters. Their lipid-rich hydrophobic outer membrane is advantageous for surface adherence and disinfectant resistance. Certain species are known to cause ulcerations, such as M ulcerans, therefore must be part of one’s differential.5 Increased time to healing can lead to more organism colonization, which can later result in infection, especially in at-risk hosts such as those with diabetes. 3 One can begin to diagnose infection of such ulcers using a wound swab and culture.6
Venous ulceration pathogenesis involves macroscopic and microscopic processes. Venous ulcer formation encompasses macrocirculatory dysfunction, varicose vein formation with reflux, and damage to microcirculation and structure of the dermis. Microcirculatory venous hypertension causes extravasation of macromolecules and erythrocytes and excessive iron deposition into the interstitium. Erythrocyte degradation products, hemoglobin, iron, and protein extravasation cause a chronic inflammatory signal. This injury results in venous ulcer formation.7 Expression of matrix metalloproteinases (MMPs) and cytokines has detrimental effects on the vein wall and valve, as well as the destruction of the dermis, which results in ulcer formation.8 Clinically, the most common ulcer location is usually the medial malleolus.
Lastly, the clinician should also consider methotrexate-induced ulceration. Methotrexate provides treatment for a variety of dermatologic and rheumatologic conditions, including rheumatoid arthritis, as in this patient’s case. Methotrexate has many side effects and may cause cutaneous ulcerations. Ulceration as a toxic adverse effect is very rare,9 therefore unlikely in this case. It is important to consider other medications the patient has recently taken. Minocycline, trimethoprim-sulfamethoxazole, and others can displace methotrexate and increase its circulating concentration, ultimately leading to ulceration development. Cessation of methotrexate can lead to complete ulcer healing.9
Answering the Key Diagnostic Questions
1. The differential diagnosis includes pyoderma gangrenosum, rheumatoid vasculitis, infectious ulceration, venous ulceration, and methotrexate-induced ulceration.
2. Pyoderma gangrenosum.
3. Key characteristics of pyoderma gangrenosum include ruling out all other causes of ulceration, such as infectious etiologies and medication-induced causes. Only after this can a diagnosis of pyoderma gangrenosum be made.
4. Initial treatment includes prednisone in combination with cyclosporine or infliximab alone. Topical steroids can treat mild cases. Second-line agents include anti-neutrophilic agents, such as dapsone or colchicine, and thalidomide or clofazimine.
What Is Pyoderma Gangrenosum?
The patient described actually had pyoderma gangrenosum, which presents as one or more irregularly shaped ulcers with a gray or violaceous coloration. The ulcers vary in size and depth and can go as deep as the muscle and tendons. Non-ulcerative forms exist and consist of pustular, bullous, and vegetative types.10
The exact pathophysiology behind pyoderma gangrenosum is unknown. Descriptions characterize it as an autoinflammatory disorder, most likely secondary to deviant activation of the innate immune system in genetically predisposed patients.10 The adaptive immune system is also believed to play a role in pathogenesis.11 It is currently thought that IL-1 could be a causative factor, as elevated levels of IL-1 were demonstrated in pyoderma gangrenosum patients.12 Studies have shown that treatment of pyoderma gangrenosum patients with medications that interfere with IL-1 was effective, suggesting IL-1 plays a crucial role in pathogenesis.13
The most commonly associated factor with pyoderma gangrenosum is inflammatory bowel disease (20.2 percent), followed by rheumatoid arthritis (11.8 percent), and hematological disorders (3.9 percent). Less commonly factors associated with it include human immunodeficiency virus (HIV), systemic lupus erythematosus, hepatitis, Takayasu’s arteritis, and pregnancy.14
What Are the Current Treatment Options?
While there are no current gold standard treatment options for pyoderma gangrenosum, the mainstay of treatment suggestions consists of systemic or topical immunosuppression along with wound care and pain management.10
First-line therapy for disseminated or multilesional disease usually includes immunosuppressive agents, such as prednisone, alone or in combination with cyclosporine.10,15 For localized mild lesions, one can use topical treatment forms, such as tacrolimus and topical cyclosporine, or intralesional therapies, such as intralesional corticosteroids. If needed, one can combine topical and systemic treatments.16 Minocycline and other tetracyclines lend their anti-inflammatory properties as adjunct therapies and are considered first-line treatments. Other increasingly used first-line therapies include infliximab and mycophenolate mofetil.17
Additionally, second-line treatments consist of anti-neutrophilic therapies that one can use as adjunct treatments, such as dapsone or colchicine. They are not typically used as monotherapies because of limited proven efficacy. Third-line treatments include thalidomide and clofazimine.17,18
In Conclusion
After exclusion of infectious and drug etiologies along with the biopsy findings showing a non-specific ulceration with a dense mixed inflammatory infiltrate, the diagnosis of pyoderma gangrenosum was made. The patient first received a 6-week taper of prednisone, starting from 60mg and decreasing to 10mg per week, in addition to topical tacrolimus 0.1% ointment around the wound edges twice daily. He began to see improvement on this regimen, however, as the prednisone taper reached 10mg he began to develop new lesions. To avoid further prednisone use, the patient was started on infliximab infusions every eight weeks after his initial loading dose. Within three months, the patient experienced full remission of his ulcerations and has remained clear for over one year.
In summary, this case highlights the importance of ruling out all possible etiologies when a patient presents with multiple lower extremity ulcerations. A detailed history, physical examination, tissue cultures, and punch biopsy should all be performed along with appropriate laboratory work before arriving at a diagnosis of pyoderma gangrenosum. It is also important to consider a multidisciplinary approach, as podiatry, wound care, and rheumatology are often needed in conjunction with dermatology to treat patients with pyoderma gangrenosum.
Ms. Druskovich is a first year medical student at Michigan State University College of Human Medicine in Grand Rapids, MI.
Dr. Ashack is an assistant professor at Michigan State University College of Human Medicine and is also a managing partner at Dermatology Associates of West Michigan in Grand Rapids, MI.
1. Rheumatoid vasculitis: an update. Curr Opin Rheumatol. 2015;27(1):63-70. doi:10.1097/BOR.0000000000000126
2. Bartels CM, Bridges AJ. Rheumatoid vasculitis: Vanishing menace or target for new treatments? Curr Rheumatol Rep. 2010;12(6):414-419. doi:10.1007/s11926-010-0130-1
3. Frank C, Bayoumi I, Westendorp C. Approach to infected skin ulcers. Can Fam Phys. 2005;51(10):1252-1359.
4. Köhler JR, Casadevall A, Perfect J. The spectrum of fungi that infects humans. Cold Spring Harb Perspect Med. 2015;5(1):a019273. doi:10.1101/cshperspect.a019273
5. Franco-Paredes C, Marcos LA, Henao-Martínez AF, et al. Cutaneous mycobacterial infections. Clin Microbiol Rev. 2018;32(1):e00069-18. doi:10.1128/CMR.00069-18
6. Laube S, Farrell AM. Bacterial skin infections in the elderly. Drugs Aging. 2002;19(5):331-342. doi:10.2165/00002512-200219050-00002
7. Crawford JM, Lal BK, Durán WN, Pappas PJ. Pathophysiology of venous ulceration. J Vasc Surg Venous Lymphat Disord. 2017;5(4):596-605. doi:10.1016/j.jvsv.2017.03.015
8. Chi YW, Raffetto JD. Venous leg ulceration pathophysiology and evidence based treatment. Vasc Med. 2015;20(2):168-181. doi:10.1177/1358863X14568677
9. Kurian A, Haber R. Methotrexate-induced cutaneous ulcers in a nonpsoriatic patient: Case report and review of the literature. J Cutan Med Surg. 2011;15(5):275-279. doi:10.2310/7750.2011.10078
10. McKenzie F, Arthur M, Ortega-Loayza AG. Pyoderma gangrenosum: What do we know now? Curr Derm Rep. 2018;7(3):147-157. doi:10.1007/s13671-018-0224-y
11. Wang EA, Steel A, Luxardi G, et al. Classic ulcerative pyoderma gangrenosum is a T cell-mediated disease targeting follicular adnexal structures: A hypothesis based on molecular and clinicopathologic studies. Front Immunol. Available at: https://www.frontiersin.org/article/10.3389/fimmu.2017.01980 . Published January 15, 2018. Accessed May 9, 2022.
12. Marzano AV, Damiani G, Ceccherini I, Berti E, Gattorno M, Cugno M. Autoinflammation in pyoderma gangrenosum and its syndromic form (pyoderma gangrenosum, acne and suppurative hidradenitis). Br J Dermatol. 2017;176(6):1588-1598. doi:10.1111/bjd.15226
13. Kolios AGA, Maul JT, Meier B, et al. Canakinumab in adults with steroid-refractory pyoderma gangrenosum. Br J Dermatol. 2015;173(5):1216-1223. doi:10.1111/bjd.14037
14. Patel F, Fitzmaurice S, Duong C, et al. Effective strategies for the management of pyoderma gangrenosum: a comprehensive review. Acta Derm Venereol. 2015;95(5):525–531. doi: 10.2340/00015555-2008
15. Marzano AV, Trevisan V, Lazzari R, Crosti C. Pyoderma gangrenosum: Study of 21 patients and proposal of a ‘clinicotherapeutic’ classification. J Dermatol Treat. 2011;22(5):254-260. doi:10.3109/09546631003686069
16. Marzano AV, Trevisan V, Lazzari R, Crosti C. Topical tacrolimus for the treatment of localized, idiopathic, newly diagnosed pyoderma gangrenosum. J Dermatol Treat. 2010;21(3):140-143. doi:10.3109/09546630903268239
17. Ahronowitz I, Harp J, Shinkai K. Etiology and management of pyoderma gangrenosum. Am J Clin Dermatol. 2012;13(3):191-211. doi:10.2165/11595240-000000000-00000
18. Ahn C, Negus D, Huang W. Pyoderma gangrenosum: a review of pathogenesis and treatment. Exp Rev Clin Immunol. 2018;14(3):225-233. doi:10.1080/1744666X.2018.1438269
