Erythema Nodosum

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OnSurg thanks collaborative partner Dr Anubhav Mittal at for making this valuable content available. Dr Mittal tweets at @anubhavnz.

Case History

A 25-year-old woman, previously healthy, awakens with a mild sore throat, fatigue, pain in both ankles, and red lesions on her legs. She has felt weakness and fatigue for 2 days, but denies fever, chills, nausea, or night sweats. She works in a restaurant. There is no history of using recreational drugs, oral contraceptives, or other medications. She has not travelled abroad for 3 years. Physical examination reveals red, tender nodules with surrounding erythema on both shins. On palpation, the nodules are deep-seated and non-mobile. Ankles are mildly swollen and tender. Chest, cardiovascular and ophthalmological examinations are normal. A chest x-ray shows left lower lobe infiltration. Her tuberculin skin test is negative. She is diagnosed with pneumococcal pneumonia.

History and Exam

- presence of risk factors
- nodules on shins
- uveitis, red eyes, retinal nodules, or candle-wax drippings
- anaesthetic patches
- nodules on other skin areas


Regardless of the cause, the lesions, in subcutaneous fat, are strikingly similar in their gross and microscopic appearance. This suggests a common pathogenesis, although the mechanism remains obscure. It is thought to result from a non-specific immune response to agents such as medications, bacteria, viruses, fungi, and anti-DNA antibodies. An increased serum macrophage activation points towards to an immunological pathogenesis. An unusually intense reaction to these antigens is thought to lead to antigen-antibody complexes of a certain size that filter out in a specific size of blood vessel in the subcutaneous fat.
The development of lesions may be a secondary effect of a primary cellular reaction. Patients with tuberculosis and coccidioidomycosis do not develop these lesions until they are skin-positive. Frei antigen induces similar lesions in patients with lymphogranuloma venereum. In sarcoidosis, lesions are associated with HLA-DRB1 x 0301 and HLA-DQB1 x 0201

Causes / Risk Factors

A variety of factors that trigger an immunological response can cause the condition, and recognition of different aetiological factors has increased since the later half of the 19th century, when "rheumatism" was considered to be the principal cause, and tuberculosis was second most common. In the first half of the 20th century, tuberculosis was the cause in over 90% of patients. In the second half of the 20th century, Behcet's disease, coccidioidomycosis, medications, and Whipple's disease were also recognised as causes. Streptococcal infection is the primary cause of recurrent cases.
The most likely underlying infectious cause depends on geographical area. Erythema nodosum associated with histoplasmosis is seen mainly in the southern and Midwestern US, the Mississippi valley, Central America, and parts of South America. In the San Joaquin Valley in California, and in patients with a history of desert camping or digging, the cause may be coccidioidomycosis. In tropical countries, tuberculosis and leprosy are leading causes. Behcet's disease is an important cause in Turkey and areas around the Mediterranean coast. Blastomycosis may be the cause in the Mississippi and Ohio River valleys, Midwestern US, and parts of Canada. Brucellosis is prevalent in tropical areas, especially the Middle East, and in dairy workers and farmers, while psittacosis is strongly associated with exposure to birds.


Erythema nodosum is a common cutaneous hypersensitivity reaction consisting of red, tender nodules over the shins, calves, and buttocks. Fever and arthralgia are often present. Lesions develop in a typical sequence. First to appear are clustered, tender patches. After a few days, lesions turn into painful nodules, often with extravasation of blood and bruises. Finally, the bruises fade and turn into pigmented, scaly macules before subsiding. Microscopy of these lesions shows septal panniculitis with inflammatory cells in the septa between subcutaneous fat lobules


Erythema nodosum occurs more frequently in Europe than in North America, although the exact incidence is not known. It can occur at any age but peaks between 20 and 30 years. Women are affected 3 to 6 times more often than men.


mild to moderately severe symptoms - bed rest and leg elevation + treatment of underlying cause
- analgesia
- potassium iodide
- analgesia
- intralesional corticosteroid injection
- analgesia
- erythema nodosum migrans variant (any stage of treatment)
-- systemic corticosteroids severe refractory symptoms - systemic corticosteroids + treatment of underlying cause
- bed rest and leg elevation
- analgesia


Patients usually recover spontaneously within 1 to 2 months, depending on severity, and there is usually no scarring. Older patients with venous insufficiency may have lasting erythematous swelling of their ankles.

Investigations / Tests

- anti-streptolysin-O (ASO) titer
- PPD skin testing

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