Erythema nodosum (EN) manifests as a classic panniculitis, or painful disorder of subcutaneous fat tissue. Its presence can signify an underlying infection, inflammatory condition, or malignancy in a patient. In addition, certain medications and even pregnancy can cause erythema nodosum. The pathogenesis of erythema nodosum remains unclear, but a nonspecific cutaneous reaction caused by a type IV delayed hypersensitivity reaction to various antigens is thought to be the most likely pathway. A majority of patients will also have evidence of recent streptococcal infection. In 15-40% of patients, there is an underlying infection, inflammatory disorder or connective tissue disease related to the lesions. More than 50% of cases will have no identifiable cause.
The classic presentation for erythema nodosum is the presence of acute tender, warm, erythematous, subcutaneous nodules on the bilateral pretibial areas that evolve into ecchymotic lesions which resolve without scarring or ulceration over a period of weeks to months. The nodules are deep and more easily palpable than visualized. A prodrome of fever, malaise, arthralgias, and arthritis is often described prior to the eruption of the skin lesions.
Erythema nodosum is rare, occurring in about 1-5 out of 100,000 people. EN occurs more in females than males with a male to female ratio of around 1:6. Peak incidence is between the ages of 20-40 years, but can occur at any age. Streptococcal infection is the most common etiology followed by sarcoidosis in adults. However, most cases are idiopathic.
- Bacterial infections – most common streptococcal infections. Other infections include Mycobacterium tuberculosis, Yersinia enterocolitica, Mycoplasma pneumonia, Salmonella, and Campylobacter.
- Fungal infections – Coccidiodomycosis, Histoplasmosis, Blastomycosis
- Drugs – sulfonamides, sulfonylurea, oral contraceptives
- Sarcoidosis – accounts for 10-22% of all EN cases
- Pregnancy – occurs in 4% of patients around second trimester
- Inflammatory Bowel Disease – ulcerative colitis, Crohn’s disease (correlates with flares)
- Behcet’s disease
- Nodular vasculitis (erythema induratum) – nodules often located on calves and heals with scars
- Weber-Christian disease (relapsing febrile nodular panniculitis)
- Subcutaneous infections due to bacteria or fungi
- Superficial thrombophlebitis – nodules often located medial or lateral aspects of lower legs, and manifest as hard, irregular plaques
- Cutaneous polyarteritis nodosa – nodules are often located on calves and are ulcerated; associated with livedo reticularis
- Subcutaneous sarcoidosis – granulomatous involvement found on skin biopsy
- Erythema nodosum leprosum – vasculitis that develops in patients with lepromatous leprosy with nodular, necrotic, pustular or hemorrhagic skin lesions
- Cutaneous B-cell lymphoma
Skin nodules have poorly defined borders and are usually located on the bilateral pretibial area. Because of their subcutaneous location, it may require deep palpation. The nodules are warm and erythematous. The overlying skin is red, shiny, and smooth. They can range from 1-5 centimeters in size and very tender to palpation to the point that pain may be out of proportion to appearance of lesion. While skin nodules occasionally can be located on the upper extremities, trunk or thighs, this is uncommon. Evolving lesions may appear ecchymotic, but resolving lesions will not leave scars or ulcerations and can disappear between 1-2 weeks or last up to 6 weeks. New lesions may appear during this time.
A thorough history and physical guides which laboratory studies should be ordered. A complete blood cell count, basic metabolic panel, hepatic function panel, urine pregnancy test, and urinalysis should be obtained. Leukocytosis may be suggestive of an underlying infection. Acute phase reactants, including ESR and CRP, are elevated and often return to normal after the lesions resolve.
A streptococcal antibody profile or an antistreptolysin-O titer may be measured at diagnosis and 2-4 weeks later to assess for preceding streptococcal infection. A 30% change in antistreptolysin-O titer is indicative of a recent streptococcal infection.
A skin biopsy is required only in atypical cases in which the skin lesions do not follow the typical pattern of EN. Consider a skin biopsy if the nodules appear in atypical areas, persist beyond 8 weeks, or develop areas of ulceration. A deep excisional biopsy with a sample of subcutaneous fat is required for diagnosis. Pathology often shows deposition of immune complexes in the venules of the septae of the subcutaneous fat without evidence of a vasculitis.
A chest x-ray is helpful to assess for hilar adenopathy or other evidence of pulmonary sarcoidosis, tuberculosis, or fungal infection. The presence of EN along with hilar lymphadenopathy in sarcoidosis is known as Löfgren syndrome.
Treatment of underlying disease is the mainstay of treatment. Symptomatic relief with rest, elevation of lower extremities, and light compression stockings is encouraged. Most cases are self-limited and will resolve on their own. Non-steroidal anti-inflammatory drugs (NSAID) are often used for pain control. Indomethacin 25-75 milligrams (mg) by mouth (PO) every 8-12 hours, ibuprofen 200-600 mg PO every 6-8 hours, or naproxen 250-500 mg PO every 8-12 hours are commonly used.
Second line agents for consideration include potassium iodide, although it is difficult to obtain. Potassium iodide is contraindicated in pregnancy and may be difficult to tolerate due to side effects, which include abdominal pain, nausea, vomiting, and diarrhea. Colchicine has also been used as a second line agent. Systemic corticosteroids are rarely indicated in erythema nodosum, are contraindicated in the presence of infection such as tuberculosis, and are reserved for severe cases.
On physical exam, improvement of the skin nodules is often characterized by their evolution into flat, bruise-like yellow lesions without scarring or ulceration.
Patients should be informed that lesions may continue to erupt for up to 8 weeks. Up to 40% of patients have recurrences and they are more likely in patients with unknown etiology of erythema nodosum.
Avoid NSAIDs in renal failure and cirrhosis. Avoid potassium iodide therapy in patients with acute and chronic kidney disease, thyroid disease (Hashimoto’s disease, Graves disease, or history of radioactive iodine treatment), pregnancy, patients on ACE inhibitors, potassium sparing agents, amiodarone, lithium, or sulfonamides. Colchicine may cause pancytopenia if taken at high doses for a prolonged period of time.
If pain worsens, consider additional dose of NSAID, potassium iodide or colchicine (depending on which agent they are on but do not exceed maximum daily dose).
Length of stay depends on time required to diagnose underlying cause, whether diagnostic approach can be continued or completed safely as outpatient, whether underlying cause requires inpatient treatment, if biopsy was required and result has returned, and if patient’s pain is adequately controlled on oral medication.
When the patient’s pain is adequately controlled with oral medication and patient is ambulatory.
Patient should be seen within 1-2 weeks of discharge by primary care physician to evaluate whether lesions are improving and to complete diagnostic workup if not completed during hospitalization. If an underlying etiology or disease process is identified, patient should also follow up with the subspecialty physician (pulmonary, infectious disease, oncology, etc.) within 2 weeks.
Patients should be informed that lesions should resolve without scarring but may continue to erupt for up to 8 weeks. Up to 40% of patients have recurrences and are more likely in patients with unknown etiology of erythema nodosum.
Blake, T, Manhan, M. “Erythema Nodosum – A Review of an Uncommon Panniculitis”. . vol. 20. 2014.
Requena, L, Requena, C. “Erythema Nodosum”. . vol. 8. 2002. pp. 4
Schwartz, R, Nervi, S. “Erythema Nodosum: A Sign of Systemic Disease”. . vol. 75. 2007. pp. 695-700.
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