This is presumed to be a hypersensitivity reaction. It is often a dermatological manifestation of infectious, or other, disease.¹

Epidemiology

The prevalence varies from country to country. In the UK it is 24 cases per 100,000 per year. It can affect any age but is most common between the ages of 18 and 35 with women affected 4 times as often as men.¹

Presentation²

The eruptive phase begins with fever, aching and arthralgia whilst a painful rash usually appears within a couple of days.
Lesions begin as red, tender nodules. The borders are poorly defined and they are 2 to 6 cms in diameter.

Associated diseases and causes^2,3

• Erythema nodosum is often indicative of an underlying infectious disease but a cause is not always found. Some underlying causes are not infectious.
• Streptococcal infection is the most common underlying cause and so it may be a feature of other diseases including scarlet fever and rheumatic fever, although in the UK nowadays the former is uncommon and the latter rare.
• Sarcoidosis is also commonly involved in adults although it is not infectious in origin.
• Tuberculosis must be considered.
• Leprosy can produce a clinical picture of erythema nodosum although the histological picture of the lesions is different.
• Various forms of gastroenteritis, especially Yersinia enterocolitica, Salmonella spp. and Campylobacter spp. can be associated.
• Lymphogranuloma venereum may be a cause.
• Mycoplasma pneumonia can be associated.
• Fungal infections are less common in the UK but coccidioidomycosis is important in the Southwest United States of America. It may occur in histoplasmosis and blastoplasmosis.
• Sulphonamides are used less often nowadays but other drugs to be implicated include sulphonylureas, gold and oral contraceptives.
• It may correlate with flare-up of Crohn's disease or ulcerative colitis.
• It can precede the diagnosis of Hodgkin's disease and non-Hodgkin's lymphoma by months and it can accompany Behçet's syndrome.
• It may occur in pregnancy when it is usually in the second trimester. It is likely to recur in future pregnancies and may occur with oral contraceptives.
• In many cases no cause is found.

Investigations

Although in many cases it is idiopathic, it is important to exclude serious underlying disease:

• A throat swab for streptococcus is the first test, although it may well be negative, even with streptococcal disease.
• Anti-streptococcal O (ASO) titre may be more helpful although a normal titre does not exclude infection. A rising titre may be more valuable.
• Serum anti-deoxyribonuclease B (AntiDNAseB) antibodies and anti-hyaluronidase levels are more sensitive than ASO titre in cases of recent serious streptococcal skin infection.^4,5
• Arrange an FBC and ESR. ESR is often very high regardless of the aetiology and C-reactive protein may be more contributory.
• Stool examination for Y. enterocolitica, Salmonella spp. and Campylobacter spp. may yield results, as may blood cultures
• In sarcoidosis, calcium is often raised.
• Chest X-ray may show bilateral hilar lymphadenopathy (BHL) in sarcoidosis, unilateral or asymmetrical adenopathy in malignancy, or evidence of pulmonary tuberculosis.
• Intradermal skin tests may be required to exclude tuberculosis and coccidioidomycosis.
• Excisional biopsy may be helpful where the diagnosis is in doubt.

Differential diagnosis^2,3

• Erysipelas
• Erythema induratum (modular vasculitis)
• Insect bites
• Acute urticaria
• Familial Mediterranean fever
• Superficial migratory thrombophlebitis
• Thrombophlebitis

Management¹

• Most cases are self-limiting and require only symptomatic relief.
• If an infective aetiology has been discovered then appropriate therapy is in order but it should not be given blind.
• A degree of relief can be obtained with cool compresses and bed rest with elevation of the foot of the bed. Bed rest has been advocated for many years and is anecdotally useful but the evidence base is lacking.
• Non-steroidal anti-inflammatory drugs (NSAIDs) are useful and no other drugs are usually needed.⁶ Steroids are beneficial but should be used with caution and may be contra-indicated if infection has not been excluded.
• In difficult cases, oral potassium iodide may be valuable, as may tetracycline, and, in erythema nodosum of leprosy, thalidomide has seen a resurgence.^7,8

Prognosis

The condition usually resolves within 6 weeks but it may be more protracted, especially if the underlying cause remains or when it is idiopathic. Serious complications are unusual unless part of the underlying disease. Chronic or recurrent disease is rare. Lesions heal without atrophy or scarring.²

Document references

1. Hebel J, Habif T; Erythema Nodosum. eMedicine, 2009.
2. Requena L, Requena C.; Erythema nodosum.Dermatol Online J. 2002 Jun;8(1):4.
3. Schwartz RA, Nervi SJ; Erythema nodosum: a sign of systemic disease. Am Fam Physician. 2007 Mar 1;75(5):695-700. [abstract]
4. Antideoxyribonuclease B (AntiDNAseB) antibodies (serum); Manual of Use and Interpretation of Pathology Tests: Third Edition 2007 The Royal College of Pathologists of Australasia
5. Chin TK; Rheumatic Fever. eMedicine, 2009.; Paediatric perspective.
6. Atzeni F, Carrabba M, Davin JC, et al; Skin manifestations in vasculitis and erythema nodosum. Clin Exp Rheumatol. 2006 Jan-Feb;24(1 Suppl 40):S60-6. [abstract]
7. Marshall JK, Irvine EJ; Successful therapy of refractory erythema nodosum associated with Crohn's disease using potassium iodide. Can J Gastroenterol. 1997 Sep;11(6):501-2. [abstract]
8. Joglekar S, Levin M; The promise of thalidomide: evolving indications. Drugs Today (Barc). 2004 Mar;40(3):197-204. [abstract]

Internet and further reading

• Medical Protection Society; Warning to look for TB with erythema nodosum

Acknowledgements