Erythema Nodosum

Introduction

Erythema nodosum is the commonest form of panniculitis - inflammation of subcutaneous fat - and presents with characteristic tender, red nodules, almost always on the shins. It occurs most often in young adults, is around five times more common in women, and has its peak incidence between the ages of 20 and 45.¹

The most important thing to understand about erythema nodosum is that it is a reaction pattern rather than a disease in its own right - the skin's non-specific response to a wide range of underlying triggers. The clinical task is not simply to recognise the rash, which is usually straightforward, but to identify why it has occurred, since the list of possible causes ranges from a self-limiting streptococcal sore throat to tuberculosis or sarcoidosis.

Pathophysiology

Erythema nodosum is thought to be a delayed-type (type IV) hypersensitivity reaction, with immune complexes depositing in and around the septae of subcutaneous fat lobules, provoking a septal panniculitis - inflammation concentrated in the fibrous septae between fat lobules rather than within the lobules themselves, which is the histological hallmark that distinguishes it from lobular panniculitides.²

The shins are the classic site partly because of the relatively poor collateral circulation and lower ambient temperature of that region, which is thought to predispose the local vasculature and connective tissue to this type of inflammatory reaction. As the inflammatory infiltrate resolves, extravasated red cells within the fat are broken down in the same sequence as a bruise, which is why individual lesions visibly progress through red, purple, green and yellow before fading - a distinctive and diagnostically useful feature.

Causes

Roughly 30-50% of cases have no identifiable cause and are labelled idiopathic. Among the remainder, infection, systemic inflammatory disease, pregnancy and drugs account for most cases.³

Clinical features

Erythema nodosum presents with tender, warm, erythematous nodules, typically 2-6 cm across, most often bilateral and symmetrical over the shins (the pretibial surface), though the forearms, thighs and trunk can occasionally be affected.

Nodules are ill-defined rather than sharply marginated, and unlike most other panniculitides, they never ulcerate or scar - a useful discriminating feature. Over 2-6 weeks, individual lesions flatten and fade through the colour sequence of a resolving bruise (red to purple-blue to green-yellow) before disappearing completely.

Systemic symptoms frequently accompany the rash and can precede it by days: fever, malaise, and arthralgia or frank arthritis, most often affecting the ankles and knees. These systemic features, alongside any symptoms pointing to a specific cause (sore throat, cough, diarrhoea, weight loss), are as important to elicit as the rash itself.

Clinical examination

• Distribution and evolution - bilateral pretibial nodules at varying stages of the bruise-like colour sequence is highly suggestive
• Absence of ulceration - important to note explicitly, since ulceration points towards an alternative panniculitis
• Lymphadenopathy - particularly cervical or generalised, which might point towards an infective or lymphomatous cause
• Joint examination - swelling or tenderness, especially ankles and knees
• Chest examination - for signs relevant to tuberculosis or sarcoidosis, though findings are often normal even with significant intrathoracic disease
• Abdominal examination and a brief systems review - for symptoms suggesting inflammatory bowel disease

Differential diagnosis

• Erythema induratum (nodular vasculitis) - a lobular panniculitis, typically on the calves rather than the shins, that characteristically does ulcerate; historically associated with tuberculosis⁴
• Superficial thrombophlebitis - a tender, cord-like, linear lesion following a vein rather than discrete round nodules
• Cellulitis - typically unilateral, with more diffuse spreading erythema and systemic signs of infection, rather than discrete symmetrical nodules
• Insect bite reactions - usually more acute in onset and less symmetrically distributed
• Polyarteritis nodosa - can cause tender subcutaneous nodules along the course of arteries, usually with other systemic vasculitic features
• Panniculitis of other causes (pancreatic panniculitis, lupus panniculitis) - distinguished by the clinical context and, where needed, biopsy

Investigations

The diagnosis of erythema nodosum itself is clinical. Investigation is directed entirely at finding the underlying cause.

• FBC, ESR/CRP - raised inflammatory markers are typical and support an active inflammatory process, though non-specific
• Throat swab and anti-streptolysin O (ASO) titre - if a preceding streptococcal infection is suspected, especially in children
• Chest X-ray - looking for bilateral hilar lymphadenopathy (sarcoidosis, Lofgren syndrome) or changes suggesting tuberculosis
• Interferon-gamma release assay or tuberculin skin test - if tuberculosis is a realistic possibility from the history or chest X-ray
• Stool studies and faecal calprotectin, or referral for colonoscopy - if bowel symptoms suggest inflammatory bowel disease
• Skin biopsy - reserved for atypical presentations, since it is rarely needed when the clinical picture is classical, but distinguishes septal from lobular panniculitis when the diagnosis is in doubt

Management

Management has two parallel strands: treating any identified underlying cause, and controlling the symptoms of the rash itself, which is usually self-limiting regardless.

• Treat the underlying cause where one is found - for example antibiotics for streptococcal infection, standard anti-tuberculous therapy for tuberculosis, or optimising control of underlying inflammatory bowel disease
• Rest and leg elevation - reduces oedema and discomfort in the affected legs
• NSAIDs - first-line for symptomatic relief of pain and inflammation, used with the usual cautions⁸
• Stop any potentially causative drug (combined oral contraceptive, sulfonamide, penicillin) where a drug cause is suspected
• Potassium iodide - a recognised, effective second-line option for persistent idiopathic disease not settling with the above
• Colchicine or a short course of oral corticosteroids - considered for severe or persistent disease once infection, particularly tuberculosis, has been excluded, since corticosteroids can worsen an unrecognised infective cause

Complications

• Chronic or recurrent erythema nodosum - a minority of patients, particularly with an ongoing underlying cause such as inflammatory bowel disease, have repeated episodes
• Progression of the underlying disease if the trigger is not identified and treated - the rash itself resolves regardless, so failing to investigate risks missing a condition such as tuberculosis or inflammatory bowel disease that needs its own treatment
• Persistent joint symptoms - arthralgia can occasionally outlast the skin lesions by weeks
• Post-inflammatory bruising/pigmentation at the site of resolved nodules, though true scarring does not occur

Red flags

Prognosis

Erythema nodosum itself is a self-limiting condition, with individual lesions resolving over 2-6 weeks without scarring, even without specific treatment for the rash. The long-term outlook is determined entirely by the underlying cause: idiopathic disease and streptococcal-associated disease in children generally have an excellent prognosis with no recurrence, while erythema nodosum associated with inflammatory bowel disease often recurs in parallel with flares of the underlying condition.⁶

Lofgren syndrome, despite its dramatic radiological appearance, resolves spontaneously in the great majority of patients within 6-24 months and rarely progresses to chronic sarcoidosis, which is worth explaining clearly to patients who understandably find a chest X-ray showing lymphadenopathy alarming.⁷