Erythema Nodosum: Causes, Images, Symptoms, and Treatment

What is Erythema Nodosum?

Erythema nodosum is an acute inflammatory condition that affects the deepest layer of the skin, known as the hypodermis (or the subcutis or subcutaneous layer). Because the hypodermis consists mainly of adipose tissue (fat), inflammation in this layer is called panniculitis. This term comes from panniculus adiposus, the fatty layer of the skin. Erythema nodosum is therefore the most common form of panniculitis.

Clinically, it presents as painful, red, raised nodular lesions most commonly located on the shins (anterior surface of the lower legs). The condition predominantly affects women between the ages of 25 and 40, though it can occur at any age and in both sexes.

Prognosis and Natural Course

The prognosis is generally good, though recurrences are frequent. Erythema nodosum often resolves spontaneously, especially when patients get adequate rest and symptomatic treatment. The typical natural history follows a predictable pattern:

• Each individual nodule evolves and regresses over approximately 10 days
• As one nodule resolves, new ones may appear in successive “crops”.
• Complete resolution of an episode typically occurs within 6 to 8 weeks
• The nodules never ulcerate or rupture and do not leave scars

Important: When erythema nodosum is associated with an underlying streptococcal infection, complications affecting internal organs (such as post-streptococcal glomerulonephritis or rheumatic fever) may occasionally occur, underscoring the importance of identifying and treating the underlying cause.

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Causes

Erythema nodosum is not a primary skin disease but rather a reactive inflammatory response of the deep dermal and subcutaneous tissue to a variety of triggering conditions. It is considered a form of delayed-type hypersensitivity reaction, an immune response typically triggered 3–6 weeks after the initial stimulus.

Most Common Cause: Streptococcal Infection

Beta-hemolytic Streptococcus Group A (Streptococcus pyogenes) is the most frequently identified trigger, typically manifesting as streptococcal pharyngitis (sore throat) or tonsillitis. The skin lesions typically appear approximately 3 weeks after the initial throat infection, as part of an immune-mediated delayed reaction.

Other Infectious Causes

Other infectious agents, which are less common than streptococcus, that can trigger erythema nodosum include:

• Bacterial infections:

  • Tuberculosis (Mycobacterium tuberculosis): historically a major cause, it must always be excluded.
  • Yersiniosis (Yersinia enterocolitica or Yersinia pseudotuberculosis), particularly associated with abdominal pain
  • Cat scratch disease (Bartonella henselae).
  • Mycoplasma pneumoniae.
  • Chlamydophila pneumoniae.

• Viral infections:

  • Viral hepatitis (A, B, or C)
  • Infectious mononucleosis (Epstein-Barr virus)
  • HIV infection

Inflammatory and Systemic Diseases

Erythema nodosum can be the presenting sign or a manifestation of several systemic inflammatory conditions:

• Sarcoidosis: The combination of bilateral hilar lymphadenopathy on chest X-ray, erythema nodosum, and arthritis is known as Löfgren syndrome, an acute, generally self-limiting form of sarcoidosis with a good prognosis.
• Ulcerative colitis and Crohn’s disease: Erythema nodosum is the most common cutaneous manifestation of inflammatory bowel disease (IBD), occurring in 5–15% of patients, often correlating with disease activity.
• Behçet’s syndrome: A multisystem vasculitis in which erythema nodosum-like lesions are one of the diagnostic criteria.

Medications

Drug-induced erythema nodosum is an important and often overlooked cause:

• Oral contraceptives (estrogen-containing): Among the most common drug triggers; estrogenic stimulation is thought to play a role
• NSAIDs (non-steroidal anti-inflammatory drugs)
• Antibiotics: Including minocycline, penicillin, sulfonamides, and others
• Biologics and immunomodulatory agents: Increasingly recognized triggers in patients receiving these therapies for autoimmune conditions

Malignancies

In rare cases, erythema nodosum may be associated with underlying malignancy:

• Lymphomas
• Leukemias

Idiopathic Erythema Nodosum

Despite thorough investigation, 15 to 50% of cases remain without an identifiable cause and are classified as idiopathic erythema nodosum. This wide range reflects differences in the extent of workup performed across different centers.

Summary of Causes

Transmission and Contagiousness

Erythema nodosum itself is not contagious. It is a reactive immune phenomenon, not a directly transmissible infection. However, when it is caused by an underlying infection (e.g., streptococcal pharyngitis), that underlying infection may be contagious while it is in its active phase.

📋 Practical note: If a person has active streptococcal pharyngitis triggering erythema nodosum, standard respiratory hygiene precautions (hand washing, covering coughs) should be followed to prevent spread of the streptococcal infection. The skin lesions themselves pose no infection risk.

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Symptoms and Signs

Prodromal Phase (3–6 Days Before Skin Lesions)

The appearance of the characteristic skin lesions is typically preceded by a prodromal (pre-lesion) phase lasting 3 to 6 days, during which the patient experiences non-specific systemic symptoms:

• Fever often low to moderate grade
• Fatigue and malaise (asthenia)
• Joint pains (arthralgia) often affecting the ankles and knees
• Abdominal pain particularly when Yersinia is the underlying cause
• Sore throat suggesting streptococcal etiology

The Characteristic Skin Lesions

The hallmark of erythema nodosum is the appearance of multiple, painful, raised (or deep infiltrated) nodular lesions in the skin. These lesions have the following characteristics:

Morphology

• Nodular: raised above the surrounding skin surface or palpable as deep, firm infiltrations beneath it
• Hard consistency: distinctly indurated (firm) on palpation
• Shape: Round or oval
• Size: Typically 1–5 cm in diameter
• Surface: Smooth, warm, and shiny overlying skin

Color Evolution

The nodules undergo a characteristic color change over time, a clinically useful diagnostic feature:

This color evolution, identical to the resolution of a deep bruise or hematoma, is characteristic of erythema nodosum and reflects the breakdown of extravasated red blood cells in the deep dermis.

💡 Key distinguishing feature: The nodules of erythema nodosum never ulcerate, never rupture, and never leave scars, a characteristic that helps differentiate it from other panniculitides.

Distribution

• Predominantly on the anterior surface (shins) of both lower legs, the most classic and characteristic location
• Usually bilateral (both legs involved), though lesions may be asymmetric
• Less commonly on the thighs, forearms, or trunk
• Associated ankle edema (malleolar edema) is frequently present and contributes to the discomfort

Pain

• The nodules are markedly painful, both spontaneously and on palpation.
• Pain is significantly worsened by standing or walking (due to gravity-dependent blood pooling and increased pressure).
• Patients often seek relief by lying down with legs elevated, which reduces both pain and edema.

Clinical Course

• Individual nodules evolve and resolve within approximately 10 days.
• However, as existing lesions resolve, new ones may appear, occurring in successive crops over weeks.
• The total duration of an episode is typically 6 to 8 weeks.
• Recurrences are common, particularly when the underlying cause is not identified or treated.

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Diagnosis

Clinical Diagnosis

In most patients, the diagnosis of erythema nodosum is clinical, based on the characteristic appearance, distribution, and behavior of the skin lesions, combined with the typical patient profile and associated symptoms.

Key clinical features supporting the diagnosis:

• Bilateral, tender, erythematous nodules on the anterior shins
• Prodromal phase with fever, arthralgia, and malaise
• Age and sex of the patient (young to middle-aged woman)
• Color evolution mimicking a bruise
• No ulceration or scarring

Skin Biopsy

In atypical or diagnostically uncertain cases, a skin biopsy with histopathological examination provides definitive confirmation. The specimen must include a sufficient depth of subcutaneous tissue to visualize the hypodermis. Histologically, erythema nodosum shows a septal panniculitis without vasculitis: inflammation localized to the fibrous septa between fat lobules, without involvement of blood vessel walls.

Laboratory Investigation: Finding the Underlying Cause

Once the diagnosis is established clinically, investigation focuses on identifying the underlying trigger. Key tests include:

Inflammatory Markers

• Full blood count (CBC): Leukocytosis (elevated white blood cell count) indicates active inflammation or infection
• Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP): Invariably elevated in active erythema nodosum; useful for monitoring disease activity

Infection Screening

• Throat swab for culture: To detect Group A Streptococcus, the most common cause
• Anti-streptolysin O (ASO) titer: Elevated in recent streptococcal infection; more sensitive than culture for documenting recent infection
• Stool culture: To detect Yersinia enterocolitica, particularly relevant when abdominal pain is a prominent symptom
• Chest X-ray: Essential to detect bilateral hilar lymphadenopathy (suggesting sarcoidosis) or pulmonary infiltrates (suggesting tuberculosis)
• Tuberculin skin test (Mantoux) or IGRA test: To exclude tuberculosis, especially in high-risk patients or endemic regions

Additional Tests Based on Clinical Suspicion

• Serology for hepatitis A, B, C (if hepatic involvement suspected)
• EBV and CMV serology (if mononucleosis suspected)
• Angiotensin-converting enzyme (ACE) level (elevated in sarcoidosis)
• Anti-nuclear antibodies (ANA) and other autoimmune markers
• Pregnancy test in women of reproductive age, as pregnancy itself is a recognized trigger
• Inflammatory bowel disease workup (colonoscopy) if gastrointestinal symptoms are present

Differential Diagnosis

Several conditions can produce painful nodules or erythema of the lower legs and must be distinguished from erythema nodosum:

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Erythema Nodosum in Pregnancy

Pregnancy is a recognized predisposing condition for erythema nodosum. The current hypothesis is that it represents a hypersensitivity reaction to the markedly altered estrogen and progesterone levels that characterize pregnancy, rather than being directly caused by an infection in most cases.

Key points for management in pregnancy:

• The condition generally follows the same clinical course as non-pregnant patients

• Pharmacological treatment should be minimized during pregnancy due to risks to the fetus

• First-line management consists of:

  • Bed rest with legs elevated above heart level: the most effective non-pharmacological measure to reduce edema and pain
  • Compression bandaging of the lower legs (applied by a trained professional) to support venous and lymphatic return
  • Cold compresses applied to lesions for symptomatic relief

• If pharmacological treatment is unavoidable in severe cases, it should be carefully discussed with the treating physician and obstetrician, weighing risks and benefits on an individual basis

• NSAIDs should be avoided in the third trimester (risk of premature closure of the ductus arteriosus and prolonged labor)

• Corticosteroids should be used with great caution and only when strictly necessary

📋 Women who develop erythema nodosum during pregnancy should be reassured that the condition itself does not harm the fetus and typically resolves after delivery, though it may recur in subsequent pregnancies.

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Treatment

The management of erythema nodosum is based on two parallel approaches:

1. Treating the underlying cause (when identifiable)
2. Symptomatic relief to reduce pain and inflammation

Treatment of the Underlying Cause

Whenever a specific trigger is identified, targeted treatment is initiated:

• Streptococcal infection → full course of oral penicillin or amoxicillin (or macrolide if penicillin-allergic)
• Tuberculosis → standard anti-tuberculosis combination therapy
• Yersinia infection → antibiotics (doxycycline or fluoroquinolones) in moderate-to-severe cases
• Inflammatory bowel disease → optimization of IBD-specific therapy (often parallels activity of bowel disease)
• Drug-induced → discontinuation of the offending drug
• Oral contraceptive-induced → consider switching to a progestogen-only or non-hormonal contraceptive method

Symptomatic Treatment

Pending the identification of the specific cause, or in idiopathic cases, symptomatic management is the cornerstone:

Rest and Leg Elevation

• Bed rest with legs elevated above heart level is the single most effective symptomatic measure
• Reduces venous and lymphatic pressure on inflamed tissues, significantly decreasing edema and pain
• Patients should minimize standing and walking during the acute phase

Compression Bandaging

• Elastic compression bandages or stockings help reduce edema and provide mechanical support to inflamed tissues
• Should be applied by a trained professional to ensure appropriate pressure gradient

Analgesics and Anti-Inflammatory Drugs

• Paracetamol (acetaminophen): First-line analgesic; safe and effective for pain and fever management.
• NSAIDs (e.g., ibuprofen, naproxen, ketoprofen): More potent anti-inflammatory effect; can significantly reduce both pain and the inflammatory process. Use with caution in patients with gastrointestinal, renal, or cardiovascular risk factors.
• Potassium iodide (saturated solution): A traditional and effective treatment for erythema nodosum, particularly in recalcitrant cases; its mechanism of action in this condition is not fully understood. Available in some countries for this indication.

Corticosteroids

• Oral corticosteroids (e.g., prednisone) provide rapid and effective reduction of inflammation and pain.
• However, they must only be used after infectious causes have been definitively excluded, because corticosteroids suppress immune function and can cause dangerous worsening of an unrecognized infection, particularly tuberculosis.
• Reserved for severe, refractory, or idiopathic cases where infection has been ruled out.

Prevention of Recurrence

Given the tendency of erythema nodosum to recur, prevention strategies are important:

• Treat any identifiable predisposing condition consistently and thoroughly (e.g., optimize IBD management, maintain glycemic control in diabetics)
• Avoid known triggers where possible (e.g., review and change oral contraceptive if implicated)
• Screen for and treat streptococcal carriage in patients with recurrent episodes linked to throat infections
• In selected patients with frequently recurring episodes, long-term suppressive therapy (e.g., long-term NSAIDs, potassium iodide, hydroxychloroquine) may be considered under specialist supervision

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Sources and Bibliography

• Saurat J, Grosshans E, Laugier P, Lachapelle J. Dermatologia e malattie sessualmente trasmesse. Edizione italiana a cura di Girolomoni G. e Giannetti A. Terza edizione 2006. Masson.
• Fitzpatrick T, Johnson R, Wolff K. Atlante di dermatologia clinica. Edizione italiana a cura di Stefano Veraldi. Quarta edizione. McGraw-Hill.
• Acosta KA, Haver MC, Kelly B. “Etiology and therapeutic management of erythema nodosum during pregnancy: an update”. Am J Clin Dermatol. 2013;14(3):215–222. doi:10.1007/s40257-013-0024-x. PubMed
• Blake T, Manahan M, Rodins K. “Erythema nodosum – a review of an uncommon panniculitis”. Dermatol Online J. 2014;20(4):22376. PubMed
• Schwartz RA, Nervi SJ. “Erythema nodosum: a sign of systemic disease”. Am Fam Physician. 2007;75(5):695–700.
• Gilchrist H, Patterson JW. “Erythema nodosum and erythema induratum (nodular vasculitis): diagnosis and management”. Dermatol Ther. 2010;23(4):320–327. doi:10.1111/j.1529-8019.2010.01332.x
• Requena L, Yus ES. “Panniculitis. Part I. Mostly septal panniculitis”. J Am Acad Dermatol. 2001;45(2):163–183.