Erythema Nodosum

Erythema nodosum is an immune-mediated panniculitis (inflammation of

the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity
reaction. It commonly manifests in young women as tender, erythematous
nodules on the shins. The underlying etiology varies and may be
associated with infection, drug exposure, inflammatory bowel disease,
pregnancy, or malignancy. The lesions often self-resolve within 8 weeks
without scarring. Management focuses on identifying and treating the
underlying cause.

Last updated: May 17, 2024

CONTENTS

Epidemiology and Etiology

Pathophysiology
Clinical Presentation
Diagnosis and Management
Differential Diagnosis
Clinical Relevance

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 Epidemiology and Etiology
Epidemiology:
Erythema nodosum (EN) is most common in women in their 2nd–4th
decades.
Women are affected 3–6 times more often than men.
All ages and racial groups can be affected.
Most common form of panniculitis (inflammation of subcutaneous fat)

Etiology:
Half of cases have an unknown etiology.
Infection is the most commonly identified cause, especially
streptococcal infection, but other bacteria, as well as fungi and
viruses, are known etiologic agents, including
coronavirus disease 2019 (COVID-19) (rare).
Drugs: oral contraceptives, penicillin, sulfonamides, others
Inflammatory bowel disease
Malignancy: hematologic malignancies and carcinoma
Miscellaneous: pregnancy, sarcoidosis, others

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 Classification Etiologies Examples

Infectious Bacterial Streptococcal infections (most

causes common), especially pharyngitis
Tuberculosis
Mycoplasma pneumonia

Viral Infectious mononucleosis

Hepatitis B virus

Fungal Coccidiomycosis
Histoplasmosis
Blastomycosis

Noninfectious Drugs Penicillins

causes Sulfonamide
Oral contraceptive pills

Malignancy Leukemia
Lymphoma
Solid malignancies

Inflammatory Ulcerative colitis

bowel Crohn’s disease
disease

Miscellaneous Sarcoidosis: Lofgren's syndrome

Pregnancy
Behcet's disease

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 Pathophysiology
An immune-mediated reaction to various antigens results in
subcutaneous fat inflammation.
Type IV hypersensitivity reaction (delayed-type hypersensitivity) to
various antigens is considered to be the main immunologic
mechanism, but other pathways may be involved, including immune
complex deposition in subcutaneous fat.
Causes erythematous, tender nodules, typically on the shins, but
other areas may be involved
Histology shows septal panniculitis without primary vasculitis, a
mixed inflammatory infiltrate including eosinophils, Meischer's
"radial" granulomas in the early stages (such as histiocyte
aggregates surrounding extracellular clefts with neutrophils at the
periphery), and multinucleated giant cells in the later stages.
Secondary vasculitis may be seen if there are dense neutrophil
infiltrates.

Clinical Presentation

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 Prodromal symptoms may precede the eruption of skin lesions and
include:
Fatigue
Fever
Malaise
Arthralgia/arthritis
Characteristic skin lesions:
Erythematous, tender nodules on both shins
Nonulcerated
Immobile
Slightly raised
Typically 2–5 cm
Develop over several days
Usually self-resolve without scarring within 8 weeks of
presentation
Bruising or residual hyperpigmentation may occur during
resolution.
Less common sites of nodules:
Ankles
Thighs
Buttocks
Calves
Face

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 Diagnosis and Management
Diagnosis
Erythema nodosum is usually diagnosed clinically by history and
physical examination.
An acute onset of tender nonulcerated nodules or plaques on
both shins is typical.
Skin biopsy should be reserved for confirming the diagnosis if
there are atypical lesions or the patient is immunosuppressed.
Patients should be evaluated for underlying disease.
Thorough history and physical examination should include:
Medication history
Travel history
Review of respiratory, gastrointestinal, and
constitutional symptoms
Examination of the throat and tonsils (to rule out
streptococcal infection)
Laboratory workup may include:
CBC
Erythrocyte sedimentation rate (ESR) and/or C-reactive
protein (CRP)
Throat culture and antistreptolysin-O (ASO) titers
Tuberculin skin test/interferon-gamma release assay
Pregnancy test
Imaging may include chest radiographs.

Management

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 Erythema nodosum is self-limiting and usually resolves within 8
weeks.
Symptomatic treatment includes:
Rest and leg elevation
Venous compression by stocking (if tolerated)
Analgesics, such as nonsteroidal anti-inflammatory drugs
(NSAIDs)
Potassium iodide (inhibits neutrophil chemotaxis and
generation of reactive oxygen species)
If infectious causes can be ruled out, systemic
glucocorticoid therapy (prednisone 20 mg/day for 7–10
days) can improve both pain and the appearance of
erythema nodosum.
The underlying causes should also be identified and treated.

Differential Diagnosis

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 Nodular vasculitis: a lobular panniculitis frequently associated with
tuberculosis. Often occurs on the posterior calves with ulcerated,
draining nodules. Patients would be expected to have a positive
tuberculin skin test.
Subcutaneous infections: may be due to a bacterial, fungal, or
mycobacterial infection. Often occurs on the legs/feet with fluctuant,
ulcerated, draining lesions. Patients would be expected to have
systemic signs of infection.
Cutaneous polyarteritis nodosa: characterized by painful
subcutaneous nodules on the legs. However, these nodules are also
associated with livedo racemosa, necrosis, and ulcerations.
Histology shows segmental necrotizing medium artery vasculitis.
Pancreatic panniculitis: These nodules differ in that they are
fluctuant and ulcerative with oily fluid drainage. They often heal with
scarring. Patients would be expected to have symptoms of
pancreatitis including fever and abdominal pain. Laboratory results
would reveal elevated lipase and amylase.
Alpha-1 antitrypsin deficiency: This genetic defect may be
associated with subcutaneous nodules or plaques that frequently
ulcerate and drain.

Clinical Relevance
EN can offer clues to the presence of a serious underlying
treatable disease, such as streptococcal infection, sarcoidosis,
tuberculosis, and coccidioidomycosis.
EN may have prognostic value in a few situations because it is
associated with the following:
A lower incidence of disseminated disease in
coccidioidomycosis
A less aggressive form of sarcoidosis (Lofgren syndrome triad
of EN, hilar lymphadenopathy, and acute arthritis/periarthritis)
EN may precede or be coincident with an acute flare of
inflammatory bowel disease

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