Dermatology · PANCE / PANRE

Erythema Nodosum

Septal panniculitis presenting as tender erythematous nodules on the anterior shins.

Also known as: EN, septal panniculitis, erythema contusiforme

Overview

Acute, self-limited septal panniculitis characterized by symmetric, tender, erythematous, ill-defined subcutaneous nodules typically on the anterior shins. It represents a hypersensitivity reaction to a wide range of antigenic triggers rather than a primary skin disease.

Epidemiology

Most common form of panniculitis. Peak incidence 20-40 years; female predominance 3-5:1. Up to 50% of cases are idiopathic. Geographic variation reflects underlying infectious triggers (e.g., coccidioidomycosis in the southwestern US, tuberculosis worldwide).

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Question 1DermatologyMedium
A 29-year-old woman presents with a 10-day history of painful, tender, erythematous nodules over both anterior shins. She reports low-grade fever, malaise, and bilateral ankle pain. She takes no medications and is not pregnant. On exam she has several 2-4 cm poorly demarcated, deep, non-ulcerated tender nodules on both shins and mild ankle effusions. ESR and CRP are markedly elevated. A throat culture and ASO titer are pending. Which of the following is the most appropriate next diagnostic test?
  • APosteroanterior chest radiograph
  • BPunch biopsy of a shin lesion
  • CSerum antinuclear antibody panel
  • DLower-extremity venous ultrasound
Reveal answer & full explanation
Correct answer: A — Posteroanterior chest radiograph
  • APosteroanterior chest radiograph
  • BPunch biopsy of a shin lesion
  • CSerum antinuclear antibody panel
  • DLower-extremity venous ultrasound

Why Posteroanterior chest radiograph is correct

  • Bilateral tender shin nodules plus fever and ankle arthritis in a young woman are classic for erythema nodosum, and this triad raises strong suspicion for Löfgren syndrome (EN + bilateral hilar lymphadenopathy + ankle arthritis/fever), an acute form of sarcoidosis.
  • A chest radiograph is the essential next study in every patient with EN: it screens for the bilateral hilar adenopathy of sarcoidosis as well as pulmonary tuberculosis and endemic fungal disease (coccidioidomycosis, histoplasmosis), the other major systemic triggers.
  • Löfgren syndrome carries an excellent prognosis and usually resolves spontaneously, so identifying it on imaging changes counseling and management.

Why the others are wrong

  • Lower-extremity venous ultrasound is appropriate for suspected DVT or superficial thrombophlebitis, which produce a unilateral linear cord along a vein, not bilateral symmetric shin nodules, and would not explain the systemic findings.
  • Punch biopsy of a shin lesion is unhelpful because EN is a clinical diagnosis when classic nodules accompany a recognized trigger, and punch specimens are typically too shallow to capture the subcutaneous septal panniculitis; a deep incisional biopsy is reserved for atypical cases.
  • Serum antinuclear antibody panel is used to evaluate suspected lupus (including lupus panniculitis), but this presentation lacks lupus features, making it a low-yield, non-discriminating test and not the appropriate first step.
Question 2DermatologyMedium
A 28-year-old woman develops a sudden eruption of tender, warm, poorly demarcated erythematous nodules on both anterior shins two weeks after a sore throat. She also reports low-grade fever and aching ankles. The nodules are 2-4 cm, do not ulcerate, and are evolving through bruise-like color changes. A deep incisional biopsy shows widened, neutrophil-infiltrated connective tissue septa of the subcutaneous fat with relatively spared fat lobules and no vasculitis. Which of the following best explains the findings?
  • AIgE-mediated mast cell degranulation in the superficial dermal layers
  • BDirect bacterial invasion and proliferation throughout the dermis
  • CAutoantibodies targeting epidermal desmoglein adhesion molecules
  • DDelayed (type IV) hypersensitivity reaction within the fat septa
Reveal answer & full explanation
Correct answer: D — Delayed (type IV) hypersensitivity reaction within the fat septa
  • AIgE-mediated mast cell degranulation in the superficial dermal layers
  • BDirect bacterial invasion and proliferation throughout the dermis
  • CAutoantibodies targeting epidermal desmoglein adhesion molecules
  • DDelayed (type IV) hypersensitivity reaction within the fat septa

Why Delayed (type IV) hypersensitivity reaction within the fat septa is correct

  • Erythema nodosum is a delayed (type IV) hypersensitivity reaction to circulating antigens (here, streptococcal) that drives neutrophilic inflammation within the connective tissue septa of subcutaneous fat.
  • The septa widen and become infiltrated while the fat lobules are relatively spared, producing the defining histology of a septal panniculitis without vasculitis; Miescher radial granulomas are characteristic.
  • The clinical picture (tender, non-ulcerating bilateral shin nodules in a young woman after pharyngitis, with fever and arthralgias) fits the classic post-streptococcal trigger.

Why the others are wrong

  • IgE-mediated mast cell degranulation in the superficial dermal layers — the type I hypersensitivity mechanism of urticaria and anaphylaxis, producing transient wheals rather than deep tender subcutaneous nodules with septal panniculitis.
  • Autoantibodies targeting epidermal desmoglein adhesion molecules — cause pemphigus vulgaris, producing intraepidermal acantholysis and flaccid blisters, not a panniculitis.
  • Direct bacterial invasion and proliferation throughout the dermis — describes cellulitis, which is unilateral, warm, expanding erythema without nodularity; erythema nodosum is a reactive immunologic process, not a skin infection, and the biopsy here shows no organisms.
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Risk factors

  • Infections: streptococcal pharyngitis (most common identifiable cause in children and adults), tuberculosis, coccidioidomycosis, histoplasmosis, Yersinia, Salmonella, Mycoplasma, HIV, hepatitis B/C, EBV
  • Sarcoidosis (Löfgren syndrome triad: EN, bilateral hilar lymphadenopathy, arthralgias/fever)
  • Inflammatory bowel disease (Crohn > ulcerative colitis)
  • Drugs: oral contraceptives, sulfonamides, penicillins, bromides, iodides
  • Pregnancy
  • Behçet disease, lymphoma/leukemia (rarely)

Pathophysiology

A delayed-type hypersensitivity reaction to circulating antigens leads to immune complex deposition and neutrophilic inflammation within the connective tissue septa of subcutaneous fat. The septa widen and become infiltrated, while fat lobules remain relatively spared — the defining feature of septal panniculitis. Miescher radial granulomas (small histiocytic aggregates around central clefts) are characteristic on biopsy.

Clinical presentation

Symptoms

  • Sudden eruption of painful, tender, warm, erythematous nodules — typically over 1-2 weeks
  • Symmetric distribution on anterior shins, occasionally extending to thighs, forearms, or trunk
  • Prodromal or accompanying constitutional symptoms: low-grade fever, malaise, arthralgias
  • Lesions evolve through bruise-like color changes ('erythema contusiforme') over weeks and resolve without scarring

Signs / physical exam

  • 1-5 cm poorly demarcated, deep, tender erythematous nodules
  • No ulceration (an important negative)
  • Joint tenderness or effusion (especially ankles) — common with Löfgren syndrome
  • Lymphadenopathy or hepatosplenomegaly if infectious or sarcoid trigger

Classic findings

Tender bilateral shin nodules in a young woman after streptococcal pharyngitis or sarcoidosis.

Differential diagnosis

  • Erythema induratum (nodular vasculitis) — Lobular panniculitis with vasculitis; tender nodules on posterior calves; often ulcerate; classically tuberculin-associated
  • Cellulitis — Unilateral, warm, expanding erythema with systemic signs; not nodular; responds to antibiotics
  • Thrombophlebitis — Linear cord along a vein, palpable thrombosed vessel, often after IV access; Doppler diagnostic
  • Cutaneous polyarteritis nodosa — Painful subcutaneous nodules with livedo reticularis on lower extremities; medium-vessel vasculitis on biopsy
  • Subcutaneous fat necrosis (post-trauma) — Localized nodules at site of trauma; lobular panniculitis with foamy macrophages
  • Lupus panniculitis — Indurated plaques, often on proximal limbs or face; lobular panniculitis with lymphocytic infiltrate

Diagnostic workup

Diagnostic criteria

Diagnosis is clinical when classic tender shin nodules accompany a recognized trigger. Deep incisional or excisional biopsy (punch biopsies often inadequate) showing septal panniculitis without vasculitis confirms the diagnosis when atypical features are present.

Labs

  • CBC, ESR, CRP (often markedly elevated)
  • ASO titer and throat culture for group A streptococcus
  • PPD or interferon-gamma release assay (IGRA) for tuberculosis
  • Hepatitis B and C, HIV serology
  • Stool studies for Yersinia / Salmonella in patients with GI symptoms
  • Pregnancy test in reproductive-age women
  • Medication review for hormonal contraceptives, sulfas, etc.

Imaging

  • Chest x-ray — essential to screen for sarcoidosis (bilateral hilar adenopathy of Löfgren syndrome) and pulmonary tuberculosis or coccidioidomycosis
  • Further imaging (chest CT, abdominal imaging) driven by clinical findings

Diagnostic algorithm

Trigger CategoryExamplesClue / Screen
InfectionGroup A strep, TB, coccidioides, Yersinia, EBV, HIVThroat culture, ASO, PPD/IGRA, geography-guided serologies
Sarcoidosis (Löfgren)EN + hilar adenopathy + ankle arthritisChest x-ray, ACE level, serum calcium
IBDCrohn disease > UCGI symptoms, CRP/fecal calprotectin, colonoscopy
DrugsOCPs, sulfonamides, penicillins, bromides, iodidesTemporal medication review
PregnancyOften resolves postpartumβ-hCG
MalignancyLymphoma, leukemia (rare)CBC with smear; further workup if atypical
Idiopathic~50% of casesDiagnosis of exclusion
Common triggers of erythema nodosum and their initial screening tests.

Treatment

First-line

  • Identify and treat the underlying trigger (e.g., antibiotics for streptococcal infection, treatment of TB or sarcoidosis, stopping offending drug)
  • NSAIDs (naproxen, ibuprofen, indomethacin) for pain and inflammation — mainstay of symptomatic therapy
  • Bed rest, leg elevation, compression stockings
  • Avoid potential triggers (e.g., switch hormonal contraception if temporally associated)

Second-line / adjunct

  • Potassium iodide (SSKI) 300-900 mg/day for persistent or severe disease — avoid in pregnancy and thyroid disease
  • Colchicine 0.6 mg twice daily, particularly for Behçet-associated EN
  • Systemic corticosteroids (prednisone) for severe, debilitating, or recurrent disease only after excluding infection
  • Hydroxychloroquine, dapsone, or TNF inhibitors for chronic/recurrent idiopathic EN refractory to other therapy

Complications

  • Recurrence in 5-15% of patients
  • Chronic dull post-inflammatory hyperpigmentation
  • Rarely, persistence beyond 6 months ('chronic EN' or EN migrans) requires re-evaluation for occult disease
  • Complications of the underlying condition (TB, sarcoidosis, IBD) drive prognosis more than the panniculitis itself

PANCE pearls

  • Always obtain a chest x-ray — sarcoidosis (especially Löfgren syndrome: EN + bilateral hilar adenopathy + ankle arthritis + fever) carries an excellent prognosis and resolves spontaneously.
  • Streptococcal infection is the most common identifiable trigger in many populations; check ASO titer.
  • Lesions never ulcerate — ulceration should prompt reconsideration of the diagnosis (erythema induratum, vasculitis, infection).
  • Punch biopsies often miss the panniculus; deep incisional biopsy through fat is needed if histology is required.
  • Septal panniculitis without vasculitis is the histologic signature; lobular panniculitis points to other diagnoses.
  • Symptomatic therapy with NSAIDs and rest is sufficient for most patients; lesions resolve over 3-8 weeks without scarring.

References

  • BAD/AAD reviews — Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease (Am Fam Physician 2007; updated reviews)
  • Löfgren original description — Löfgren S. Primary pulmonary sarcoidosis: clinical course and prognosis (Acta Med Scand 1953)
  • Mert et al. — Erythema nodosum: an evaluation of 100 cases (Clin Exp Rheumatol 2007)

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