Erythema Nodosum – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

  • A delayed-type hypersensitivity reaction to infectious agents, medications, or malignancies, or in the setting of autoimmune disorders, presenting as a subcutaneous panniculitis
  • Clinical pattern of multiple, bilateral, erythematous, tender subcutaneous nodules that undergo a characteristic pattern of color changes, similar to that seen in bruises. Unlike erythema induratum, the lesions of erythema nodosum do not typically ulcerate.
  • Occurs most commonly on the shins, less commonly on the thighs and forearms
  • May be accompanied by fever and arthralgias
  • Often idiopathic but may be associated with a number of clinical entities
  • Usually remits spontaneously in weeks to months without scarring or atrophy
  • Synonym(s): Dermatitis contusiformis

Pregnancy Considerations

May have repeat outbreaks during pregnancy

Epidemiology

Incidence

  • 1-5/100,000
  • Predominant age: 20–30 years
  • Predominant sex: Female > Male (3:1).

Prevalence

Varies geographically depending on the prevalence of disorders associated with erythema nodosum

Risk Factors

See “Etiology.”

Etiology

  • Idiopathic: 37–60%
  • Bacterial: Streptococcal infections (most common cause in children), tuberculosis, leprosy, tularemia, gonorrhea, Yersinia enterocolitica,CampylobacterSalmonellaShigella
  • Sarcoid
  • Drugs: Sulfonamides, amoxicillin, oral contraceptives, bromides
  • Pregnancy
  • Fungal: Dermatophytes, coccidioidomycosis, histoplasmosis, blastomycosis
  • Viral/chlamydial: Infectious mononucleosis, lymphogranuloma venereum, paravaccinia
  • Enteropathies: Ulcerative colitis, Crohn disease, Behçet disease (1), celiac disease (2)
  • Malignancies: Lymphoma/leukemia, sarcoma, after radiation therapy

Commonly Associated Conditions

See “Etiology.”

Erythema nodosum, Non-steroidal anti-inflammatory drug, Nodular vasculitis, Salmonella, Cutaneous conditions, erythema nodosum, infectious mononucleosis, erythema induratum, oral contraceptives, streptococcal infections, coccidioidomycosis,

Diagnosis

History

  • Increasingly tender and aching nodules on the legs, usually over the shins.
  • Fever, malaise, chills, fatigue
  • Eruptions often preceded by symptoms of pharyngitis or upper respiratory infection
  • Headache
  • Arthralgias

Physical Exam

  • Initially warm, tender, brightly erythematous nodules, which may be raised, on anterior shins; lesions become bluish and fluctuant, gradually fading to yellowish, resembling a bruise.
  • May occur on any area with subcutaneous fat
  • Diameter usually 2–6 cm, but may rarely be larger

Diagnostic Tests & Interpretation

Diagnosis is usually clinical.

Lab

  • Erythrocyte sedimentation rate (ESR). May be elevated or normal.
  • Complete blood count (CBC): Mild leukocytosis
  • Antistreptolysin titers may be elevated.
  • Throat culture (usually negative because the infection typically resolves before lesions appear)
  • Stool culture and leukocytes, if indicated
  • Skin testing for mycobacteria, if indicated
  • Drugs that may alter lab results: Antecedent antibiotics may affect cultures.

Imaging

CXR for hilar adenopathy or infiltrates related to sarcoidosis or tuberculosis

Diagnostic Procedures/Surgery

Deep incisional skin biopsy including subcutaneous fat; rarely necessary except in atypical cases with ulceration, duration greater than 12 weeks or a presentation that does not include skin lesions.

Pathological Findings

  • Septal panniculitis without vasculitis.
  • Neutrophilic infiltrate in septa of fat tissue early in course.
  • Actinic radial (Miescher’s) granulomas, consisting of collections of histocytes around a central stellate cleft, may be seen (3).
  • Fibrosis, paraseptal granulation tissue, lymphocytes, and multinucleated giant cells predominate late in course.

Differential Diagnosis

  • Nodular vasculitis or erythema induratum (warm ulcerating calf nodules)
  • Superficial thrombophlebitis
  • Cellulitis
  • Septic emboli
  • Weber-Christian disease (violaceous, scarring nodules)
  • Lupus panniculitis
  • Cutaneous polyarteritis nodosa
  • Sarcoidal granulomas
  • Cutaneous T-cell lymphoma
  • Erythema nodosum leprosum (clinically similar to EN but shows vasculitis on histopathology)
  • Vasculitis

Treatment

All medications listed as treatment for erythema nodosum are off-label uses of the medications. There are no FDA-approved medications for erythema nodosum.

Medication

First Line

  • Medication usually more effective in acute than in chronic disease
  • Condition often self-limited
  • Nonsteroidal anti-inflammatory drugs (NSAIDs):
    • Ibuprofen: 400 mg po q4–6 hours (not to exceed 3200 mg per day)
    • Indomethacin: 25–50 mg po t.i.d.
    • Naproxen (Naprosyn): 250–500 mg po b.i.d.
  • Aspirin: 325 mg 1–2 tablets po q4–6 hours (not to exceed 12 tablets a day); use enteric-coated tablets to decrease GI upset.
  • Contraindications:
    • Active or recent peptic ulcer disease
    • History of hypersensitivity to NSAIDs
  • Precautions:
    • GI upset/bleeding
    • Fluid retention
    • Dose reduction in elderly, especially those with renal disease, diabetes, or heart failure
    • May mask fever
    • NSAIDs may elevate liver function tests.
  • Significant possible interactions:
    • May blunt antihypertensive effects of diuretics and β-blockers
    • NSAIDs can elevate plasma lithium levels.
    • Caution is advised with naproxen or any highly protein-bound drug because it may compete for albumin binding and elevate levels.
  • NSAIDs can cause significant elevation and prolongation of methotrexate levels.

Second Line

  • Potassium iodide 400–900 mg/d divided 2–3×/day × 3–4 weeks (for persistent lesions). Need to monitor for hypothyroidism with prolonged use. Pregnancy Class D.
  • Corticosteroids for severe, refractory cases in which an infectious workup is negative. Prednisone 1mg/kg/d for 1–2 weeks often helps resolve the lesions (4). Potential side effects include hyperglycemia, hypertension, weight gain, mood changes, bone loss, osteonecrosis, myopathy.
  • Recent reports of improvement with colchicine 0.6–1.2 mg b.i.d.
  • Hydroxychloroquine, thalidomide and cyclosporine may also be used.

Additional Treatment

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General Measures

  • Mild compression bandages and leg elevation may reduce pain. (Wet dressings, hot soaks, and topical medications are not useful.)
  • Discontinue potentially causative drugs.
  • Treat underlying disease.

Complementary and Alternative Medicine

Vitamin B12 replacement. A single case report of resolution of lesions with B12 replacement in a patient who had B12 deficiency and erythema nodosum (5).

In-Patient Considerations

Admission Criteria

Occasionally, admission may be needed for the antecedent illness (e.g., tuberculosis).

Ongoing Care

Follow-Up Recommendations

  • Keep legs elevated.
  • Elastic wraps or support stockings may be helpful when patients are ambulating.

Patient Monitoring

Monthly follow-up or as dictated by underlying disorder

Diet

No restrictions

Patient Education

  • Lesions will resolve over a few weeks to months.
  • No scarring is anticipated.
  • Joint aches and pains may persist.
  • <20% recur.

Prognosis

  • Individual lesions resolve generally within 2 weeks.
  • Total time course of 6–12 weeks but may vary with underlying disease.
  • Joint aches and pains may persist for years.
  • Lesions do not scar.
  • Recurrences in 12–14% of patients: Occurs over variable periods, averaging several years; seen most often in sarcoid, streptococcal infection, pregnancy, and oral contraceptive use

Complications

  • Vary according to underlying disease
  • None expected from lesions of erythema nodosum

References

1. Psychos DN, Voulgari PV, Skopouli FN, et al. Erythema nodosum: the underlying conditions. Clin Rheumatol. 2000;19:212–6.

2. Bartyik K, Várkonyi A, Kirschner A, et al. Erythema nodosum in association with celiac disease. Pediatr Dermatol. 2004;21:227–30.

3. Schwartz RA, Nervi SJ et al. Erythema nodosum: a sign of systemic disease.Am Fam Physician. 2007;75:695–700.

4. Requena L, Yus ES et al. Erythema nodosum. Dermatol Clin. 2008;26:425–38, v

5. Volkov I, et al. Successful treatment of chronic erythema nodosum with vitamin B12. J Am Board Fam Pract. 2005;18:6.

Additional Reading

González-Gay MA, García-Porrúa C, Pujol RM, et al. Erythema nodosum: a clinical approach. Clin Exp Rheumatol. 2001;19:365–8.

Habif T. Clinical Dermatology, 4th ed. St. Louis, MO: CV Mosby, 2004.

Requena L, et al. Erythema nodosum. Dermatol Online J. 2002;8:4.

Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York: McGraw-Hill Professional, 2007.

Codes

ICD9

695.2 Erythema nodosum

Snomed

32861005 erythema nodosum (disorder)

Clinical Pearls

  • Lesions of erythema nodosum appear to be erythematous patches, but when palpated, their underlying nodularity is appreciated.
  • Erythema nodosum in the setting of hilar adenopathy may be seen with multiple etiologies and does not exclusively indicate sarcoidosis.
  • In patients with a history of Hodgkin lymphoma, erythema nodosum may be a warning of impending recurrence.

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