para>May have repeat outbreaks during pregnancy
Pediatric Considerations
Rare pediatric variant has lesions only on palms or soles, often unilateral. Typically has a shorter duration in children than adults.
EPIDEMIOLOGY
Incidence
- 1 to 5/100,000/year
- Predominant age: 20 to 30 years
- Predominant sex: female > male (6:1) in adults
Prevalence
Varies geographically depending on the prevalence of disorders associated with EN
ETIOLOGY AND PATHOPHYSIOLOGY
- Idiopathic: up to 55%
- Infectious: 44%. Streptococcal pharyngitis (most common), mycobacteria, mycoplasma, chlamydia, mycoplasma, coccidiodomycosis, rarely can be caused by Campylobacter spp., ricketssiae, Salmonella spp., psittacosis, syphilis
- Sarcoidosis: 11-25%
- Drugs: 3-10%. sulfonamides amoxicillin, oral contraceptives, bromides, azathioprine, vemurafenib
- Pregnancy: 2-5%,
- Enteropathies: 1-4%. Ulcerative colitis, Crohn disease, Beh §et disease, celiac disease, diverticulitis
- Rare causes: <1% (1)
- Fungal: dermatophytes, coccidioidomycosis, histoplasmosis, blastomycosis
- Viral/chlamydial: infectious mononucleosis, lymphogranuloma venereum, paravaccinia, HIV
- Malignancies: lymphoma/leukemia, sarcoma, myelodysplastic syndrome
- Sweet syndrome
RISK FACTORS
See "Etiology and Pathophysiology."
COMMONLY ASSOCIATED CONDITIONS
See "Etiology and Pathophysiology."
DIAGNOSIS
HISTORY
- Often a prodrome 1 to 3 weeks prior to onset of lesions; can consist of malaise, fever, weight loss, cough, and arthralgia
- Increasingly tender nodules on the legs, usually over the shins
- Fever, malaise, chills, fatigue
- Headache
- Can precede systemic process by weeks
PHYSICAL EXAM
- Lesions initially present as warm, tender, erythematous firm nodules and become fluctuant, gradually fading to resemble a bruise over 1 to 2 months (erythema contusiformis).
- Typically pretibial, although can extend proximally to involve thighs or trunk (atypically can involve extensor surface of forearms)
- Diameter varies from 1 to 10 cm with poor demarcation.
DIFFERENTIAL DIAGNOSIS
- Nodular vasculitis or erythema induratum (warm ulcerating calf nodules)
- Superficial thrombophlebitis
- Cellulitis
- Weber-Christian disease (violaceous, scarring nodules)
- Lupus panniculitis
- Cutaneous polyarteritis nodosa
- Sarcoidal granulomas
- Cutaneous T-cell lymphoma
- EN leprosum (clinically similar to EN but shows vasculitis on histopathology)
- Subcutaneous infection (including staphylococcus, Sporothrix schenckii, Nocardia brasiliensis, Mycobacterium marinum, Leishmania braziliensis)
DIAGNOSTIC TESTS & INTERPRETATION
Diagnosis is made clinically, with support of testing
- ESR or C-reactive protein (CRP): often elevated, but can be normal in up to 40% (2)[C]
- CBC: mild leukocytosis (2)[C]
- Urine pregnancy test (2)[C]
- Throat culture, antistreptolysin O titer (2)[C]
- Blood and/or stool culture, stool ova and parasites (O&P)
- Tuberculin skin testing (2)[C]
- Seronegative rheumatoid factor
Initial Tests (lab, imaging)
CXR for hilar adenopathy or infiltrates related to sarcoidosis or tuberculosis (2)[C]
Diagnostic Procedures/Other
Deep-incisional or excisional skin biopsy including subcutaneous tissue; rarely necessary except in atypical cases with ulceration, duration >12 weeks, or absence of nodules overlying lower limbs (3)[C]
Test Interpretation
- Septal panniculitis without vasculitis
- Neutrophilic infiltrate in septa of fat tissue early in course
- Actinic radial (Miescher) granulomas, consisting of collections of histocytes around a central stellate cleft, may be seen.
- Fibrosis, paraseptal granulation tissue, lymphocytes, and multinucleated giant cells predominate late in course (4)
TREATMENT
- Condition usually self-limited within 1 to 2 months
- All medications listed as treatment for EN are off-label uses of the medications. There are no specific FDA-approved medications.
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.
- Indication for treatment is poorly defined in literature; hence, therapy specifically for EN is directed towards symptom management.
MEDICATION
First Line
- NSAIDs:
- Ibuprofen 400 mg PO q4-6h (not to exceed 3,200 mg/day)
- Indomethacin 25 to 50 mg PO TID
- Naproxen 250 to 500 mg PO BID
- Precautions
- GI upset/bleeding (avoid in Crohn or ulcerative colitis)
- Fluid retention
- Renal insufficiency
- Dose reduction in elderly, especially those with renal disease, diabetes, or heart failure
- May mask fever
- NSAIDs can increase cardiovascular (CV) risk.
- Significant possible interactions
- May blunt antihypertensive effects of diuretics and β-blockers
- NSAIDs can elevate plasma lithium levels.
- NSAIDs can cause significant elevation and prolongation of methotrexate levels.
Second Line
- Potassium iodide 400 to 900 mg/day divided BID or TID 3 to 4 weeks (for persistent lesions); need to monitor for hyperthyroidism with prolonged use; pregnancy class D (5)[B]
- Corticosteroids for severe, refractory, or recurrent cases in which an infectious workup is negative. Prednisone 1 mg/kg/day for 1 to 2 weeks is the recommended dose/duration. Potential side effects include hyperglycemia, hypertension, weight gain, worsening gastroesophageal reflux disease, mood changes, bone loss, osteonecrosis, and proximal myopathy (1)
- For EN related to Beh §et disease, one can also consider colchicine 0.6 to 1.2 mg BID. Potential side effects include GI upset and diarrhea (6)[B].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
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
- Scarring is unlikely.
- Joint aches and pains may persist.
- <20% recur
PROGNOSIS
- Individual lesions resolve generally within 2 weeks.
- Total time course of 6 to 12 weeks but may vary with underlying disease.
- Joint aches and pains may persist for years.
- Lesions do not scar.
- Recurrences: occurs over variable periods, averaging several years; seen most often in sarcoid, streptococcal infection, pregnancy, and oral contraceptive use. If medication induced, avoid recurrent exposure.
COMPLICATIONS
- Vary according to underlying disease
- None expected from lesions of EN
REFERENCES
11 Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician. 2007;75(5):695-700.22 Cribier B, Caille A, Heid E, et al. Erythema nodosum and associated diseases. A study of 129 cases. Int J Dermatol. 1998;37(9):667-672.33 Requena L, Yus ES. Erythema nodosum. Dermatol Clin. 2008;26(4):425-438.44 S ¡nchez Yus E, Sanz Vico MD, de Diego V. Miescher's radial granuloma. A characteristic marker of erythema nodosum. Am J Dermatopathol. 1989;11(5):434-442.55 Horio T, Imamura S, Danno K, et al. Potassium iodide in the treatment of erythema nodosum and nodular vasculitis. Arch Dermatol. 1981;117(1):29-31.66 Yurdakul S, Mat C, T ¼z ¼n Y, et al. A double-blind trial of colchicine in Beh §et's syndrome. Arthritis Rheum. 2001;44(11):2686-2692.
ADDITIONAL READING
- Bartyik K, V ¡rkonyi A, Kirschner A, et al. Erythema nodosum in association with celiac disease. Pediatr Dermatol. 2004;21(3):227-230.
- Chong TA, Hansra NK, Ruben BS, et al. Diverticulitis: an inciting factor in erythema nodosum. J Am Acad Dermatol. 2012;67(1):e60-e62.
- Harris T, Henderson MC. Concurrent Sweet's syndrome and erythema nodosum. J Gen Intern Med. 2011;26(2):214-215.
- Jeon HC, Choi M, Paik SH, et al. A case of assisted reproductive therapy-induced erythema nodosum. Ann Dermatol. 2011;23(3):362-364.
- Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician. 2007;75(5):695-700.
- Then C, Langer A, Adam C, et al. Erythema nodosum associated with myelodysplastic syndrome: a case report. Onkologie. 2011;34(3):126-128.
CODES
ICD10
- L52 Erythema nodosum
- A18.4 Tuberculosis of skin and subcutaneous tissue
ICD9
- 695.2 Erythema nodosum
- 017.10 Erythema nodosum with hypersensitivity reaction in tuberculosis, unspecified
SNOMED
- 32861005 Erythema nodosum (disorder)
- 74610006 Tuberculous erythema nodosum (disorder)
- 402969008 Erythema nodosum due to streptococcal infection (disorder)
- 240411003 Erythema nodosum leprosum (disorder)
- 297940005 Drug-induced erythema nodosum (disorder)
- 240360007 Yersinia erythema nodosum (disorder)
CLINICAL PEARLS
- Lesions of EN appear to be erythematous patches, but when palpated, their underlying nodularity is appreciated.
- Evaluation for a concerning underlying etiology is necessary in EN, but most cases are idiopathic.
- EN 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, EN may be an early sign of recurrence.