Erythema Nodosum: Clinical Presentation and Management

Clinical Features and Associated Symptoms

Fever, malaise, and extreme fatigue that may persist for weeks to months are common systemic symptoms in patients with erythema nodosum 1
Arthralgias affecting multiple joints, typically symmetrical, involving distal lower extremities without joint effusions, are associated with erythema nodosum 1
Drenching night sweats and weight loss in infectious etiologies, such as coccidioidomycosis, can occur in patients with erythema nodosum 1

Inflammatory bowel disease, such as ulcerative colitis and Crohn's disease, occurs in 4.2-7.5% of IBD patients and is associated with erythema nodosum 2
Behçet's disease, characterized by oral and genital ulcers, can manifest with erythema nodosum as a dominant lesion, and colchicine is preferred for treatment 3
Coccidioidomycosis, a fungal infection endemic in the southwestern United States, can cause erythema nodosum, and antifungal therapy is not recommended for this condition 1
Histoplasmosis, another fungal infection, can also cause erythema nodosum, and NSAIDs alone are sufficient for treatment 4

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the cornerstone of symptomatic treatment for pain and inflammation in erythema nodosum 4
Systemic corticosteroids are reserved for severe cases with significant inflammation or IBD-associated erythema nodosum, and should be used cautiously after excluding infectious causes 2
Azathioprine and TNF-alpha inhibitors, such as infliximab or adalimumab, can be used for frequent relapses or IBD-associated erythema nodosum 2

Erythema nodosum is characterized by raised, tender, red or violet subcutaneous nodules of 1-5 cm in diameter, typically affecting the extensor surfaces of the extremities, particularly the anterior tibial areas 5
Diagnosis is primarily made on clinical grounds based on characteristic features; biopsy is not usually necessary except in atypical cases 5, 6

Address the underlying condition if identified (e.g., treat streptococcal infection, manage inflammatory bowel disease) 5, 6
Systemic corticosteroids are indicated in severe cases but should be used cautiously, typically reserved for cases with significant inflammation or when associated with inflammatory bowel disease flares 5, 6

For persistent or recurrent EN associated with inflammatory bowel disease or other systemic conditions, consider colchicine, particularly when EN is associated with Behçet's syndrome 7, 8
Immunomodulators such as azathioprine for frequent relapses 5, 6
Biologic agents (TNF-alpha inhibitors like infliximab or adalimumab) may be effective in resistant cases associated with inflammatory bowel disease 6

EN associated with sarcoidosis may respond to hydroxychloroquine in addition to standard therapy 9
Recurrent EN may indicate persistent underlying disease activity and warrants reassessment 6

Neglecting to monitor for disease activity in associated conditions like inflammatory bowel disease or sarcoidosis 5, 9

The diagnosis is clinical, based on tender subcutaneous nodules 1–5 cm in size on extensor surfaces (especially the anterior tibial area), bilateral symmetric distribution, and lack of ulceration; routine skin biopsy is unnecessary in typical cases. 10

Erythema nodosum does not cause complement abnormalities; an isolated C4 rise should be regarded as unrelated to EN and investigated separately. 10
In EN patients without angioedema or renal involvement, extensive complement testing (C3, C1q, C1‑inhibitor) is not indicated. 10
A normal C4 level during an acute hereditary angioedema attack effectively excludes HAE as the cause of C4 elevation. 11
When complement‑mediated disease is suspected (e.g., recurrent angioedema or renal signs), measurement of C3, C1q, and C1‑inhibitor antigen + function is recommended. 11
Elevated C4 is not characteristic of complement‑mediated glomerulonephritis, which typically shows low C4. 12
An isolated C4 rise may represent an acute‑phase reactant response or be an incidental finding. 13

Management should first address the underlying trigger; EN usually resolves once the precipitating condition is treated. 10
First‑line symptomatic care includes bed rest, leg elevation, and NSAIDs (e.g., indomethacin, naproxen) for pain and inflammation. 10
For severe or IBD‑associated EN, systemic corticosteroids may be employed after infectious causes—particularly tuberculosis—have been excluded. 10
In refractory or recurrent EN:
- Colchicine is especially effective when EN is the dominant lesion or associated with Behçet’s disease. 14
- Azathioprine can be considered for patients with frequent relapses. 10
- TNF‑α inhibitors (infliximab or adalimumab) are options for resistant cases, particularly when linked to inflammatory bowel disease. 10

Do not perform routine skin biopsy for typical EN; reserve it for atypical presentations. 10
Do not attribute an elevated C4 level to EN; it requires independent evaluation. [10][11]

In patients with sarcoidosis who present with acute arthritis, erythema nodosum occurs in roughly 85 % and most cases resolve spontaneously without specific treatment, indicating an excellent prognosis. 15
Löfgren’s syndrome—characterized by bilateral hilar adenopathy together with erythema nodosum and/or peri‑articular arthritis—is considered a highly predictive clinical pattern that strongly supports a diagnosis of sarcoidosis. 16

Erythema nodosum is a recognized extra‑articular manifestation of seronegative spondyloarthropathies, which encompass ankylosing spondylitis, psoriatic arthritis, and inflammatory‑bowel‑disease‑associated arthritis. 17
Psoriatic arthritis is specifically classified within the seronegative spondyloarthropathy group. 17
These disorders share common clinical features, including inflammatory arthritis, enthesitis, and a frequent association with inflammatory bowel disease. 18

EN is identified clinically by the abrupt appearance of tender, raised subcutaneous nodules 1–5 cm in diameter, typically bilateral and symmetric on the pretibial (anterior tibial) surfaces. 19

Skin biopsy is reserved only for atypical presentations in which the diagnosis is uncertain; routine biopsy is unnecessary for classic EN. [19] [20]

When respiratory symptoms or exposure to endemic areas are present, serologic testing for coccidioidomycosis or histoplasmosis should be added to the work‑up. 21