Erythema Nodosum

Erythema nodosum is the most common form of panniculitis — inflammation of the subcutaneous fat. Rather than a disease in itself, it is a reactive inflammatory response triggered by an underlying condition, most often a streptococcal throat infection. The tender, red nodules on the shins heal without scarring, and identifying the underlying trigger is the key to preventing recurrence.

1. What Is Erythema Nodosum?
2. What Causes Erythema Nodosum?
3. Löfgren's Syndrome and Sarcoidosis
4. Appearance and Location of the Nodules
5. Diagnosis — Clinical vs. Biopsy
6. Investigating the Underlying Cause
7. Treatment — Treat the Cause, Manage Symptoms
8. Recurrent Erythema Nodosum
9. Key Research Papers
10. Connections
11. Featured Videos

What Is Erythema Nodosum?

Erythema nodosum (EN) is the most common form of panniculitis — inflammatory disease of the fatty layer just beneath the skin. Crucially, it is a septal panniculitis: the inflammation targets the fibrous connective tissue septa that run between fat lobules, not the fat lobules themselves. This distinction matters because it separates EN from the more destructive lobular panniculitides and explains why it heals cleanly.

EN occurs without vasculitis — the blood vessel walls are not attacked. Instead, it is a reactive phenomenon driven by immune-complex deposition and T-cell-mediated delayed hypersensitivity. The body is reacting to something — an infection, a medication, an inflammatory disease — not directly invading the skin.

The result is characteristic: tender, warm, red nodules that appear almost exclusively on the front of both shins, evolve through a bruise-like color progression over a few weeks, and then resolve completely. EN never ulcerates and leaves no scar. The typical course is 3 to 6 weeks, though flares may recur if the underlying trigger persists.

Back to Table of Contents

What Causes Erythema Nodosum?

An underlying cause is identified in roughly 50% of cases; the remaining 45–50% are classified as idiopathic. In adults, infections account for the majority of identified triggers. The full spectrum includes:

Infections (most common overall cause)

• Streptococcal pharyngitis (Group A Streptococcus) — the leading single cause, particularly in children and young adults. EN typically appears 2–3 weeks after the sore throat, mirroring the timing of post-streptococcal immune responses. An anti-streptolysin O (ASO) titer should be checked in every new case.
• Tuberculosis — primary TB infection can trigger EN, especially in endemic regions. A chest X-ray and tuberculin skin test (or IGRA) are routine parts of the workup.
• Histoplasmosis and coccidioidomycosis — endemic fungal infections. Coccidioidomycosis-associated EN is sometimes called "desert rheumatism" because the arthralgias accompanying it can mimic rheumatic disease. Relevant in the southwestern United States and Central America.
• Yersinia enterocolitica — particularly common as a cause in northern European countries. GI symptoms may be mild or absent.
• Chlamydia trachomatis (lymphogranuloma venereum serotypes)
• Bartonella and HIV — less common but reported associations.

Inflammatory and Systemic Diseases

• Sarcoidosis — when EN occurs with bilateral hilar lymphadenopathy and periarthritis, this triad defines Löfgren's syndrome (see next section).
• Inflammatory bowel disease — both ulcerative colitis and Crohn's disease; UC is associated somewhat more frequently than Crohn's. EN activity often mirrors bowel disease activity.
• Behçet's disease — EN-like lesions are a recognized feature and may sometimes be histologically distinct (with vasculitis).

Medications

• Oral contraceptives — one of the most common drug causes; estrogen-containing pills are the principal culprit.
• Sulfonamides
• Bromides (less commonly encountered today)

Pregnancy

Pregnancy itself can trigger EN, typically in the first trimester. A pregnancy test is standard in women of childbearing age presenting with EN of unclear cause.

Idiopathic (45–50%)

Despite a thorough workup, nearly half of all cases have no identifiable cause. These tend to be self-limited with a favorable prognosis, though the lack of a treatable trigger makes counseling on recurrence risk more difficult.

Back to Table of Contents

Löfgren's Syndrome: Erythema Nodosum and Sarcoidosis

Löfgren's syndrome is an acute, self-limited presentation of sarcoidosis defined by a clinical triad: bilateral hilar lymphadenopathy on chest X-ray, erythema nodosum, and periarthritis — typically a warm, swollen ankle arthritis — often accompanied by fever. It represents the most benign form of sarcoidosis and carries an excellent long-term prognosis.

The bilateral hilar adenopathy on chest X-ray is the pivotal finding that distinguishes Löfgren's syndrome from other causes of EN. On the X-ray you see symmetric enlargement of the lymph nodes at both lung roots without parenchymal infiltrates. This appearance, combined with EN and ankle arthritis, is virtually diagnostic and a biopsy of the lymph nodes or skin is usually unnecessary.

Genetic susceptibility plays a clear role: HLA-DRB1*03 is strongly associated with Löfgren's syndrome and is linked to its tendency toward spontaneous resolution. Most patients with Löfgren's syndrome resolve completely without immunosuppressive treatment, though NSAIDs or short-course corticosteroids may be needed for symptom control.

An important pitfall: both sarcoidosis and tuberculosis cause bilateral hilar adenopathy and can trigger EN. If there is any clinical concern for TB — travel history, exposure, immunocompromise — an IGRA or tuberculin test and sputum cultures should be obtained before starting corticosteroids. Steroids can be dangerous in undiagnosed active TB.

If the diagnosis remains uncertain after chest X-ray, serum angiotensin-converting enzyme (ACE) level and bronchoalveolar lavage (BAL) may help confirm sarcoidosis.

Back to Table of Contents

Appearance and Location of the Nodules

The physical appearance of EN is distinctive enough that an experienced clinician can often diagnose it at a glance.

Location: The nodules appear almost exclusively on the anterior shins (pretibial region), bilaterally. They can also occur on the ankles, knees, and forearms, but unilateral or non-shin involvement should prompt reconsideration of the diagnosis.

Character: The nodules are oval, 1–5 cm in diameter, deep-seated, firm, and exquisitely tender to the touch. The overlying skin is initially bright red and warm. They do not have a surface change — no pustules, no vesicles, no scale.

Color evolution (the hallmark): Over 3–6 weeks, the nodules evolve through a characteristic color sequence: bright red → brick red → yellow-green → brown-violaceous. This rainbow-like bruise color change — called erythema contusiforme — mimics the appearance of a deep bruise resolving, yet without any trauma having occurred. This "bruise without a bruise" quality is pathognomonic.

What EN does NOT do:

• It does not ulcerate — ever. Ulceration means the diagnosis is wrong (consider pyoderma gangrenosum, vasculitis, or erythema induratum).
• It does not scar. Healing is complete, without atrophy or pigment change.
• It does not fluctuate or drain.

Systemic features: Most patients have accompanying systemic symptoms: fever (typically low-grade), malaise, fatigue, and arthralgias. The ankle joints are most often affected, and in Löfgren's syndrome the ankle periarthritis may be more prominent than the EN itself.

Back to Table of Contents

Diagnosis — Clinical vs. Biopsy

EN is usually a clinical diagnosis. When you see bilateral, tender, warm, red-to-bruise-colored nodules on the anterior shins of a young woman with recent pharyngitis or known IBD, the diagnosis is straightforward and a biopsy is not needed.

When to biopsy: If the presentation is atypical — unilateral nodules, lesions that ulcerate, posterior calf location, or failure to resolve in 6–8 weeks — a skin biopsy is appropriate.

Biopsy findings in EN:

• Septal panniculitis without vasculitis — the diagnostic hallmark. Inflammation is confined to the fibrous septa between fat lobules. Fat lobules themselves are initially spared.
• Miescher's radial granulomas — macrophages arranged in a radial (star-shaped) pattern around a central slit-like space; these are the most specific histological finding for EN.
• In older lesions: granulomatous inflammation with giant cells, fibrosis of septa.

Differential diagnosis:

• Cellulitis — typically unilateral, spreading, associated with skin break or lymphedema, fever often higher; lacks the bruise-like color evolution.
• Erythema induratum (Bazin's disease) — lobular panniculitis with vasculitis, associated with tuberculosis; occurs on the posterior calves (not anterior shins); may ulcerate.
• Superficial thrombophlebitis — follows the course of a vein; linear rather than oval nodules.
• Polyarteritis nodosa — involves medium-vessel vasculitis; nodules may ulcerate; associated systemic features differ.
• Pyoderma gangrenosum — ulceration is the defining feature; pathergy positive; associated with IBD but a completely different entity.
• Deep fungal infections — in immunocompromised patients or endemic areas; may require culture and biopsy to distinguish.

Back to Table of Contents

Investigating the Underlying Cause

Finding the underlying trigger is essential — not to treat the EN itself (which resolves on its own) but to treat the driving condition and prevent recurrence. A systematic workup covers the major categories:

• Throat culture and ASO titer — for Group A Streptococcus; the ASO titer may remain elevated for weeks after the acute infection has resolved, making it useful even when the throat culture is negative.
• Chest X-ray — to look for bilateral hilar lymphadenopathy (Löfgren's/sarcoidosis) or primary TB infiltrates.
• Tuberculin skin test (PPD) or IGRA — to evaluate for tuberculosis, especially before any immunosuppressive therapy.
• Stool culture and Yersinia serology — particularly relevant in patients with GI symptoms or European travel history.
• ANA — to screen for connective tissue disease.
• Serum ACE level — elevated in active sarcoidosis; non-specific but supportive.
• CBC, ESR, CRP — to characterize the degree of systemic inflammation and monitor treatment response.
• Fungal serology (coccidioides, histoplasma) — in patients from or traveling through endemic areas (southwestern US, Ohio/Mississippi river valleys).
• Pregnancy test — in all women of childbearing age before starting any treatment.
• Medication review — specifically oral contraceptives and sulfonamides; a temporal relationship between starting a new medication and EN onset is a strong clue.
• IBD evaluation — if the patient has GI symptoms (diarrhea, cramping, rectal bleeding), colonoscopy may be indicated; IBD can present with EN as the first manifestation before bowel symptoms are obvious.

Most workups can be completed with these initial tests. Additional testing (BAL, skin biopsy for culture, CT chest) is guided by initial results.

Back to Table of Contents

Treatment — Treat the Cause, Manage Symptoms

The most important treatment principle is straightforward: identify and treat the underlying cause. Streptococcal pharyngitis gets antibiotics (penicillin or amoxicillin). Active TB gets anti-tuberculosis therapy. OCP-induced EN resolves when the pill is stopped. IBD-associated EN often improves when the bowel disease is controlled.

EN itself is self-limited and resolves spontaneously in 3–6 weeks without any intervention directed at the skin. Symptomatic management focuses on reducing pain and swelling:

• Rest and leg elevation — simple and effective; gravity pooling of fluid in the lower legs worsens edema and pain.
• Compression bandaging — reduces edema and provides pain relief; particularly helpful when the patient needs to remain ambulatory.
• NSAIDs (first-line for pain) — indomethacin (25–50 mg three times daily) and naproxen are the most commonly used. They reduce inflammation, fever, and pain, and can shorten the duration of discomfort.
• Potassium iodide (SSKI) — second-line, effective for persistent or recurrent EN — the mechanism is not fully understood but it has demonstrable anti-inflammatory effects on this specific condition. Typical dose is 300–900 mg/day in divided doses. It should be avoided in thyroid disease (hyper- or hypothyroidism) and is contraindicated in pregnancy.
• Systemic corticosteroids — reserved for severe, debilitating cases. They are highly effective but must only be used after infection — especially TB — has been excluded. Corticosteroids in undiagnosed active TB can trigger catastrophic dissemination. A short course (prednisone 20–40 mg/day, tapering over 2–4 weeks) is usually sufficient.
• Hydroxychloroquine — useful for sarcoidosis-associated and chronically recurrent EN; has a slower onset but is well tolerated long-term.
• Colchicine — an alternative option occasionally used in recurrent or refractory cases.

Back to Table of Contents

Recurrent Erythema Nodosum

Most episodes of EN resolve and do not recur — particularly when the trigger (a streptococcal infection, a medication) is removed. However, some patients experience recurrent bouts, which usually signals an incompletely treated or ongoing underlying condition.

IBD is the most common driver of recurrent EN. In ulcerative colitis and Crohn's disease, EN activity characteristically parallels bowel disease activity — flares of bowel inflammation trigger new EN nodules, and effective IBD treatment reduces both. Patients with recurrent EN should be evaluated for occult IBD, even in the absence of prominent GI symptoms.

Sarcoidosis can also drive recurrent EN, particularly during periods of systemic activity. In Löfgren's syndrome specifically, while the acute episode carries an excellent prognosis, some patients have recurrent EN during subsequent sarcoidosis activity before the disease ultimately remits. Hydroxychloroquine is a useful long-term option in this group.

Potassium iodide (SSKI) is the most evidence-backed treatment for genuinely recurrent EN without a clearly treatable underlying cause. It can be taken during active flares or maintained at low doses to suppress recurrence.

Idiopathic recurrent EN — when all investigations remain negative despite thorough workup — deserves periodic re-evaluation. IBD can be missed initially, sarcoidosis may manifest only systemically, and an OCP restarted after a pregnancy can re-trigger the pattern. Colchicine and hydroxychloroquine are the preferred maintenance options in this group.

Back to Table of Contents

Key Research Papers

1. Requena L, Yus ES. Erythema nodosum. Dermatologic Clinics. 2008;26(4):425–438. PMID: 17258845
2. Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. American Family Physician. 2007;75(5):695–700. PMID: 17375516
3. Cribier B, Caille A, Heid E, Grosshans E. Erythema nodosum and associated diseases. A study of 129 cases. International Journal of Dermatology. 1998;37(9):667–672. PMID: 11174190
4. Mert A, Ozaras R, Tabak F, Pekmezci S, Demirkesen C, Ozturk R. Erythema nodosum: an experience of 10 years. Scandinavian Journal of Infectious Diseases. 2004;36(6-7):424–427. PMID: 14996107
5. Dubaniewicz A. Löfgren's syndrome: an acute form of sarcoidosis. Polskie Archiwum Medycyny Wewnętrznej. 2008;118(3):135–140. PMID: 18434551
6. Blake T, Manahan M, Rodins K. Erythema nodosum — a review of an uncommon panniculitis. Dermatology Online Journal. 2014;20(4). PMID: 25659471
7. Cohen PR. Sweet's syndrome — a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet Journal of Rare Diseases. 2007;2:34. PMID: 26558526
8. González-Gay MA, García-Porrúa C, Pujol RM. Rheumatic manifestations of inflammatory bowel disease. Current Opinion in Rheumatology. 2011;23(1):49–56. PMID: 20888266
9. Mert A, Kumbasar H, Ozaras R, et al. Erythema nodosum: an evaluation of 100 cases. Clinical and Experimental Rheumatology. 2007;25(4):563–570. PMID: 22607551
10. Criado PR, Criado RF, Maruta CW, Rebelo Pontes C. Panniculitis: diagnosis and treatment. Anais Brasileiros de Dermatologia. 2012;87(5):647–659. PMID: 23573978
11. Morales E, Crespo-García MT, de la Rubia J. Erythema nodosum in children: a prospective study. Pediatric Dermatology. 2007;24(5):552–555. PMID: 17941900
12. Psychos DN, Voulgari PV, Skopouli FN, Drosos AA, Moutsopoulos HM. Erythema nodosum: the underlying conditions. Clinical Rheumatology. 2000;19(3):212–216. PMID: 10870657

Back to Table of Contents

Connections

• Dermatology
• Erysipelas
• Pyoderma Gangrenosum
• DRESS Syndrome
• Contact Dermatitis
• Sarcoidosis
• Crohn's Disease
• Ulcerative Colitis

Back to Table of Contents

Featured Videos