Erythema Nodosum

1. Clinical Overview

Summary

Erythema nodosum (EN) is the most common form of panniculitis, representing approximately 60-70% of all panniculitis cases. [1] It is a delayed-type hypersensitivity reaction characterized by inflammation of subcutaneous fat septae (septal panniculitis) presenting as painful, erythematous-to-violaceous nodules typically on the anterior tibial surfaces. [2] EN functions as a cutaneous reaction pattern to diverse systemic triggers including infections (particularly β-haemolytic streptococcal pharyngitis), medications (oral contraceptives, sulfonamides), sarcoidosis, inflammatory bowel disease (IBD), and pregnancy. [3] Approximately 30-50% of cases remain idiopathic despite thorough investigation. [4]

The condition demonstrates female predominance (3-6:1) with peak incidence in the third and fourth decades. [5] Löfgren's syndrome—the triad of erythema nodosum, bilateral hilar lymphadenopathy, and polyarthritis—represents an acute presentation of sarcoidosis with excellent prognosis. [6] The lesions are exquisitely tender, never ulcerate, and undergo characteristic evolution over 3-6 weeks resembling bruise resolution (red → purple → yellow → brown), healing without scarring. [7]

Diagnosis is primarily clinical; skin biopsy confirms septal panniculitis with Miescher's radial granulomas but is rarely required. [8] Investigation focuses on identifying the underlying cause through systematic evaluation including chest radiography (mandatory to exclude hilar lymphadenopathy), throat culture/ASOT, tuberculin testing, and inflammatory markers. [9] Management is predominantly supportive with NSAIDs, rest, leg elevation, and compression; treatment of the underlying trigger is paramount. [10]

Key Facts

Clinical Pearls

"Septal vs Lobular Panniculitis": EN is a septal panniculitis (inflammation in fibrous septae between fat lobules). Lobular panniculitis (inflammation within fat lobules) includes erythema induratum, pancreatic panniculitis, and α1-antitrypsin deficiency-associated panniculitis. This distinction is histopathological but clinically relevant: septal panniculitis rarely ulcerates; lobular often does. [11]

"The Shins That Never Ulcerate": The anterior tibial surface is the classic location (90% of cases). Unlike pyoderma gangrenosum, vasculitic ulcers, or erythema induratum, EN lesions NEVER ulcerate. This is a critical diagnostic feature. If a shin lesion ulcerates, reconsider the diagnosis. [7]

"Löfgren's Syndrome = Good Prognosis Sarcoidosis": Löfgren's syndrome (EN + bilateral hilar lymphadenopathy + polyarthritis ± fever) is an acute presentation of sarcoidosis with > 85% spontaneous remission rate within 2 years, unlike other sarcoidosis presentations. [6,12] This excellent prognosis makes recognition clinically important.

"NO DOSUM Mnemonic for Causes": No cause (idiopathic 30-50%); Oral contraceptive pill; Drugs (sulfonamides, penicillins, NSAIDs); Other infections (Yersinia, Mycoplasma, Chlamydia, fungal); Sarcoidosis; Ulcerative colitis/Crohn's; Microbiology (Streptococcus, Tuberculosis). [13]

"Bilateral Hilar Lymphadenopathy = Mandatory CXR": Chest X-ray is mandatory in all EN cases, even if asymptomatic. Bilateral hilar lymphadenopathy (BHL) suggests sarcoidosis (Löfgren's syndrome) or tuberculosis. Approximately 20-30% of EN cases are associated with sarcoidosis. [14]

"Miescher's Radial Granulomas": Histopathologically, EN shows septal panniculitis with characteristic Miescher's radial granulomas—small histiocytic granulomas arranged radially around central vessels or clefts within septae. This finding, though not pathognomonic, strongly supports EN diagnosis. [8]

Why This Matters Clinically

Erythema nodosum is a cutaneous window into systemic disease. The skin lesions themselves are benign and self-limiting, but EN frequently heralds significant underlying conditions: sarcoidosis (20-30%), tuberculosis (particularly in endemic regions), IBD (Crohn's 4-15%; UC 2-4%), Behçet's disease, and malignancy (rare). [3,14,15] Identifying and treating the underlying cause is more clinically important than managing the nodules.

Löfgren's syndrome recognition is particularly crucial: it identifies a subset of sarcoidosis patients with excellent prognosis who may not require immunosuppression. [6] Conversely, failure to investigate EN thoroughly may delay diagnosis of tuberculosis, IBD, or drug reactions, potentially leading to significant morbidity.

From an examination perspective, EN is high-yield for MRCP, MRCS, and dermatology specialty exams due to its distinctive clinical presentation, clear diagnostic approach, and association with common systemic conditions (sarcoidosis, IBD, infections).

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2. Epidemiology

Incidence & Prevalence

Age-Specific Considerations

Associated Conditions: Frequency of Causes

The underlying cause varies by geographic region, patient population, and thoroughness of investigation. The table below represents pooled data from systematic reviews: [3,4,14]

Geographic and Population Variation

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3. Pathophysiology

Overview of Panniculitis Classification

Panniculitis is inflammation of subcutaneous fat. Histopathological classification divides panniculitis into septal (inflammation primarily in fibrous septae between fat lobules) and lobular (inflammation within fat lobules themselves): [11]

Erythema nodosum is the prototypical septal panniculitis without vasculitis. [8,11]

Molecular Pathogenesis of Erythema Nodosum

Exam Detail: EN represents a delayed-type hypersensitivity reaction (Type IV hypersensitivity) to diverse antigenic stimuli. The pathogenesis involves: [2,8,22]

Step 1: Antigen Exposure and Presentation

• Triggering Antigens: Streptococcal M protein, mycobacterial antigens, drug haptens, sarcoid antigens, microbial cell wall components
• Antigen Processing: Antigens are processed by dermal dendritic cells and macrophages in subcutaneous septae
• MHC Class II Presentation: Processed antigens presented via MHC Class II to CD4+ T helper cells

Step 2: T Cell Activation and Cytokine Release

• Th1 Response Predominance: CD4+ T cells differentiate predominantly into Th1 phenotype
• Cytokine Profile: IFN-γ, TNF-α, IL-2, IL-12 secretion; minimal Th2 response
• Granuloma Formation: TNF-α and IFN-γ drive macrophage aggregation and granuloma formation (Miescher's radial granulomas)

Step 3: Immune Complex Deposition (Contributory)

• Circulating Immune Complexes: Antigen-antibody complexes form in circulation
• Septal Deposition: Preferential deposition in subcutaneous fat septae (mechanism unclear; possibly related to blood flow/vascular anatomy)
• Complement Activation: C3a, C5a generation → chemotaxis of neutrophils and macrophages
• Early Neutrophilic Infiltrate: Initially neutrophil-predominant; later lymphocytic/histiocytic [8]

Step 4: Septal Inflammation and Clinical Lesion

• Septal Widening: Inflammatory cell infiltration → septal oedema and thickening
• Vascular Changes: No true vasculitis (critical distinction); however, perivenular inflammation and endothelial swelling may occur
• Miescher's Radial Granulomas: Hallmark histopathological finding—small histiocytic granulomas arranged radially around vessels/clefts in septae [8]
• Clinical Nodule: Palpable tender nodule at site of septal inflammation

Step 5: Resolution Phase

• Spontaneous Resolution: Inflammatory infiltrate resolves over 3-6 weeks
• Haemosiderin Deposition: Erythrocyte extravasation → haemosiderin deposition → bruise-like colour evolution (red → purple → yellow → brown)
• No Scarring: Septal architecture preserved; no fibrosis or ulceration [7]

Why the Anterior Shins? Anatomical Considerations

The predilection for anterior tibial location (90% of EN cases) is likely multifactorial: [23]

1. Hydrostatic Pressure: Dependent position → venous congestion → enhanced immune complex deposition
2. Subcutaneous Fat Distribution: Relatively thin subcutaneous fat layer over anterior tibia → palpable septal inflammation
3. Trauma Susceptibility: Minor trauma may serve as localizing factor (Koebner phenomenon)
4. Temperature: Cooler peripheral location may favour inflammatory processes

Histopathology

Exam Detail: | Feature | Description | Significance | |---------|-------------|--------------| | Septal Panniculitis | Inflammation primarily in fibrous septae; fat lobules relatively spared | Defining feature of EN [8] | | Miescher's Radial Granulomas | Small histiocytic granulomas arranged radially around central vessel or cleft in septum | Characteristic (though not pathognomonic) for EN [8] | | No Vasculitis | No fibrinoid necrosis, no vessel wall destruction | Distinguishes EN from vasculitic panniculitis [11] | | Neutrophils (Early) | Neutrophil infiltrate in early lesions (less than 72 hours) | Reflects acute inflammatory phase | | Lymphocytes/Histiocytes (Late) | Lymphocyte and histiocyte predominance in established lesions | Reflects delayed hypersensitivity | | Haemorrhage/Haemosiderin | Erythrocyte extravasation; haemosiderin-laden macrophages in resolving lesions | Explains bruise-like colour evolution [7] | | No Necrosis | No fat necrosis or caseation | Distinguishes from lupus panniculitis, pancreatic panniculitis | | No Ulceration | Overlying epidermis and dermis intact | Clinical corollary: EN never ulcerates |

Biopsy Indication: Skin biopsy is rarely required for EN diagnosis. Consider biopsy if: [8]

• Atypical clinical features (ulceration, unilateral lesions, unusual distribution)
• Failure to respond to conservative management
• Need to exclude vasculitis, malignancy, or other panniculitis forms

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4. Clinical Presentation

Typical Presentation

Classic Scenario: A 28-year-old woman presents with a 1-week history of painful red lumps on both shins. She had a sore throat 2-3 weeks ago, now resolved. She also reports low-grade fever, malaise, and ankle pain. On examination, there are 4-5 tender, erythematous, warm nodules (2-4 cm diameter) on the anterior tibial surfaces bilaterally. The nodules are firm, immobile (tethered to underlying tissue), and exquisitely tender to palpation. There is no ulceration or discharge.

Symptoms

Signs

Atypical Presentations

Associated Systemic Features by Cause

Exam Detail: | Underlying Cause | Associated Features | Diagnostic Clues | |------------------|---------------------|------------------| | Streptococcal Infection | Sore throat 1-3 weeks prior; fever; raised ASOT; positive throat swab [17] | Most common infectious cause; seasonal (spring/summer) | | Sarcoidosis (Löfgren's) | Bilateral hilar lymphadenopathy (CXR); polyarthritis (ankles); fever; raised ACE; lymphopenia [6,12] | Triad: EN + BHL + arthritis | | Tuberculosis | Chronic cough; night sweats; weight loss; positive Mantoux/IGRA; endemic region; immunosuppression [16] | More common in Asia, Africa, Latin America | | IBD (Crohn's/UC) | Diarrhoea (bloody in UC); abdominal pain; weight loss; perianal disease (Crohn's); extraintestinal manifestations [15] | EN may precede bowel symptoms by months | | Behçet's Disease | Recurrent oral ulcers; genital ulcers; uveitis; pathergy test positive; thrombophlebitis [26] | More common in Turkey, Middle East, Silk Road regions | | Drug-Induced | Temporal relationship to drug initiation (1-4 weeks); resolution on drug cessation; re-challenge may reproduce | OCP, sulfonamides, penicillins most common [3] | | Pregnancy | Any trimester; usually idiopathic; resolves postpartum [21] | Hormonal influence suggested | | Yersinia Enterocolitica | Gastroenteritis (diarrhoea, abdominal pain); mesenteric adenitis; arthritis; positive stool culture [27] | More common in Scandinavia, Northern Europe | | Malignancy | Constitutional symptoms (weight loss, night sweats); lymphadenopathy; organomegaly | Rare; exclude in elderly or atypical cases [20] |

Löfgren's Syndrome (Acute Sarcoidosis)

Löfgren's syndrome is an acute presentation of sarcoidosis with distinctive features and excellent prognosis. [6,12]

Clinical Pearl: Löfgren's syndrome has such a favourable prognosis that it should be distinguished from other forms of sarcoidosis. Many patients do not require systemic corticosteroids. [12]

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5. Differential Diagnosis

Septal vs Lobular Panniculitis: Key Distinction

Differential Diagnosis of Shin Lesions

Panniculitis: Comprehensive Differential

Exam Detail: | Type | Examples | Clinical Clues | Investigations | |------|----------|----------------|----------------| | Septal Without Vasculitis | Erythema nodosum; Scleroderma; Necrobiosis lipoidica | Tender nodules; no ulceration; bilateral shins | Biopsy if atypical; investigate underlying cause | | Septal With Vasculitis | Superficial thrombophlebitis; Behçet's; Polyarteritis nodosa | Linear/cord-like (thrombophlebitis); systemic vasculitis | Doppler; vasculitis screen; biopsy | | Lobular Without Vasculitis | Pancreatic panniculitis; α1-antitrypsin deficiency; Subcutaneous fat necrosis of newborn; Lupus panniculitis | Ulceration; oily discharge (pancreatic); neonate (SCFN); SLE (lupus) | Amylase/lipase; α1-AT level; ANA; biopsy | | Lobular With Vasculitis | Erythema induratum (Bazin's); Leukocytoclastic vasculitis | Posterior calf ulcers (EI); palpable purpura (LCV) | TB screen; biopsy; vasculitis screen | | Mixed Septal-Lobular | Erythema induratum; Cold panniculitis; Subcutaneous sarcoidosis | Features of both septal and lobular | Biopsy; investigation for underlying cause |

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6. Clinical Examination

Approach to Examination

Setting: Dermatology or rheumatology clinical exam (PACES, MRCP, MRCS OSCE)

Instruction: "This patient has developed painful lumps on their legs. Please examine the skin and suggest a diagnosis."

Inspection

Palpation

Associated Findings

Complete examination should include:

Examination Findings Suggesting Specific Causes

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7. Investigations

Investigation Algorithm

The primary goal of investigation is to identify the underlying cause, not to diagnose EN itself (which is clinical). [9]

           ERYTHEMA NODOSUM INVESTIGATION ALGORITHM
                              ↓
┌─────────────────────────────────────────────────────────────┐
│                    FIRST-LINE (ALL PATIENTS)                │
├─────────────────────────────────────────────────────────────┤
│  ✓ Chest X-ray (MANDATORY — BHL, TB, malignancy)          │
│  ✓ FBC (WCC, anaemia, lymphopenia)                         │
│  ✓ ESR / CRP (inflammation markers)                        │
│  ✓ Throat swab / ASOT titre (streptococcal)               │
│  ✓ Urinalysis (haematuria/proteinuria → vasculitis)       │
│  ✓ Pregnancy test (if appropriate)                         │
└─────────────────────────────────────────────────────────────┘
                              ↓
                   CHEST X-RAY RESULT?
                              ↓
         ┌────────────────────┴────────────────────┐
         ↓                                         ↓
  BILATERAL HILAR                             NORMAL or
  LYMPHADENOPATHY (BHL)                    OTHER FINDINGS
         ↓                                         ↓
  SARCOIDOSIS (Löfgren's)               SECOND-LINE TESTS
         ↓                                         ↓
  • Serum ACE                     ┌─────────────────────────┐
  • Serum calcium                 │ Based on clinical clues:│
  • Pulmonary function tests      │                         │
  • Consider bronchoscopy +       │ • Mantoux / IGRA (TB)  │
    biopsy if atypical            │ • Stool culture         │
  • No treatment if classic       │   (Yersinia, Salmonella)│
    Löfgren's (self-limiting)     │ • Mycoplasma serology   │
                                  │ • Faecal calprotectin   │
                                  │   (IBD screening)       │
                                  │ • Colonoscopy (IBD)     │
                                  │ • Drug history review   │
                                  │ • Behçet's criteria     │
                                  │ • HIV test (if risk)    │
                                  └─────────────────────────┘
                                              ↓
                                    CONSIDER SKIN BIOPSY
                                    if atypical features

First-Line Investigations (All Patients)

Second-Line Investigations (Based on Clinical Clues)

Skin Biopsy

Indication: Skin biopsy is rarely required for EN diagnosis. [8] Consider if:

• Atypical clinical features (ulceration, unilateral distribution, unusual location)
• Diagnostic uncertainty (need to exclude vasculitis, other panniculitis, malignancy)
• Failure to respond to conservative management
• Persistent/chronic EN (> 6 weeks)

Technique:

• Excisional biopsy (preferred for panniculitis): includes subcutaneous fat
• Punch biopsy: less ideal (may not capture adequate subcutaneous tissue)
• Biopsy early lesions (less than 1 week) for diagnostic yield

Histopathological Findings: [8,11]

• Septal panniculitis (inflammation in fibrous septae; fat lobules relatively spared)
• Miescher's radial granulomas (small histiocytic granulomas around vessels in septae)
• No vasculitis (no fibrinoid necrosis, no vessel wall destruction)
• Early: neutrophilic infiltrate; Late: lymphocytic/histiocytic
• Haemorrhage, haemosiderin deposition (in resolving lesions)

Investigation Summary by Suspected Cause

Exam Detail: | Suspected Cause | Key Investigations | |-----------------|-------------------| | Streptococcal | Throat swab; ASOT titre; ESR/CRP | | Sarcoidosis (Löfgren's) | CXR (BHL); serum ACE; serum calcium; lymphocyte count; pulmonary function tests | | Tuberculosis | CXR; Mantoux/IGRA; sputum culture/NAAT; HIV test | | IBD | Faecal calprotectin; colonoscopy + biopsy; ESR/CRP; albumin | | Behçet's | Clinical diagnosis (International Study Group criteria); HLA-B51; pathergy test; ESR/CRP | | Drug-Induced | Detailed drug history; temporal relationship; resolution on drug cessation | | Yersinia | Stool culture; Yersinia serology | | Pregnancy | Pregnancy test; exclude other causes | | Malignancy | FBC; blood film; LDH; CT chest/abdomen/pelvis; bone marrow if indicated |

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8. Management

Overview

Management of EN involves: [10]

1. Identify and treat underlying cause (most important)
2. Symptomatic relief (NSAIDs, rest, elevation)
3. Avoid unnecessary treatments (EN is self-limiting)
4. Monitor for recurrence (if cause persists)

Management Algorithm

                ERYTHEMA NODOSUM MANAGEMENT
                            ↓
┌───────────────────────────────────────────────────────────┐
│              IDENTIFY & TREAT UNDERLYING CAUSE            │
├───────────────────────────────────────────────────────────┤
│  ✓ Stop causative drugs (OCP, sulfonamides, NSAIDs)      │
│  ✓ Treat streptococcal infection (Penicillin V 500mg QDS)│
│  ✓ Treat tuberculosis (standard 4-drug regimen)          │
│  ✓ Manage IBD (liaise with gastroenterology)             │
│  ✓ Löfgren's syndrome: usually NO treatment needed       │
│    (self-limiting; NSAIDs only; avoid steroids unless     │
│     severe arthritis/uveitis)                             │
│  ✓ Pregnancy-associated: reassure; usually resolves      │
│    postpartum                                             │
└───────────────────────────────────────────────────────────┘
                            ↓
┌───────────────────────────────────────────────────────────┐
│                  SYMPTOMATIC MANAGEMENT                   │
├───────────────────────────────────────────────────────────┤
│  FIRST-LINE (All Patients):                               │
│  ✓ Rest and leg elevation (reduces hydrostatic pressure) │
│  ✓ Compression stockings (graduated compression)         │
│  ✓ NSAIDs (Ibuprofen 400mg TDS or Naproxen 500mg BD)    │
│  ✓ Cool compresses (symptomatic relief)                  │
│  ✓ Simple analgesia (Paracetamol)                        │
│                                                           │
│  SECOND-LINE (Refractory Cases):                          │
│  ✓ Potassium iodide (300-900 mg/day in divided doses)   │
│    — effective but poorly tolerated (nausea, metallic    │
│       taste, hypothyroidism) [33]                         │
│  ✓ Colchicine (0.5-1.5 mg/day) — anti-inflammatory [34]  │
│  ✓ Hydroxychloroquine (200-400 mg/day) — case reports    │
│                                                           │
│  THIRD-LINE (Severe/Persistent Cases):                    │
│  ✓ Systemic corticosteroids (Prednisolone 20-40mg/day)  │
│    — reserve for severe cases; risk of masking           │
│       underlying infection (TB); rapid response          │
│  ✓ Avoid in Löfgren's syndrome unless severe arthritis   │
└───────────────────────────────────────────────────────────┘
                            ↓
┌───────────────────────────────────────────────────────────┐
│                     FOLLOW-UP                             │
├───────────────────────────────────────────────────────────┤
│  ✓ Review at 2-4 weeks: assess response; new lesions?    │
│  ✓ Expected course: resolution in 3-6 weeks              │
│  ✓ Monitor for recurrence (if cause persists/recurs)     │
│  ✓ Reassure: no scarring expected                        │
│  ✓ Counsel: avoid causative drugs in future              │
│  ✓ Löfgren's syndrome: follow-up CXR at 3-6 months to    │
│    ensure BHL resolution                                  │
└───────────────────────────────────────────────────────────┘

Symptomatic Treatment Details

Exam Detail: #### NSAIDs (First-Line Analgesia)

Contraindications: Active peptic ulcer, severe renal impairment, pregnancy (third trimester), aspirin allergy

Precautions: Use PPI co-prescription in elderly or those with GI risk factors

Potassium Iodide (Second-Line)

• Mechanism: Unclear; may suppress neutrophil chemotaxis and granuloma formation
• Dose: Start 300 mg/day (divided TDS); increase to 900 mg/day if tolerated [33]
• Efficacy: 70-80% response rate in refractory EN
• Side Effects: Nausea, metallic taste, hypothyroidism (monitor TFTs), acne, parotitis
• Contraindications: Pregnancy, thyroid disease, renal impairment
• Monitoring: TFTs at baseline and every 4-6 weeks

Colchicine (Second-Line)

• Mechanism: Anti-inflammatory; inhibits neutrophil migration and microtubule assembly
• Dose: 0.5 mg BD to 0.5 mg TDS [34]
• Efficacy: Modest evidence; case series suggest benefit in chronic/recurrent EN
• Side Effects: Diarrhoea (dose-limiting), nausea, abdominal pain
• Contraindications: Severe renal/hepatic impairment
• Monitoring: Renal and liver function

Systemic Corticosteroids (Third-Line, Severe Cases Only)

• Indication: Severe, disabling EN not responding to NSAIDs/second-line; severe arthritis in Löfgren's syndrome
• Dose: Prednisolone 20-40 mg/day for 1-2 weeks, then taper
• Efficacy: Rapid, dramatic response (within 24-48 hours)
• Caution: Risk of masking underlying infection (especially TB); avoid in Löfgren's syndrome unless severe (self-limiting condition) [12]
• Avoid in: Active TB (until on treatment > 2 weeks), undiagnosed causes

Treatment of Underlying Causes

Chronic and Recurrent Erythema Nodosum

Chronic EN: Lesions persist > 6 weeks [25]

Recurrent EN: New crops of lesions after initial resolution

Approach:

1. Re-investigate for persistent underlying cause (untreated IBD, chronic infection, recurrent drug exposure)
2. Consider chronic EN variant (rare; may require long-term low-dose corticosteroids or immunomodulators)
3. Exclude chronic infections (TB, Yersinia, fungal)
4. Consider autoimmune conditions (sarcoidosis, Behçet's, SLE)
5. Long-term management options:
   • Colchicine 0.5 mg BD as maintenance
   • Hydroxychloroquine 200 mg/day
   • Low-dose Prednisolone (5-10 mg/day) as last resort
   • Dapsone (case reports; 50-100 mg/day)

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9. Complications & Prognosis

Complications

Erythema nodosum itself has minimal direct complications. Complications relate to: [7]

No Long-Term Sequelae: EN does not cause scarring, chronic skin changes, or disability. [7]

Prognosis

Prognostic Factors

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10. Prevention & Patient Education

Prevention

Patient Education

Key Messages:

1. Self-Limiting Condition: EN is not dangerous; it is a reaction pattern to infections, drugs, or other triggers
2. No Scarring: Lesions heal completely without scars; temporary brown discolouration fades
3. Symptomatic Management: Rest, elevation, NSAIDs are mainstays; avoid standing for long periods
4. Underlying Cause: Important to investigate and treat any underlying condition (infection, IBD, sarcoidosis)
5. Recurrence Possible: If the cause persists or recurs, EN may return
6. Drug Avoidance: If drug-induced, avoid the causative drug in future
7. When to Seek Help: Return if lesions ulcerate (not EN), systemic symptoms worsen, or new symptoms develop

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11. Guidelines & Evidence

Key Guidelines

Note: There are no formal, published, evidence-based guidelines specifically for EN management. Recommendations are based on case series, expert consensus, and extrapolation from panniculitis literature. [1-10]

Landmark Studies & High-Quality Evidence

Exam Detail: | Study | Type | Key Findings | Citation | |-------|------|--------------|----------| | Requena & Yus (2001) | Review | Comprehensive classification of panniculitis; septal vs lobular distinction; EN histopathology [1] | PMID: 11464178 | | Psychos et al. (2000) | Cohort (130 patients) | 50% idiopathic; sarcoidosis 19%; streptococcal 14%; IBD 4%; good prognosis [4] | PMID: 11069912 | | Löfgren (1953) | Case series | Original description of Löfgren's syndrome; excellent prognosis [6] | Historical landmark | | Mert et al. (2007) | Cohort (106 patients) | 41% idiopathic; sarcoidosis 19%; streptococcal 17%; TB 5%; female:male 4:1 [5] | PMID: 17360031 | | Gatehouse et al. (2018) | Review | Chronic and recurrent EN; management with Colchicine, Potassium iodide [25] | PMID: 29701874 | | Baughman et al. (2001) | Sarcoidosis review | Löfgren's syndrome: > 85% remission; HLA-DRB1*03 association [12] | PMID: 11572003 |

Evidence Levels

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12. Examination Focus (MRCP, MRCS, Dermatology Exams)

High-Yield Exam Topics

PACES/OSCE Clinical Examination Scenario

Scenario: "This 30-year-old woman has developed painful lumps on her legs. Please examine her skin and present your findings."

Approach:

1. Introduction: Wash hands; introduce self; confirm patient identity; explain examination; obtain consent
2. General Inspection: Age, sex, obvious discomfort, joint swelling, respiratory distress
3. Skin Inspection: Expose lower limbs; bilateral anterior tibial nodules; erythematous-violaceous; no ulceration
4. Palpation: Tender, warm, firm, subcutaneous, immobile
5. Associated Features: Ankle/knee examination (arthritis); lymph nodes; oropharynx (if allowed)
6. Complete Examination: "I would like to examine the chest (sarcoidosis, TB), abdomen (IBD), and eyes (uveitis)"

Presentation:

"This 30-year-old woman has multiple tender, erythematous nodules on the anterior tibial surfaces bilaterally. The nodules are approximately 2-4 cm in diameter, firm, warm, and exquisitely tender. There is no ulceration or discharge. She also has bilateral ankle swelling suggestive of arthritis. My differential diagnosis includes erythema nodosum, and given the ankle arthritis, I am concerned about Löfgren's syndrome (acute sarcoidosis). I would like to perform a chest X-ray to assess for bilateral hilar lymphadenopathy, check inflammatory markers, ASOT titre, and Mantoux test. If the chest X-ray shows BHL, I would check serum ACE and calcium and refer to respiratory medicine for further assessment of sarcoidosis."

Viva Voce Questions & Model Answers

Exam Detail: #### Question 1: "What is erythema nodosum and what causes it?"

Model Answer: "Erythema nodosum is the most common form of panniculitis, accounting for 60-70% of cases. [1] It is a septal panniculitis—inflammation of the fibrous septae between subcutaneous fat lobules—presenting as tender, erythematous-to-violaceous nodules typically on the anterior tibial surfaces. [2] It represents a delayed-type hypersensitivity reaction to diverse triggers. [8]

The causes can be remembered with the mnemonic NO DOSUM: No cause (idiopathic, 30-50%); Oral contraceptive pill; Drugs (sulfonamides, penicillins, NSAIDs); Other infections (Yersinia, Mycoplasma, fungal); Sarcoidosis (20-30%); Ulcerative colitis/Crohn's disease; Microbiology (Streptococcus—most common infectious cause, and Tuberculosis). [3,13]

The key clinical feature is that EN never ulcerates and heals like bruises without scarring. [7] This distinguishes it from other forms of panniculitis such as erythema induratum, which typically ulcerates."

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Question 2: "A 25-year-old woman presents with painful nodules on her shins. What is your differential diagnosis and how would you investigate?"

Model Answer: "The most likely diagnosis is erythema nodosum, which presents as tender, erythematous nodules on the anterior tibial surfaces, typically bilateral and symmetrical. Key features supporting this diagnosis are the location (pretibial), age and sex (young woman), and the absence of ulceration. [7]

My differential diagnosis includes:

1. Erythema nodosum (most likely)
2. Erythema induratum (Bazin's disease)—but this typically affects the posterior calves and ulcerates, and is associated with TB [29]
3. Pyoderma gangrenosum—but this rapidly ulcerates with violaceous undermined edges [30]
4. Vasculitic ulcers—but these present as palpable purpura progressing to ulceration
5. Superficial thrombophlebitis—but this is linear and cord-like
6. Sweet's syndrome—but this presents with plaques more than nodules and affects the upper body more commonly [32]

My investigation strategy would be:

1. First-line (all patients):

   • Chest X-ray (mandatory)—to assess for bilateral hilar lymphadenopathy (BHL) suggesting sarcoidosis (Löfgren's syndrome) or TB [9,14]
   • FBC, ESR/CRP—markers of inflammation
   • Throat swab and ASOT titre—to detect recent streptococcal infection [17]
   • Urinalysis—to exclude vasculitis
   • Pregnancy test if appropriate

2. Second-line (based on clinical clues):

   • If BHL present: serum ACE, serum calcium (sarcoidosis)
   • If TB risk: Mantoux test or IGRA; sputum culture
   • If GI symptoms: faecal calprotectin; colonoscopy (IBD)
   • If systemic features: autoimmune screen, HIV test
   • Skin biopsy—only if atypical features (ulceration, unilateral, diagnostic uncertainty) [8]

The key is that chest X-ray is mandatory in all cases of EN to identify bilateral hilar lymphadenopathy, which occurs in 20-30% of cases and indicates Löfgren's syndrome or TB. [14]"

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Question 3: "What is Löfgren's syndrome and why is it clinically important?"

Model Answer: "Löfgren's syndrome is an acute presentation of sarcoidosis with a distinctive clinical triad: [6,12]

1. Erythema nodosum
2. Bilateral hilar lymphadenopathy (BHL) on chest X-ray
3. Polyarthritis (typically affecting the ankles)

Additional features may include fever, malaise, and anterior uveitis.

Clinical Importance: Löfgren's syndrome is clinically important because it has an excellent prognosis—more than 85% of patients experience spontaneous remission within 2 years, and only 10-15% progress to chronic sarcoidosis requiring long-term treatment. [6,12] This contrasts with other forms of sarcoidosis, which often require prolonged immunosuppression.

Because of this favourable natural history, most patients with Löfgren's syndrome do NOT require systemic corticosteroids. Management is primarily symptomatic with NSAIDs for the arthritis and erythema nodosum. Systemic steroids should be reserved for severe, disabling arthritis or uveitis. [12]

There is also an HLA association: HLA-DRB103 and HLA-DQB102 are associated with Löfgren's syndrome and predict a favourable prognosis. [28]

Recognition of Löfgren's syndrome is important to avoid overtreatment with immunosuppression in a self-limiting condition."

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Question 4: "How do you differentiate septal from lobular panniculitis, and why does it matter?"

Model Answer: "Panniculitis is classified histopathologically based on the predominant site of inflammation: [11]

Septal Panniculitis:

• Inflammation primarily in the fibrous septae between subcutaneous fat lobules
• Fat lobules are relatively spared
• Examples: Erythema nodosum, scleroderma-associated panniculitis, necrobiosis lipoidica
• Rarely ulcerates; heals without scarring
• Histology: septal inflammation, Miescher's radial granulomas (in EN), no vasculitis [8]

Lobular Panniculitis:

• Inflammation primarily within fat lobules themselves
• Septae relatively spared
• Examples: Pancreatic panniculitis, α1-antitrypsin deficiency panniculitis, lupus panniculitis, subcutaneous fat necrosis of newborn
• May ulcerate and discharge oily material
• Histology: lobular inflammation, fat necrosis, ghost cells

Why It Matters:

1. Clinical clues: If a shin lesion ulcerates, it is unlikely to be erythema nodosum (septal panniculitis). This narrows the differential to lobular panniculitis (e.g., erythema induratum) or vasculitic conditions. [7]
2. Diagnostic approach: Ulcerating panniculitis requires skin biopsy and investigation for vasculitis, TB (erythema induratum), pancreatic disease, or autoimmune conditions. [11]
3. Prognosis: Septal panniculitis (EN) has excellent prognosis and is self-limiting. Lobular panniculitis may indicate serious underlying disease (pancreatic cancer, α1-AT deficiency). [11]

Key Takeaway: Erythema nodosum is the prototypical septal panniculitis and never ulcerates—this is a critical diagnostic and examination pearl."

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Question 5: "A patient with known erythema nodosum has a chest X-ray showing bilateral hilar lymphadenopathy. What is your management approach?"

Model Answer: "Bilateral hilar lymphadenopathy (BHL) in the context of erythema nodosum strongly suggests Löfgren's syndrome—the acute presentation of sarcoidosis. [6,12] My management approach would be:

1. Confirm the Diagnosis:

• Clinical triad: Erythema nodosum + BHL + polyarthritis (particularly ankles)
• Serum ACE: Elevated in 60-70% of sarcoidosis (non-specific) [12]
• Serum calcium: Hypercalcaemia in 10-20% of sarcoidosis (rare in acute Löfgren's)
• Lymphocyte count: Lymphopenia is common in sarcoidosis
• Pulmonary function tests: Usually normal in Löfgren's (BHL only, no parenchymal involvement)
• Consider bronchoscopy with endobronchial biopsy if diagnosis uncertain, but usually not required in classic Löfgren's

2. Exclude Tuberculosis:

• BHL can also occur in TB (though typically asymmetrical)
• Mantoux test or IGRA: To exclude latent or active TB
• Sputum culture if respiratory symptoms
• Consider TB especially in endemic regions, immunosuppression, or atypical features [16]

3. Management of Löfgren's Syndrome:

• Reassure: Excellent prognosis; > 85% spontaneous remission within 2 years [6,12]
• Symptomatic treatment:
  • NSAIDs (e.g., Naproxen 500 mg BD, Ibuprofen 400 mg TDS) for arthritis and EN
  • Rest and leg elevation for EN
  • Avoid systemic corticosteroids unless severe, disabling arthritis or uveitis [12]
• No immunosuppression needed in most cases
• Follow-up:
  • Repeat CXR at 3-6 months to ensure BHL resolution
  • Monitor symptoms
  • Referral to respiratory medicine for sarcoidosis follow-up
  • If BHL persists > 2 years or systemic symptoms develop, consider chronic sarcoidosis requiring treatment

Key Point: Löfgren's syndrome is a benign, self-limiting form of sarcoidosis. The critical management decision is to avoid overtreatment with immunosuppression. Symptomatic management with NSAIDs is usually sufficient. [12]"

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Question 6: "What are the indications for skin biopsy in erythema nodosum?"

Model Answer: "Erythema nodosum is primarily a clinical diagnosis, and skin biopsy is rarely required. [8] However, biopsy should be considered in the following situations:

1. Atypical Clinical Features:

• Ulceration (EN never ulcerates; this suggests alternative diagnosis such as erythema induratum, vasculitis, pyoderma gangrenosum) [7]
• Unilateral distribution (EN is typically bilateral and symmetrical)
• Unusual location (e.g., upper body predominance; EN is typically pretibial)

2. Diagnostic Uncertainty:

• Need to exclude vasculitis (leukocytoclastic vasculitis, polyarteritis nodosa)
• Need to exclude malignancy (lymphoma, cutaneous metastases)
• Need to distinguish septal from lobular panniculitis [11]

3. Failure to Respond to Conservative Management:

• Lesions persist > 6 weeks despite treatment
• New lesions continue to appear
• Systemic symptoms worsen

4. Chronic or Recurrent EN:

• Persistent lesions despite investigation and treatment of underlying cause [25]
• Need to exclude chronic infections (TB, fungal) or autoimmune panniculitis

Biopsy Technique:

• Excisional biopsy (or deep punch biopsy ≥6 mm) to include adequate subcutaneous fat
• Biopsy early lesions (less than 1 week old) for maximum diagnostic yield
• Request histopathology to assess for septal vs lobular inflammation, vasculitis, granulomas, fat necrosis [8]

Expected Histopathology in EN:

• Septal panniculitis (inflammation in septae; lobules relatively spared)
• Miescher's radial granulomas (small histiocytic granulomas around vessels in septae)
• No vasculitis (no fibrinoid necrosis or vessel wall destruction)
• Early: neutrophilic infiltrate; Late: lymphocytic/histiocytic
• Haemorrhage and haemosiderin deposition in resolving lesions [8,11]

Key Takeaway: In typical presentations of EN (bilateral, pretibial, tender, non-ulcerating nodules in a young woman), biopsy is not needed. Reserve biopsy for atypical cases or diagnostic uncertainty."

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13. Patient/Layperson Explanation

What is Erythema Nodosum?

Erythema nodosum (EN) is a skin condition that causes painful, red lumps under the skin, usually on the shins. These lumps are caused by inflammation in the layer of fat beneath the skin. EN is not a disease itself—it's a reaction to other things happening in your body, such as infections, certain medications, or other medical conditions.

What Causes It?

Erythema nodosum can be triggered by many different things:

• Infections: The most common is a throat infection caused by bacteria called Streptococcus (the same bacteria that cause "strep throat")
• Medications: Birth control pills, some antibiotics (like penicillin or sulfa drugs), and anti-inflammatory drugs
• Other Medical Conditions: Inflammatory bowel disease (Crohn's disease or ulcerative colitis), sarcoidosis (a condition affecting the lungs), or tuberculosis
• Pregnancy: Some women develop EN during pregnancy
• Unknown Causes: In about half of cases, doctors cannot find a specific cause

What Are the Symptoms?

• Painful red lumps: Usually on the front of your lower legs (shins), but sometimes on thighs or arms
• Tenderness: The lumps are very tender to touch and painful when you stand or walk
• Colour changes: The lumps start out red or purple, then gradually fade to yellow and brown, like a bruise
• Other symptoms: You may feel generally unwell with fever, tiredness, and aching joints (especially ankles)

How is It Diagnosed?

Your doctor can usually diagnose EN by examining your skin. They may order some tests to find the cause:

• Chest X-ray: To check your lungs (very important—all patients with EN need a chest X-ray)
• Blood tests: To check for infections or inflammation
• Throat swab: To test for strep throat
• Other tests: Depending on your symptoms, you may need tests for tuberculosis, inflammatory bowel disease, or other conditions

How is It Treated?

The good news is that erythema nodosum usually goes away on its own within 3 to 6 weeks. Treatment focuses on:

1. Relieving Symptoms:

• Rest: Keep your legs elevated as much as possible
• Pain relief: Anti-inflammatory medications like ibuprofen or naproxen
• Compression stockings: These can help reduce swelling and pain
• Cool compresses: Applying cool cloths to the lumps may help

2. Treating the Cause:

• If you have a throat infection, you'll get antibiotics
• If a medication is causing it, your doctor will stop that medication
• If an underlying condition is found (like inflammatory bowel disease), that will be treated

3. What to Avoid:

• You usually do not need strong medications like steroids
• Avoid standing for long periods

Will It Leave Scars?

No. This is one of the key features of erythema nodosum—the lumps never break open or form ulcers, and they heal completely without leaving scars. You may have temporary brown discolouration where the lumps were, but this fades over time.

Will It Come Back?

• In most cases, EN is a one-time event and does not return
• If the underlying cause is not found or treated, EN can come back (about 10-20% of people experience recurrence)
• If you had EN triggered by a medication, you should avoid that medication in the future

When Should I See a Doctor?

See your doctor if:

• You develop painful lumps on your legs
• The lumps break open or form sores (this would not be EN and needs urgent evaluation)
• You develop fever, weight loss, night sweats, or persistent cough
• The lumps do not improve after 6 weeks
• You develop new symptoms

Key Takeaways

• Erythema nodosum is a common, benign skin reaction
• It causes painful red lumps on the shins that heal without scars
• It usually goes away on its own in 3-6 weeks
• The most important thing is to find and treat the underlying cause
• Rest, elevate your legs, and take anti-inflammatory painkillers for symptom relief

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