Skin & Subcutaneous Tissue

Erythema nodosum: differential and workup

Clinical Overview and When to Suspect Erythema Nodosum

— Adult (especially women 20–40, F:M ≈ 4:1) with sudden bilateral, painful, warm shin nodules

— Antecedent sore throat, GI illness, new medication, or pulmonary symptoms in the prior 1–3 weeks

— Prodrome of fever, malaise, arthralgias (especially ankles)

— Lesions that never ulcerate and resolve over 3–6 weeks with bruise-like color change ("erythema contusiforme") and no scarring

— No cause identified (idiopathic, ~30–50%)

— Oral contraceptives, pregnancy (hormonal)

— Drugs: sulfonamides, penicillins, bromides, iodides

— Occult or overt infection: streptococcal pharyngitis (#1 identified cause in adults and children), TB, Yersinia, Salmonella, Campylobacter, coccidioidomycosis, histoplasmosis

— Sarcoidosis (Löfgren syndrome)

— Ulcerative colitis / Crohn disease

— Malignancy (lymphoma, leukemia) — uncommon but board-relevant

Erythema nodosum (EN) is the most common septal panniculitis — a delayed-type hypersensitivity reaction of subcutaneous fat producing tender, erythematous, poorly demarcated nodules, classically on the anterior pretibial shins.

It is a reaction pattern, not a disease — the central Step 3 task is to identify the underlying trigger while providing symptomatic care.

When to suspect:

Top etiologic categories (mnemonic NODOSUM):

Board pearl: In the US, streptococcal infection is the most common identifiable cause overall; in endemic regions, suspect coccidioidomycosis ("desert bumps") or TB. In Europe, sarcoidosis climbs the list.

Key distinction: EN is reactive and self-limited — workup is aimed at the trigger, not at the skin. A biopsy is rarely needed unless the presentation is atypical (unilateral, ulcerating, persistent >8 weeks, or non-pretibial).

Presentation Patterns and Key History

— Recent infection: sore throat (GAS), diarrhea (Yersinia, Salmonella, Campylobacter), respiratory symptoms (TB, Mycoplasma, fungi, sarcoid)

— Travel/exposure: Southwest US (coccidioidomycosis), Ohio/Mississippi valleys (histoplasmosis), TB endemic areas, unpasteurized dairy

— Medications started 1–3 weeks prior: sulfonamides (Bactrim, sulfasalazine), penicillins, oral contraceptives or hormonal therapy, halides, TNF inhibitors paradoxically

— Pregnancy (1st–2nd trimester)

— GI symptoms: chronic diarrhea, hematochezia, weight loss → IBD (especially Crohn)

— Pulmonary: cough, dyspnea, bilateral hilar adenopathy on prior imaging → Löfgren syndrome

— Constitutional: night sweats, weight loss → lymphoma, TB

— EN + bilateral hilar lymphadenopathy + migratory polyarthralgias (ankles) ± fever/uveitis

— Excellent prognosis, often resolves in <2 years; biopsy often unnecessary if classic

Classic onset: abrupt eruption over 1–2 days of 3–10 cm tender, erythematous, indurated nodules on the bilateral shins; lesions feel warm and deep, "more palpable than visible."

Prodrome (50–75%): fever, fatigue, arthralgias of the ankles and knees, occasionally frank arthritis — can precede skin lesions by 1–3 weeks.

Evolution: lesions never suppurate, never ulcerate, and heal without scarring, fading through bruise-like colors (red → purple → yellow-green). New crops may appear over 3–6 weeks.

Targeted history — the trigger hunt:

Löfgren syndrome triad (acute sarcoidosis):

Step 3 management: Build your differential before ordering tests — a structured history (recent strep, travel, GI symptoms, drugs, pregnancy, pulmonary symptoms) drives a focused workup rather than shotgun panels, which is the high-value-care answer on the exam.

Board pearl: Migratory periarticular ankle inflammation with EN is virtually pathognomonic for Löfgren syndrome until proven otherwise.

Physical Exam Findings (and Hemodynamic Assessment when relevant)

— Bilateral, symmetric tender erythematous nodules, 1–5 cm, on the anterior shins (pretibial); thighs, forearms, and extensor surfaces possible but less typical

— Poorly demarcated, deep, palpable more than visible — feel like "bruises under the skin"

— Warm and exquisitely tender to palpation; pain may limit ambulation

— No ulceration, no fluctuance, no scarring, no atrophy — these features should redirect the differential

— Color evolution mimics a contusion (erythema contusiforme)

— Pharynx: erythema, exudate, tender anterior cervical nodes → strep

— Lungs: dry cough, normal exam often; consider sarcoid, TB, fungi

— Lymph nodes: generalized adenopathy → sarcoid, lymphoma, TB

— Abdomen: RLQ tenderness, perianal disease, oral aphthae → Crohn; bloody diarrhea → UC

— Eyes: anterior uveitis, conjunctivitis → sarcoid, IBD, Behçet

— Joints: symmetric ankle/knee tenderness with effusion — periarticular more than intra-articular

— Genital/oral ulcers: Behçet

— Skin elsewhere: lupus pernio, scars infiltrated with sarcoid; pyoderma gangrenosum (IBD); pathergy (Behçet)

Cutaneous exam — the defining features:

Systemic exam — clue to underlying etiology:

Vital signs: low-grade fever common; hemodynamic instability is NOT a feature of EN itself — if present, suspect a complication of the underlying disease (sepsis, IBD flare with hypovolemia).

Key distinction: EN vs erythema induratum (nodular vasculitis) — induratum favors posterior calves, ulcerates, and is associated with TB; histology is lobular panniculitis with vasculitis, whereas EN is septal panniculitis without vasculitis.

Board pearl: Lesions on posterior calves, with ulceration or scarring, should prompt biopsy and TB workup — that is not classic EN.

Diagnostic Workup — Initial Labs and Imaging

— CBC with differential — leukocytosis (infection), eosinophilia (drug/parasitic), cytopenias (malignancy, lupus)

— ESR and CRP — almost always elevated; useful for tracking, not diagnosis

— Comprehensive metabolic panel — baseline before NSAIDs/steroids; LFTs (sarcoid, hepatitis)

— Throat culture or rapid strep antigen + ASO titer (or anti-DNase B if delayed presentation, since ASO peaks at 3–6 weeks)

— Pregnancy test in reproductive-age women (etiology and therapy implications)

— Chest X-ray — single highest-yield test: bilateral hilar adenopathy (sarcoid/Löfgren), unilateral hilar or apical infiltrate (TB), nodules (fungi, malignancy)

— PPD or interferon-gamma release assay (IGRA, e.g., QuantiFERON) — exclude TB before any steroid course

— GI symptoms: stool culture (Yersinia, Salmonella, Campylobacter), fecal calprotectin, consider colonoscopy if IBD suspected

— Travel/exposure: Coccidioides serology, Histoplasma urine antigen

— Drug exposure: review timeline; stop offending agent

— Suspected sarcoid: serum ACE (insensitive but supportive), serum calcium, 1,25-OH vitamin D

— Behçet suspicion: pathergy test

EN is a clinical diagnosis; testing is aimed at identifying a treatable trigger and excluding mimics. Order targeted, not shotgun, studies.

Universal baseline (every patient):

Targeted by history:

Step 3 management: In a young woman with classic bilateral pretibial EN, ankle arthralgias, and recent sore throat, the high-value initial panel is CBC, ESR/CRP, ASO/throat culture, chest X-ray, and PPD/IGRA — not a broad rheumatology screen.

Board pearl: Chest X-ray is mandatory in every EN patient — it simultaneously screens for sarcoidosis, TB, and lymphoma, the three high-stakes etiologies.

Diagnostic Workup — Advanced or Confirmatory Studies

— Reserved for atypical presentations: unilateral, ulcerating, lesions >8 weeks, non-pretibial sites, or diagnostic uncertainty

— Requires a deep incisional or excisional biopsy down to subcutaneous fat — a standard punch is too shallow and frequently nondiagnostic

— Classic histology: septal panniculitis without vasculitis, Miescher radial granulomas (small histiocytic aggregates around a central cleft) are pathognomonic

— Chest CT if CXR is suggestive but nondiagnostic, or if persistent pulmonary symptoms — characterizes hilar/mediastinal adenopathy, parenchymal nodules

— Abdominal imaging or colonoscopy if IBD suspected (calprotectin elevated, chronic diarrhea, weight loss)

— Sarcoidosis: transbronchial biopsy showing non-caseating granulomas if imaging atypical; in classic Löfgren syndrome, biopsy is often unnecessary — diagnosis can be clinical

— TB: sputum AFB ×3, NAAT, culture; treat latent TB before immunosuppression

— Fungal: serology, urine antigens, occasionally bronchoscopy

— IBD: colonoscopy with biopsy

— Behçet: clinical criteria (recurrent oral ulcers + 2 of: genital ulcers, eye lesions, skin lesions, positive pathergy)

— Lymphoma: lymph node biopsy if persistent adenopathy

Skin biopsy — when and how:

Imaging escalation:

Serologic and microbiologic confirmation by suspected etiology:

Key distinction: Septal panniculitis without vasculitis = EN; lobular panniculitis with vasculitis = erythema induratum (Bazin), often TB-associated; lobular panniculitis without vasculitis = pancreatic, lupus, or α1-antitrypsin panniculitis.

Board pearl: Miescher radial granulomas on deep biopsy are the histologic signature of EN. If the stem describes "punch biopsy was nondiagnostic," the lesson is biopsy depth — repeat with an incisional sample.

Step 3 management: Do not start systemic steroids until TB has been excluded and a CXR obtained — a common test trap.

Risk Stratification and First-Line Management Logic

— Step 1: Identify and treat the underlying cause (strep, IBD flare, sarcoid, discontinue offending drug)

— Step 2: Symptomatic relief of pain and inflammation

— Step 3: Escalate to systemic agents only if persistent, recurrent, or disabling

— Mild: few lesions, ambulatory, minimal arthralgias → bed rest, leg elevation, compression, NSAIDs

— Moderate: multiple painful lesions, impaired ambulation → add potassium iodide (SSKI) if no thyroid disease, or short corticosteroid course after TB exclusion

— Severe/recurrent/chronic: colchicine, hydroxychloroquine, or immunomodulators; search harder for an underlying systemic disease

— Leg elevation and rest — gravitational stasis worsens lesions

— Compression stockings (15–20 mmHg) once acute tenderness allows

— Cool compresses

— NSAIDs: ibuprofen 400–800 mg TID or naproxen 500 mg BID — caution in IBD (may worsen flare), pregnancy (avoid in 3rd trimester), and renal disease

— Discontinue oral contraceptives if temporally related

— Stop culprit drug (sulfa, penicillin, halides)

— Treat documented streptococcal pharyngitis with penicillin V or amoxicillin

EN is self-limited in the majority — most cases resolve in 3–6 weeks without sequelae. Management hierarchy:

Severity stratification:

General supportive care (first-line for all):

Triggers to remove immediately:

Step 3 management: In a primary care visit, a patient with classic EN, normal CXR, and recent strep should be sent home with NSAIDs, leg elevation, penicillin for documented GAS, and a 2-week follow-up — not steroids, not biopsy.

Board pearl: Never start oral steroids for EN without ruling out TB and occult infection first — this is a recurring exam trap.

Key distinction: Treating the trigger often resolves EN; treating only the skin without finding the trigger is a board-wrong answer.

Pharmacotherapy — First-Line Drug Regimen

— Ibuprofen 400–800 mg PO every 6–8 hours, or naproxen 500 mg PO BID, or indomethacin 25–50 mg PO TID

— Duration: 2–4 weeks until lesions involute

— Avoid in IBD-associated EN — may precipitate flare; use acetaminophen + topical/short steroids instead

— Avoid in 3rd-trimester pregnancy (ductus closure), CKD, active GI bleed

— Dose: 300–900 mg/day PO in divided doses (typically 5 drops TID of saturated solution, titrated)

— Mechanism: suppresses neutrophil chemotaxis and granuloma formation

— Best response when started early (<1 month); often dramatic within days

— Contraindications: pregnancy (fetal goiter/hypothyroidism), known thyroid disease, hyperkalemia

— Monitor TSH if used >1 month

— Prednisone 40 mg PO daily, tapered over 2–4 weeks

— Prerequisites: rule out TB (PPD/IGRA + CXR) and active infection first

— Avoid if EN is the presenting feature of an undiagnosed infection — can mask and worsen

— Use cautiously in IBD (may help bowel disease simultaneously)

— GAS pharyngitis: penicillin V 500 mg PO BID × 10 days or amoxicillin 1 g daily

— Sarcoidosis/Löfgren: NSAIDs usually sufficient; reserve steroids for organ involvement

— IBD: treat underlying disease — mesalamine, steroids, biologics

NSAIDs — first-line for pain and inflammation:

Potassium iodide (SSKI) — second-line, often very effective:

Systemic corticosteroids — for severe, disabling, or refractory cases only:

Colchicine 0.6 mg BID — useful in Behçet-associated EN and recurrent disease

Hydroxychloroquine 200–400 mg/day — chronic/recurrent EN, particularly with sarcoid

Other: dapsone, methotrexate, TNF inhibitors for refractory cases (specialist territory)

Etiology-specific therapy:

Board pearl: SSKI is the classic "non-steroid escalation" answer for EN unresponsive to NSAIDs — but contraindicated in pregnancy; choose acetaminophen + rest there.

Step 3 management: Document negative TB screen in the chart before any steroid course — a defensible, exam-correct safety habit.

Expanded Pharmacology and Trigger-Directed Therapy

— Confirm with throat culture/rapid antigen or rising ASO/anti-DNase B

— Penicillin V 500 mg PO BID × 10 days (first-line); amoxicillin 1 g daily × 10 days; cephalexin, azithromycin, or clindamycin for penicillin allergy

— Recurrent strep-associated EN: consider tonsillectomy in select cases

— Latent TB (positive IGRA/PPD, normal CXR): isoniazid + rifapentine weekly × 12 weeks (3HP) or isoniazid daily × 9 months

— Active TB: RIPE therapy

— Must complete latent treatment before immunosuppression

— Most cases self-resolve; NSAIDs ± colchicine suffice

— Prednisone 20–40 mg/day if pulmonary, cardiac, neurologic, ocular, or hypercalcemic involvement

— Steroid-sparing: methotrexate, hydroxychloroquine

— Treat the bowel disease — EN parallels disease activity

— Mesalamine for mild UC; steroids for flare; anti-TNF (infliximab, adalimumab) for moderate–severe disease, which also reliably controls EN

— Stop the drug — sulfonamides, penicillins, OCPs, halides, sometimes vaccines, TNF inhibitors paradoxically

— Resolution within 2–6 weeks expected

— EN signals good immune containment and often does not require antifungal therapy

— Treat with fluconazole if disseminated, immunocompromised, or symptomatic

— Usually self-limits postpartum; supportive care only

Because EN is non-procedural, the "interventional" management is trigger-directed therapy:

Streptococcal disease:

Tuberculosis:

Sarcoidosis/Löfgren syndrome:

IBD-associated EN:

Drug-induced EN:

Coccidioidomycosis:

Pregnancy-associated:

CCS pearl: On CCS, a typical EN case advances as: CBC, ESR/CRP, throat culture, ASO, chest X-ray, PPD/IGRA, pregnancy test → counsel rest/elevation, NSAID → 2-week follow-up → if persistent, add SSKI or escalate workup. Don't order broad ANA/rheum panels reflexively — they lose points.

Board pearl: Treating the underlying disease resolves EN more reliably than skin-directed therapy.

Special Populations — Elderly and Renal/Hepatic Impairment

— EN is less common after age 70 — when it occurs, raise suspicion for occult malignancy (especially lymphoma, leukemia, solid tumors) and drug etiology (polypharmacy)

— Broader workup justified: age-appropriate cancer screening up-to-date, peripheral smear, LDH, SPEP if indicated, imaging if B-symptoms

— Comorbid CAD, HF, CKD limit NSAID use → favor acetaminophen, topical measures, and short low-dose prednisone after infection exclusion

— Avoid NSAIDs — risk of AKI, hyperkalemia, worsening CKD

— Avoid SSKI with significant CKD — iodide accumulates; risk of iodism (metallic taste, coryza, rash, GI upset) and hyperkalemia (potassium load)

— Preferred: acetaminophen, leg elevation, compression, low-dose prednisone short course

— Adjust steroids minimally (no major renal dose change), but monitor glucose, BP, fluid status

— NSAIDs generally tolerated in compensated disease; avoid in decompensated cirrhosis (variceal bleed, hepatorenal risk)

— Acetaminophen safe at ≤2 g/day in cirrhosis

— Steroids: monitor for infection, hyperglycemia, fluid retention; cautious in viral hepatitis (reactivation risk for HBV → check HBsAg, anti-HBc before steroid course)

— NSAIDs + ACEi/ARB + diuretic = "triple whammy" AKI

— NSAIDs + warfarin or DOAC = bleeding

— Prednisone + insulin/sulfonylurea = hyperglycemia

— SSKI + ACEi/ARB/spironolactone = hyperkalemia

Elderly patients:

Renal impairment (CKD stage 3–5):

Hepatic impairment:

Drug-drug interaction landmines in older adults:

Step 3 management: In a 75-year-old with new EN and weight loss, the next best step is age-appropriate cancer evaluation (CBC with diff, peripheral smear, LDH, CXR, imaging of suspicious findings, ensure colonoscopy and mammography up to date) — not empiric steroids.

Board pearl: New-onset EN in an older adult with B-symptoms = think lymphoma until proven otherwise.

Special Populations — Pregnancy, Pediatrics, and Other Subgroups

— EN occurs in ~2% of pregnancies, typically 1st–2nd trimester; hormonally driven

— Usually self-resolves postpartum; recurrence in subsequent pregnancies or with OCPs is characteristic

— Treatment: rest, leg elevation, compression, acetaminophen

— Avoid NSAIDs in 3rd trimester (premature ductus closure, oligohydramnios)

— SSKI contraindicated — fetal goiter and congenital hypothyroidism

— Systemic steroids: prednisone preferred (extensively metabolized by placental 11β-HSD2) if essential; avoid dexamethasone/betamethasone (cross placenta, fetal effects) unless fetal indication

— Always exclude other pregnancy-related causes: infections, IBD flare

— Streptococcal pharyngitis is the dominant cause in children

— Other pediatric considerations: EBV, Mycoplasma, Yersinia, IBD, Kawasaki, JIA, primary TB

— Workup mirrors adults: throat culture, ASO, CBC, ESR/CRP, CXR, PPD/IGRA

— Sarcoidosis rare in children; if suspected → consider Blau syndrome (early-onset sarcoid + arthritis + uveitis, NOD2 mutation)

— Treat with acetaminophen and NSAIDs, leg elevation; treat strep with amoxicillin

— Temporal association → trial discontinuation of OCP

— Counsel on alternative contraception (copper or progestin-only IUD, barrier methods)

— EN may recur in subsequent pregnancy — anticipate, not alarming

— Lower threshold for infectious workup including atypical mycobacteria, deep fungi

— TNF inhibitors paradoxically cause EN-like reactions — recognize as drug etiology

Pregnancy:

Pediatrics:

Reproductive-age women on OCPs:

Immunocompromised patients (HIV, transplant, biologics):

Board pearl: Pregnancy + EN = supportive care only; avoid NSAIDs late, avoid SSKI entirely, avoid empiric immunosuppression — most resolve postpartum.

Step 3 management: A young woman on OCPs with recurrent EN → stop OCP, switch contraceptive method, recheck in 4–6 weeks; if it recurs off OCP, search harder for sarcoid/IBD.

Complications and Adverse Outcomes

— Recurrent disease (~30%) — particularly idiopathic and IBD-associated forms

— Chronic EN (>6 months) — persistent nodules without ulceration; suggests ongoing trigger (sarcoid, IBD, occult infection)

— Functional impairment: pain, difficulty ambulating, missed work — relevant for disability and return-to-work counseling

— Post-inflammatory hyperpigmentation — common, fades over months; scarring does not occur in true EN — if scarring is present, reconsider diagnosis

— Untreated TB progressing during steroid therapy

— Occult lymphoma or solid tumor in older patients

— Active IBD unrecognized → bowel complications, fistulae

— Untreated coccidioidomycosis disseminating in immunocompromised hosts

— Behçet with progression to vascular or CNS disease

— NSAIDs: GI bleed, AKI, HTN exacerbation, IBD flare

— SSKI: iodism (metallic taste, rhinorrhea, parotid swelling, acneiform rash), thyroid dysfunction (Jod-Basedow or hypothyroidism), hyperkalemia, contraindicated in pregnancy

— Corticosteroids: hyperglycemia, hypertension, infection reactivation (TB, HBV, Strongyloides), osteoporosis, mood, adrenal suppression

— Colchicine: diarrhea, myopathy, cytopenias (especially with CKD or CYP3A4 inhibitors)

— Ulceration, scarring, atrophic changes

— Unilateral or non-pretibial location

— Duration >8 weeks despite trigger removal

— Worsening systemic symptoms

— New organ involvement

EN itself is benign and self-limited — true complications are uncommon and usually reflect either (1) the underlying disease or (2) therapy adverse effects.

Disease-related morbidity:

Missed underlying diagnosis — the real exam danger:

Treatment-related complications:

Red flags that mandate reassessment:

Board pearl: Scarring or ulceration excludes EN — biopsy is mandatory; consider erythema induratum, cutaneous polyarteritis nodosa, pancreatic panniculitis, or lupus panniculitis.

Key distinction: Most "complications" of EN on exams are really complications of the missed underlying diagnosis — TB during steroids is the canonical trap.

When to Escalate Care — ICU, Consult, or Inpatient Triage

— Hemodynamically stable, ambulatory (even if uncomfortable)

— No signs of systemic infection, sepsis, or organ involvement

— Reliable follow-up in 1–2 weeks

— Severe systemic illness suggestive of active TB, disseminated fungal infection, or sepsis

— IBD flare with dehydration, severe pain, GI bleeding, or megacolon

— Acute sarcoidosis with cardiac (heart block), neurologic (cranial neuropathy, meningitis), or severe pulmonary involvement

— Hypercalcemia from sarcoidosis with AKI or symptoms

— Suspected malignancy requiring expedited workup (lymphoma with B-symptoms, SVC syndrome)

— Behçet with neuro-Behçet, large-vessel involvement, or pulmonary artery aneurysm

— Dermatology: atypical lesions, biopsy interpretation, refractory disease, alternative panniculitides

— Rheumatology: suspected sarcoid, Behçet, vasculitis

— Pulmonology: abnormal CXR, hilar adenopathy, suspected TB or sarcoid for bronchoscopy

— Gastroenterology: suspected IBD — colonoscopy

— Infectious disease: suspected TB, endemic fungi, atypical organisms, immunocompromised host

— Hematology-oncology: persistent adenopathy, B-symptoms, abnormal CBC

— Obstetrics: pregnancy-associated EN with management questions

— Ophthalmology: any ocular symptoms in possible sarcoid, Behçet, or IBD

EN itself virtually never requires hospitalization — escalation is driven by the underlying disease or systemic toxicity.

Outpatient management is appropriate when:

Consider inpatient admission for:

Consultations to consider:

CCS pearl: A CCS EN case rarely needs admission; the high-value moves are ordering CXR and PPD/IGRA at the first visit, calling appropriate consults asynchronously, and scheduling a 2-week follow-up rather than admitting. Inappropriate admission loses points.

Step 3 management: If a patient with EN develops new chest pain, syncope, or AV block, suspect cardiac sarcoidosis — admit, telemetry, cardiology consult, cardiac MRI/PET.

Board pearl: Inability to ambulate from pain alone is not an admission criterion — manage as outpatient with rest, NSAIDs, and home support.

Key Differentials — Same-Category Causes (Other Panniculitides)

— Posterior calves, often ulcerating, scarring

— Lobular panniculitis with vasculitis on biopsy

— Strongly associated with TB (id reaction); check PPD/IGRA

— Treatment: anti-TB therapy if TB-positive; otherwise SSKI, steroids

— Tender subcutaneous nodules, often lower extremities, may ulcerate with oily discharge

— Associated with pancreatitis or pancreatic carcinoma (especially acinar cell)

— Lipase markedly elevated; "ghost cells" with saponification on biopsy (lobular panniculitis without vasculitis)

— Schmid triad: panniculitis + polyarthritis + eosinophilia

— Face, upper arms, breasts, buttocks — atypical for EN

— Heals with atrophy/lipoatrophy ("dimpling")

— Lobular panniculitis with lymphocytic infiltrate; ANA often positive

— Spontaneous or trauma-induced ulcerating nodules, often trunk

— Check α1-antitrypsin level and phenotype

— Treat with α1-antitrypsin replacement or dapsone

— Children, on cheeks after cold exposure; benign

— Chronic, recurrent nodules; constitutional symptoms; hemophagocytic syndrome risk

— Requires biopsy, hematology referral

— Tender plaques, fever, neutrophilia — overlaps clinically; favors upper extremities, face

— Associated with AML, IBD, infections, pregnancy

— Septal panniculitis without vasculitis → EN

— Septal panniculitis with vasculitis → superficial thrombophlebitis, cutaneous PAN

— Lobular panniculitis without vasculitis → pancreatic, lupus, α1-AT, cold, infectious

— Lobular panniculitis with vasculitis → erythema induratum

Erythema induratum (nodular vasculitis / Bazin disease):

Pancreatic panniculitis:

Lupus panniculitis (lupus profundus):

α1-antitrypsin deficiency panniculitis:

Cold panniculitis ("popsicle panniculitis"):

Subcutaneous panniculitis-like T-cell lymphoma:

Sweet syndrome (acute febrile neutrophilic dermatosis):

Key distinction — biopsy framework:

Board pearl: Location + ulceration + biopsy pattern discriminate panniculitides — the exam loves the anterior shin, no ulceration, septal pattern triad for EN.

Key Differentials — Other-Category Causes

— Unilateral, warm, sharply demarcated erythema; fever, leukocytosis; lymphangitic streaking

— Often a portal of entry (tinea pedis, ulcer)

— Treat with empiric antibiotics; EN is bilateral and nodular, cellulitis is unilateral and diffuse

— Unilateral leg pain, swelling; risk factors (immobility, malignancy, OCP, recent surgery)

— D-dimer, duplex ultrasound confirms

— Thrombophlebitis: palpable cord along a vein

— Pruritic, often clustered, with central punctum; history of exposure

— Painful nodules with livedo reticularis, may ulcerate; on lower legs

— Associated with HBV, HCV, strep

— Biopsy: medium-vessel vasculitis

— Target lesions on extremities, palms/soles; mucosal involvement

— Post-HSV or drug-induced; not nodular

— EN-like lesions plus oral/genital ulcers, uveitis, pathergy

— Necrotizing fasciitis: rapidly progressive pain out of proportion, crepitus, systemic toxicity — surgical emergency

— Mycobacterial or fungal infection in immunocompromised hosts

— Non-pitting, waxy, peau d'orange plaques; thyroid eye disease; elevated TSH receptor antibodies — not tender

— Chronic, bilateral, hyperpigmented, scaly; venous insufficiency; not acutely tender nodular

— Systemic features (renal, neuro, GI), HBV association, mesenteric angiography findings

Cellulitis / erysipelas:

Deep vein thrombosis / superficial thrombophlebitis:

Insect bites / arthropod reactions:

Nodular vasculitis (cutaneous polyarteritis nodosa):

Erythema multiforme:

Behçet disease cutaneous lesions:

Sweet syndrome (covered in chunk 13)

Infectious cellulitis-mimics:

Pretibial myxedema (Graves disease):

Stasis dermatitis:

Polyarteritis nodosa (systemic):

Key distinction: Bilateral, symmetric, non-ulcerating, anterior shin nodules = EN; unilateral, ulcerating, or systemic vasculitic features = alternative diagnosis.

Board pearl: A "cellulitis not improving on antibiotics" vignette with bilateral shin lesions is a classic EN disguise — stop antibiotics, search for trigger.

Secondary Prevention / Discharge Plan and Long-Term Management

— Confirm trigger (strep treated, drug stopped, IBD plan in place, sarcoid followed, etc.)

— Symptomatic care: continue NSAIDs or acetaminophen as needed; leg elevation; compression

— Activity: gradual return as tolerated; avoid prolonged standing during recovery

— Skin care: expect bruise-like discoloration for weeks; reassure no scarring

— Drug-induced: document allergy/intolerance, list in chart, MedicAlert if severe; avoid culprit class (e.g., all sulfonamides)

— OCP-related: switch to non-hormonal or progestin-only contraception

— Recurrent strep: consider tonsillectomy referral after multiple documented episodes

— IBD: optimize maintenance therapy — EN typically flares with bowel activity

— Sarcoidosis: longitudinal monitoring (pulmonary, ophthalmologic, cardiac, calcium, vitamin D)

— Ensure TB screening up to date before any future immunosuppression

— Pneumococcal, influenza, COVID vaccines, especially if on chronic steroids

— Hepatitis B screening before TNF inhibitors or steroids

— If steroids used >3 months: consider bone density, calcium/vitamin D, PJP prophylaxis if prednisone ≥20 mg/day for ≥4 weeks

— Annual TSH monitoring if SSKI used long-term

EN is reactive — "secondary prevention" means prevention of recurrence by addressing the underlying trigger and avoiding precipitants.

Discharge / outpatient plan after acute episode:

Trigger avoidance and counseling:

Vaccinations and infection prevention:

Long-term medication review:

Step 3 management: At the 2-week follow-up, confirm lesion regression, document trigger identified and addressed, and decide on referrals (GI for IBD workup, pulm/rheum for sarcoid). Re-image the chest only if symptoms persist or new findings arise.

Board pearl: Recurrence of EN within 6–12 months should prompt a more thorough evaluation for sarcoidosis, IBD, or Behçet — these are the underdiagnosed chronic causes.

Key distinction: EN does not require chronic immunosuppression — chronic therapy reflects the underlying disease, not the EN itself.

Follow-Up, Monitoring Parameters, and Counseling

— 2 weeks after initial presentation — confirm improvement, review test results (ASO, cultures, CXR, IGRA), reassess trigger

— 4–6 weeks — should be largely resolved; if not, expand workup

— 3 months — if recurrent or chronic, refer to dermatology/rheumatology

— Long-term: dictated by underlying disease (annual sarcoid surveillance, IBD maintenance schedule)

— NSAIDs: BP, renal function, GI symptoms; check Cr at 2–4 weeks if prolonged use

— SSKI: TSH at baseline and every 1–3 months; watch for iodism symptoms; serum K+ if renal disease

— Corticosteroids: glucose, BP, weight, mood, sleep; DEXA at baseline if anticipated >3 months; stress-dose planning if course >3 weeks

— Colchicine: CBC, CK, renal function, GI tolerance

— Hydroxychloroquine: baseline and annual ophthalmologic exam (retinal toxicity); CBC, LFTs

— EN is a reaction, not a disease — finding the cause is the goal

— Expect 3–6 weeks of healing with bruise-like color change, no scarring

— Rest and leg elevation are as important as medication

— Recurrence is possible (~30%); return for evaluation if new lesions, ulceration, fever, weight loss, joint swelling, eye symptoms, or GI symptoms

— Smoking cessation in sarcoid/IBD patients (worsens both)

— Lesion ulceration or scarring

— Persistent fever, B-symptoms

— New joint, eye, lung, GI, or neurologic symptoms

— No improvement after 4 weeks of supportive care

Follow-up cadence:

Monitoring parameters by therapy:

Patient counseling — key teaching points:

Return precautions (red flags):

Step 3 management: Document a trigger identified or excluded, TB screening complete, and follow-up scheduled — this is the defensible, high-value visit closure for EN.

Board pearl: Recurrent or chronic EN beyond 6 weeks mandates re-evaluation for sarcoidosis, IBD, and TB even if initial workup was normal — repeat CXR and consider colonoscopy.

Ethical, Legal, and Patient Safety Considerations

— Before initiating systemic corticosteroids, document discussion of infection reactivation (TB, HBV, Strongyloides), hyperglycemia, osteoporosis, mood — and document TB and HBV screening results in the chart

— Before SSKI in a reproductive-age woman, confirm negative pregnancy test and counsel on contraception during therapy; document teratogenic risk discussion

— For pediatric patients, obtain parental consent and assent from adolescents per state law

— Active TB discovered during EN workup → report to public health department within state-required timeframe; arrange contact tracing

— Certain reportable infectious causes (e.g., coccidioidomycosis, salmonellosis, shigellosis, typhoid) — know that local rules vary, default to reporting

— When discharging from ED or urgent care, explicitly hand off pending studies (ASO, IGRA, cultures, CXR read) to the PCP with a named follow-up date

— Avoid the "no one will check the IGRA" trap — institutional closed-loop result tracking is a patient safety best practice

— Provide written instructions on red-flag symptoms and how to access care

— Confirm patient can afford NSAIDs/contraception alternatives if OCPs are stopped

— Coordinate with social work if TB or IBD diagnosis affects employment, school, insurance

— Labeling a sulfonamide reaction as an "allergy" without specifying severity may inappropriately restrict future antibiotic options; document reaction type (EN, not anaphylaxis)

— Avoid premature closure: do not write "EN, idiopathic" until CXR, TB, strep, drug, pregnancy are addressed

— Avoid NSAIDs in 3rd trimester, SSKI throughout, and high-potency steroids without obstetric coordination

Informed consent — therapy choices with non-trivial risks:

Mandatory reporting:

Transition-of-care safety (high Step 3 yield):

Health equity and access:

Documentation pitfalls:

Pregnancy-specific safety:

Step 3 management: When starting prednisone for severe EN, the documentable safety checklist is: TB screen negative, HBV serologies checked, glucose baseline, bone health addressed if >3 months anticipated, patient counseled on infection precautions, follow-up arranged.

Board pearl: A missed positive PPD/IGRA before steroid initiation is a patient safety event — closed-loop result review is the system fix.

High-Yield Associations and Rapid-Fire Clinical Facts

Anatomy: anterior pretibial shins, bilateral, symmetric — the location is a near-required feature

Histology: septal panniculitis without vasculitis; Miescher radial granulomas are pathognomonic

Demographics: women 20–40, F:M ≈ 4:1

Most common identifiable trigger (US): streptococcal pharyngitis

Most common cause overall: idiopathic (~30–50%)

Löfgren syndrome: EN + bilateral hilar adenopathy + migratory ankle arthralgias = acute sarcoidosis with excellent prognosis

Heerfordt syndrome: parotid enlargement + uveitis + fever + facial nerve palsy = another acute sarcoid presentation (not EN per se, but tested alongside)

Drugs — classic culprits: sulfonamides, penicillins, oral contraceptives, halides (iodides, bromides)

Infections: strep, TB, Yersinia, Salmonella, Campylobacter, Coccidioides, Histoplasma, Mycoplasma, EBV

GI: Crohn > UC; EN parallels bowel activity

Mandatory test in every workup: chest X-ray (and PPD/IGRA before any steroid)

First-line therapy: rest, leg elevation, NSAIDs; treat the trigger

Second-line: SSKI (potassium iodide) — contraindicated in pregnancy and thyroid disease

Steroid prerequisite: rule out TB

Pregnancy: 1st–2nd trimester; supportive only; no SSKI, no late NSAIDs

Healing: bruise-like discoloration, no scarring, 3–6 weeks

Recurrence: ~30%; suggests sarcoid, IBD, idiopathic

Erythema induratum: posterior calves, ulcerates, TB-associated, lobular panniculitis with vasculitis

Pancreatic panniculitis: ghost cells, saponification, lipase up, ± pancreatic cancer

Coccidioidomycosis EN: signifies strong immune response, good prognosis, no antifungal usually needed

ASO peak: 3–6 weeks post-strep; use anti-DNase B if presentation is late

Biopsy depth: incisional/excisional to fat — punch is too shallow

Board pearl: "Painful red bumps on shins of a young woman after a sore throat" = EN from strep; "after a hike in Arizona" = EN from coccidioidomycosis; "with bloody diarrhea" = EN from Crohn; "with hilar nodes and ankle swelling" = Löfgren syndrome.

Key distinction: EN = reaction pattern; treat the cause, not the rash.

Board Question Stem Patterns

— Young woman, sore throat 2 weeks ago, now bilateral tender shin nodules, low-grade fever, ankle pain

— Best initial test: throat culture/ASO and CXR; best treatment: NSAIDs + penicillin

— Young adult, bilateral shin nodules, ankle arthritis, bilateral hilar lymphadenopathy on CXR

— Diagnosis: acute sarcoidosis; management: NSAIDs, observation; biopsy often unnecessary

— Patient with chronic bloody diarrhea and weight loss develops shin nodules

— Next step: colonoscopy; treat underlying IBD; avoid NSAIDs (may flare bowel disease)

— New sulfonamide or oral contraceptive started 2–3 weeks ago, now EN

— Best step: discontinue the offending agent; supportive care

— Recent travel to Arizona/California with cough, then shin nodules

— Diagnosis: coccidioidomycosis with EN (favorable immune response); no antifungal needed if immunocompetent and limited

— EN, patient started on prednisone, develops worsening pulmonary symptoms

— Lesson: TB was missed; always PPD/IGRA + CXR before steroids

— Posterior calf, ulcerated nodules, scarring

— Diagnosis: erythema induratum; workup: TB

— 2nd-trimester woman with EN

— Best therapy: acetaminophen, leg elevation; avoid SSKI and 3rd-trimester NSAIDs; expect postpartum resolution

— 72-year-old man, weight loss, EN, lymphadenopathy

— Next step: evaluate for lymphoma (CBC, LDH, imaging, biopsy)

— Nondiagnostic punch biopsy in suspected panniculitis

— Lesson: repeat with deep incisional biopsy to fat

— Stop OCP, switch to non-hormonal contraception

Pattern 1 — Post-strep classic:

Pattern 2 — Löfgren syndrome:

Pattern 3 — IBD presentation:

Pattern 4 — Drug-induced:

Pattern 5 — Endemic fungal:

Pattern 6 — TB trap:

Pattern 7 — Atypical lesion:

Pattern 8 — Pregnancy:

Pattern 9 — Older adult:

Pattern 10 — Biopsy interpretation:

Pattern 11 — Recurrent EN on OCP:

Step 3 management: Recognize the trigger-first algorithm: history → CXR + PPD/IGRA + strep workup + pregnancy test → targeted secondary tests → supportive therapy → follow-up. This decision tree wins most EN stems.

Board pearl: When in doubt on an EN question, the answer is usually "obtain chest X-ray" or "treat the underlying cause" rather than a specific drug.

One-Line Recap

— Diagnosis is clinical: bilateral, symmetric, tender, non-ulcerating anterior shin nodules with bruise-like resolution and no scarring; biopsy (deep incisional) only for atypical features and shows septal panniculitis without vasculitis with Miescher radial granulomas.

— Universal workup: CBC, ESR/CRP, throat culture + ASO/anti-DNase B, chest X-ray, PPD/IGRA, pregnancy test; expand selectively by history (stool studies, calprotectin, Coccidioides/Histoplasma serology, ACE/calcium for sarcoid).

— Treatment hierarchy: treat the trigger first (penicillin for strep, stop offending drug/OCP, manage IBD/sarcoid) → NSAIDs + leg elevation + compression → SSKI (avoid in pregnancy and thyroid disease) → short prednisone taper only after TB exclusion.

— Special populations and traps: pregnancy → supportive only, no SSKI, no 3rd-trimester NSAIDs; elderly with B-symptoms → rule out lymphoma; Löfgren syndrome (EN + bilateral hilar adenopathy + ankle arthralgias) = acute sarcoid with excellent prognosis; posterior calf ulcerating nodules = erythema induratum, evaluate for TB.

Erythema nodosum is a self-limited septal panniculitis presenting as bilateral tender pretibial nodules that signals an underlying trigger — most often streptococcal infection, sarcoidosis, drugs, IBD, pregnancy, or endemic infection — whose identification (via focused history, CBC, ESR/CRP, ASO/throat culture, chest X-ray, PPD/IGRA, and pregnancy test) drives management, while symptomatic care relies on rest, leg elevation, and NSAIDs, with SSKI or short-course steroids reserved for refractory cases only after TB is excluded.

High-yield recap bullets:

Step 3 management: The defensible visit ends with trigger identified or excluded, TB screened, follow-up scheduled in 2 weeks, and red-flag counseling documented — that closure consistently wins points on both written exams and CCS simulations.