Dermatology & Internal Medicine & Family Medicine
Erythema nodosum
Erythema nodosum is the most common form of panniculitis - inflammation of the subcutaneous adipose tissue (hypodermis) - and represents a delayed hypersensitivity reaction (type IV) to a variety of infectious, drug-induced, inflammatory or neoplastic causes. Its clinical manifestation is the sudden appearance of painful, warm, ill-defined, bright-red to purplish dermohypodermal nodules, located preferentially on the anterior surface of the legs (pretibial region), bilateral but asymmetrical, evolving spontaneously towards resolution without ulceration or scarring in 3 to 6 weeks. This resolution without ulceration or necrosis is characteristic and distinguishes erythema nodosum from other panniculitis. Erythema nodosum mainly affects women between the ages of 20 and 45 (female/male sex ratio 3 to 6:1), with an estimated incidence of 1 to 5 cases per 100,000 inhabitants per year. It is a reactionary syndrome - not a disease in itself - whose cause must be systematically sought, as it conditions specific treatment and prognosis. The cause is identified in only 50 to 60 % of cases; in the remaining 40 to 50 %, erythema nodosum is classified as idiopathic. Histology (septal panniculitis without vasculitis) is characteristic, but biopsy is not systematically necessary for diagnosis if the clinical picture is typical.
Clinical presentation, etiologies and differential diagnosis
- Typical clinical presentation : onset often preceded by a prodrome lasting 1 to 3 weeks (mild fever, arthralgia, general malaise); bilateral dermohypodermal nodules, symmetrical but asymmetric in intensity, on the anterior surface of the legs - sometimes on the thighs, arms, trunk; size 1 to 5 cm in diameter; warm, very painful on palpation and sometimes spontaneously; characteristic chromatic evolution in 3 to 6 weeks: bright red → purplish red → greenish yellow (pseudo-contusion - contusion dermis) → complete disappearance without ulceration, necrosis or scarring; moderate fever 38-38.5°C frequent at onset; arthralgias of ankles and knees in 50 % of cases (reactive arthritis or periarthritis)
- Main infectious causes : group A streptococcus (streptococcal angina - most frequent cause in pediatric and young adult series - 28 to 48 % of cases with identified cause); tuberculosis (primary tuberculosis infection - change in tuberculin test or IGRA - major cause in high-prevalence countries - systematic search in Quebec among immigrants and travelers); various respiratory infections (Mycoplasma pneumoniae, Chlamydia pneumoniae, Yersinia enterocolitica, Campylobacter, Salmonella, Bartonella); coccidioidomycosis, histoplasmosis (endemic mycoses - to be considered if traveling to endemic areas - southwestern U.S., North American river valleys)
- Medication and other causes : combined oral contraceptives (estrogens - frequent cause - to be systematically investigated in women); antibiotics (sulfonamides, amoxicillin, tetracyclines); NSAIDs; anti-TNF (paradoxically - notably etanercept in sarcoidosis); chronic inflammatory bowel disease (IBD - Crohn's disease and ulcerative colitis - erythema nodosum in 4 to 15 % of cases - often parallels bowel disease activity); sarcoidosis - Löfgren's syndrome (triad of erythema nodosum + bilateral hilar adenopathies + arthralgias/arthritis of the ankles - good prognosis - spontaneous resolution in 80-90 % of cases within 2 years); pregnancy (especially 1st trimester); hematological diseases (lymphomas - rare)
- Differential diagnosis : other panniculitis (lupus panniculitis, factitious panniculitis, pancreatic panniculitis - ulceration + elevated lipase, lipodermosclerosis); nodular vasculitis (Bazin's indurated erythema - posterior leg nodules + ulceration - associated with tuberculosis); Sweet's syndrome (febrile neutrophilic dermatosis - painful erythematous plaques + fever + neutrophilia); rheumatoid nodules (painless, pressure areas, associated RA); infectious cellulitis (asymmetric, taut shiny skin, cutaneous portal of entry, high fever)
Etiological assessment and treatment
| Appearance / Treatment | Mechanism, technique and procedures | Results, duration and precautions |
|---|---|---|
| 1st-line etiological workup Systematic in all cases of confirmed erythema nodosum |
Basic laboratory work-up: CBC (hyperleukocytosis - bacterial infection; eosinophilia - parasitosis ; lymphopenia - sarcoidosis) + ESR + CRP (almost constant biological inflammatory syndrome) + ASL (antistreptolysin O - ASLO) + antistreptodornase B (DNAase B - more sensitive than ASLO for recent streptococcal infection - high titre in 60-80 % of streptococcal erythema nodosum) + throat (culture + RDT - rapid detection test for streptococcal antigen); lung biopsy : chest x-ray (bilateral hilar adenopathies - sarcoidosis / Löfgren's syndrome; asymmetric adenopathies + infiltrate - lymphoma; tuberculosis priminfection - Ranke's complex); IGRA test (QuantiFERON) or tuberculin IDR (Mantoux): search for latent tuberculosis or primary infection; TSH + glycemia if compatible terrain. | The 2nd-line workup is guided by the results of the initial workup and the clinical context: serology Yersinia (recent diarrhoea), Bartonella, Chlamydia; ECBU + coproculture if digestive or urinary symptoms; ECA (angiotensin-converting enzyme) + calcemia + 24h calciuria (sarcoidosis - sensitivity ECA 60 %, specificity 90 %); autoimmune work-up (ANA, anti-dsDNA, ANCA) if connective tissue disease suspected; colonoscopy if digestive symptoms suggestive of IBD; skin biopsy in case of diagnostic doubt or atypical presentation (septal panniculitis without vasculitis - Miescher granulomas palisading around collagen fibers); causes not found in 40-50 % of cases → idiopathic erythema nodosum - monitoring + symptomatic treatment |
| Rest, restraint and physical measures Basic treatment - indispensable |
Rest with elevation of lower limbs: reduces venous and lymphatic dependency → reduces edema and local pain; elastic support (class II support stockings - 20 to 30 mmHg): reduces perinodular edema + improves venous return + mechanical analgesia through compression of nociceptive endings; application of local cold compresses: analgesic and local anti-inflammatory effect; limitation of standing activities and prolonged walking during the acute phase (2 to 4 weeks); these physical measures are essential and significantly improve comfort - often underestimated by patients and clinicians alike. | Strict rest is not necessary - maintaining light activity (short walk) is possible and recommended to avoid venous thrombosis; elevating the legs in a recumbent position (legs above heart level) is the most effective mechanical intervention to reduce edema and pain - recommend 2 to 3 periods of 30 min/d; compression stockings are available in pharmacies (class I-II without prescription) or by prescription (class III) - partially reimbursed by some private insurance companies; duration of physical measures : maintain throughout the active nodule phase (3 to 6 weeks on average) |
| Specific etiological treatment Treating the cause - top priority |
Confirmed streptococcal infection (high ASLO + RDT or positive culture) : amoxicillin 500 mg × 3/d × 10 days (or phenoxymethylpenicillin 500 mg × 3/d × 10d) - or azithromycin 500 mg D1 then 250 mg × 4d if allergic; treatment of streptococcal angina accelerates resolution of erythema nodosum in 60-70 % of cases; confirmed or strongly suspected tuberculosis (IDR virage or IGRA positive + context): standard anti-tuberculosis quadritherapy (RIPE - rifampicin + isoniazid + pyrazinamide + ethambutol × 2 months then dual therapy × 4 months) - mandatory MADO declaration in Quebec - coordination with DSP; oral contraceptives: discontinuation of incriminating contraceptive → spontaneous resolution expected in 4 to 8 weeks; active IBD: optimization of IBD treatment (mesalazine, corticoids, immunosuppressants, anti-TNF biotherapies) → erythema nodosum generally follows intestinal disease activity | Treating the cause is the first priority - in the vast majority of cases, erythema nodosum resolves spontaneously once the cause has been eliminated; sarcoidosis - Löfgren's syndrome: no specific sarcoidosis treatment required in this form (favorable prognosis - spontaneous resolution 80-90 % in 2 years) - sufficient symptomatic treatment (NSAIDs + rest); pregnancy : symptomatic treatment only (rest + restraint + paracetamol) - NSAIDs contraindicated in 3rd trimester; idiopathic erythema nodosum (no cause found): symptomatic treatment + monitoring - a cause may emerge during follow-up (lymphoma, IBD, incipient sarcoidosis). |
| Analgesia - NSAIDs and potassium iodide Symptomatic pain relief |
NSAIDs: naproxen 500 mg × 2/d or ibuprofen 400 mg × 3/d × 2 to 4 weeks - 1st-line symptomatic treatment - reduction of pain and local inflammation - CI : pregnancy (3rd trimester), CKD, active peptic ulcer, heart failure, anticoagulants - PPI as protection if >7 days or gastric risk factors; acetaminophen 500-1,000 mg × 3-4/d: alternative if contraindicated to NSAIDs or in combination; potassium iodide (KI) 300-400 mg × 3/d × 3 to 6 weeks: 2nd-line treatment if NSAIDs insufficient or poorly tolerated - mechanism of action poorly elucidated (inhibition of neutrophil chemotaxis + immune modulation) - efficacy reported in several clinical series - available in compound form from Canadian pharmacies; colchicine 0.5-1 mg/d: alternative option - inhibits neutrophil granulocyte migration + macrophage activation in adipose tissue - efficacy reported in chronic or recurrent forms | NSAIDs reduce pain and modestly accelerate nodule resolution - treatment of choice in the acute painful phase (VAS >5/10); potassium iodide is not available in a standard commercial formulation in Canada - compounded prescription by a qualified pharmacist - side effects: metallic taste, hyperthyroidism or hypothyroidism (monitor TSH if treatment >4 weeks) - CI : pregnancy, breast-feeding, pre-existing thyroid disease; systemic corticosteroids (prednisone 0.5-1 mg/kg/d): only as a last resort, very severe or incapacitating forms refractory to NSAIDs, and only after formal exclusion of an infectious cause (risk of dissemination of undiagnosed tuberculosis or fungal infection) |
| Chronic or recurrent erythema nodosum Forms persisting >6 weeks or recurring |
Definition: forms evolving beyond 6 weeks (chronic) or occurring repeatedly (recurrent - ≥2 episodes); approach: complete reassessment of cause - skin biopsy if not performed (histological confirmation + elimination of another panniculitis); extensive workup: colonoscopy (IBD) + thoraco-abdomino-pelvic CT (lymphoma + sarcoidosis + occult cause) + full autoimmune workup (lupus, Sjögren's, vasculitis) + extended infectious serologies; long-term treatments: hydroxychloroquine (Plaquenil 200-400 mg/d) - immunomodulating antimalarial - effective in chronic idiopathic forms or those associated with sarcoidosis/connectivitis; colchicine 0.5-1 mg/d as background treatment; dapsone 100 mg/d (available compassionately in Canada); consultation with dermatology and/or internal medicine recommended for chronic or recurrent forms. | Chronic erythema nodosum (>6 weeks) is much less frequent than the acute form - it warrants exhaustive investigation, as a serious underlying cause (lymphoma, IBD, sarcoidosis, connective tissue disease) is more frequently found in these prolonged forms; hydroxychloroquine is available in Canada (Plaquenil) and reimbursed by the RAMQ for several indications (lupus, RA) - off-label prescription for chronic erythema nodosum possible, but requires discussion with the patient; monitoring of renal and liver function + CBC under dapsone; note that in women taking oral contraceptives, discontinuation of estrogenic contraception is essential - switch to progestin-only contraception or a non-hormonal IUD to avoid recurrences |
ℹ️
Löfgren's syndrome - an acute form of sarcoidosis with a good prognosis: Löfgren's syndrome: erythema nodosum + bilateral hilar adenopathies on chest X-ray + arthralgias or arthritis of the ankles (periarthritis or true arthritis). This is an acute form of sarcoidosis with a good prognosis - spontaneous resolution in 80 to 90 % of cases within 1 to 2 years without corticosteroid treatment. Diagnosis is based on chest X-ray (bilateral symmetrical hilar adenopathies - «butterfly wing» appearance) + elevated ACE + possible hypercalcemia or hypercalciuria. Biopsy is not systematically necessary if the picture is typical. Treatment is symptomatic (NSAIDs + rest + restraint) - corticoids are not indicated in this form unless there is associated cardiac, neurological or ocular involvement.
Signs requiring prompt medical attention
Consult your physician promptly if erythema nodosum is associated with : high fever >39°C + altered general condition (severe underlying infection to be identified); ; chronic cough + weight loss + night sweats (tuberculosis or lymphoma to be excluded as a matter of urgency); ; bilateral hilar adenopathy on chest X-ray (sarcoidosis - Löfgren's syndrome - pneumological workup) ; bloody diarrhea or chronic abdominal pain (IBD to be confirmed by colonoscopy); ; ulcerated or necrotic nodules (not characteristic of erythema nodosum - other panniculitis or vasculitis to be ruled out by biopsy).
Consult at Clinique Omicron
Clinique Omicron physicians evaluate patients presenting with erythema nodosum - clinical diagnosis, 1st-line etiological workup, symptomatic treatment, and referral to dermatology, pulmonology or internal medicine depending on the cause identified. Consultations are available at our points of service in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The content of this page is provided for information purposes only and does not replace the advice of a qualified healthcare professional. Erythema nodosum is a reactive syndrome requiring a systematic etiological work-up to exclude an underlying infectious, drug or systemic cause.
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