Erythema nodosum

Management Strategies

Management of EN first requires investigation for an underlying etiology, including a detailed history, review of systems, and targeted evaluation. Numerous etiologies have been implicated, including chronic inflammatory states, infections, reactions to medications or hormones, and malignancies. Even after extensive evaluation, many cases are classified as idiopathic.

Many infectious agents have been associated with EN. Bacterial and protozoan causes include: Streptococcus (most common), Mycoplasma pneumoniae , Chlamydia pneumoniae , Chlamydia trachomatis , Yersinia enterocolitica , Salmonella enteritidis , Giardia lamblia , Shigella , Klebsiella spp., tuberculosis, brucellosis, psittacosis, cat scratch disease, chancroid, tularemia, rickettsiosis, leptospirosis, and Campylobacter . Viral causes include hepatitis B, hepatitis C, human immunodeficiency virus, and herpes simplex virus. Fungal triggers include blastomycosis, sporotrichosis, coccidioidomycosis, histoplasmosis, nocardiosis, and fungal kerions.

Chronic inflammatory conditions associated with EN include sarcoidosis (most common), inflammatory bowel disease (IBD), Behçet disease, Sweet syndrome, pyoderma faciale, and diverticulitis.

Medication-induced EN has been reported with use of oral contraceptives (most common) and other female hormone therapies, antibiotics (specifically penicillins and sulfonamides), iodides, bromides, quinolones, lidocaine injections, aromatase inhibitors, all-trans retinoic acid, propylthiouracil, granulocyte colony-stimulating factor, echinacea supplements, glatiramer acetate, valproate, non-steroidal antiinflammatory drugs (NSAIDs), thalidomide, and dapsone. Targeted chemotherapeutic agents such as BRAF and MEK inhibitors, and more recently the checkpoint inhibitor class of agents, have been described to cause an EN-like panniculitis. Multiple vaccines have been suggested as well, albeit in very small numbers – and the health benefits of vaccines outweigh the rare potential for this type of reaction.

Malignancies such as leukemias, lymphomas, myelodysplastic syndrome, and parathyroid carcinoma have rarely been implicated in triggering EN.

Skin biopsy is generally not necessary if the history and physical examination are suggestive of EN. Biopsies are typically performed in atypical cases, persistent or treatment-refractory cases, or cases where there is a broad differential diagnosis and a biopsy may help exclude alternative etiologies. Pathology classically demonstrates subcutaneous septal inflammation with limited extension into surrounding fat lobules. Inflammation may be acute or chronic, and can include histiocytes, foreign body giant cells, neutrophils, and eosinophils. Multinucleated giant cells (‘Miescher granulomas’) are occasionally seen. Other findings can include septal fibrosis and radial arrays of macrophages around blood vessels. If there is a concern for infectious panniculitis, tissue may be sent for culture and stains.

If identified, treatment or elimination of the underlying trigger will often lead to spontaneous remission of EN. This is the primary treatment strategy and should be emphasized in all cases; if there is an EN-triggering disease, it should be treated, and if there is an EN-associated medication, it should be discontinued. This may not be recommended in cases of molecular-targeted therapy.

Treatment of primary EN consists of bed rest, leg elevation, compression, NSAIDs, and potassium iodide. Naproxen and indomethacin have the most evidence in the treatment of EN, but aspirin, celecoxib, diclofenac, and ibuprofen have all been utilized. A reasonable starting dose of indomethacin is 50 mg three times daily. Note that NSAIDs have also been reported as potential EN-inducing drugs, and in such cases treatment with NSAIDs is not advised. Potassium iodide is generally well tolerated, effective, and non-immunosuppressive but may not be widely available. Typical dosing is with a supersaturated solution of potassium iodide (SSKI) starting at 1–2 drops three times daily and gradually titrating up to 5 drops (often dissolved in orange juice to increase tolerability of taste) taken three times per day. One drop of SSKI contains approximately 50 mg of iodide. SSKI tablets in 65 mg and 130 mg concentrations are also available. Side effects include hypothyroidism and hyperkalemia; rarely, concentrated iodide can induce a neutrophilic eruption (iododerma). SSKI should be used with caution in patients with dermatitis herpetiformis as it can flare the disease. Thyroid-stimulating hormone should be monitored monthly while on treatment.

In patients who fail these treatments, alternative therapies can be considered. Prednisone is highly effective and may be used in particularly refractory, widespread, or symptomatic patients to gain rapid control. Infection and malignancy should be ruled out before initiation. Colchicine, hydroxychloroquine, dapsone, and some immunomodulatory and immunosuppressive agents have anecdotal reports of efficacy.

Notably, while tumor necrosis factor (TNF)-alpha inhibitors have been efficacious in treating EN (especially in patients with underlying IBD), they have also been paradoxically associated with the development of EN.