Erythema nodosum

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Erythema nodosum

Robert A. Allen

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

(Courtesy of Herbert B. Allen, MD, Drexel University, Philadelphia, PA, USA.)

Erythema nodosum (EN) is a septal panniculitis that presents as tender, erythematous nodules and plaques located primarily on the extensor surfaces of the lower extremities. There is a predilection for females. Numerous etiologies have been implicated, including chronic inflammatory states, infections, reactions to medications, and, rarely, malignancies. There is a tendency towards spontaneous regression, which usually occurs within 6 months after the onset of the first lesions.

Management strategies

Treatment of EN depends on the suspected or documented etiology, if known. Common causes include infections, chronic inflammatory states, and drug reactions. Unfortunately, even after extensive evaluations, many cases are classified as idiopathic.

Infectious agents include, but are not limited to, multiple bacteria, viruses, and fungi. Bacterial and protozoan causes include Streptococcus, Yersinia enterocolitica, Salmonella enteritidis, Giardia lamblia, Shigella, Klebsiella spp., tuberculosis, brucellosis, psittacosis, cat scratch disease, chancroid, tularemia, rickettsiosis, and Campylobacter. Viral causes include hepatitis B, hepatitis C, HIV, and Crimean-Congo hemorrhagic fever. Fungal infectious agents causing blastomycosis, sporotrichosis, coccidioidomycosis, histoplasmosis, nocardiosis, and fungal kerions have also been implicated. Although all these infectious agents have been implicated in various reports, the streptococcus remains the most likely causative agent.

Patients with certain diseases that are characterized by chronic inflammation may develop EN. The most common disease is sarcoidosis but inflammatory bowel disease (Crohn disease and ulcerative colitis), Behçet syndrome, Sweet syndrome, pyoderma faciale, and chronic abscesses have been associated.

Medications are common inciting agents. The most likely cause is oral contraceptive use, but medicines such as iodides, bromides, quinolones, and sulfonamides have been implicated. Lidocaine injections, aromatase inhibitors, all-trans-retinoic acid, propylthiouracil, granulocyte colony-stimulating factor, echinacea supplements, and glatiramer acetate are thought to be causative.

Malignancies such as leukemias, lymphomas, myelodysplastic syndrome, and parathyroid carcinoma have been implicated. In cancer patients it may be difficult to determine the definitive cause of the EN because of the multiple treatments and possible chronic inflammation that can occur.

Skin biopsy is generally not necessary if the history and physical signs are suggestive of EN. The pathology should demonstrate inflammation in the septae between fat lobules of the subcutis. The type of inflammation may vary between acute and chronic inflammation, including multinucleated giant cells. Other findings can include fibrosis, increased thickness of the intralobular septae, and radial arrays of macrophages around blood vessels. A biopsy is usually helpful in ruling out other forms of panniculitis, and if an infectious cause is in the differential diagnosis, some tissue may be sent for culture and stains to look for organisms.

Treatment consists primarily of bed rest, activity reduction, non-steroidal anti-inflammatory agents (NSAIDs), and potassium iodide. Various NSAIDs have been used successfully, including naproxen and indomethacin. Potassium iodide has recently regained popularity but may be difficult to obtain because of stockpiling by national governments. We recommend a supersaturated solution of potassium iodide of five drops three times a day in orange juice to mask the taste. One drop per dose is added each day until clinical effectiveness is achieved. Hypothyroidism can result from long-term use of potassium iodide. Hydroxychloroquine 200 mg twice a day has been used with limited success in EN. Dapsone was successful in a patient who developed EN after starting isotretinoin for acne fulminans. Systemic corticosteroids may also be helpful in refractory cases, or to ‘jump start’ therapy.

Specific investigations

First-line therapies

imageNSAIDs E
imagePotassium iodide B

Potassium iodide in erythema nodosum and other erythematous dermatoses.

Horio T, Danno K, Okamoto H, Miyachi Y, Imamura S. J Am Acad Dermatol 1983; 9: 77–81.

Twelve of 16 patients treated with potassium iodide experienced improvement within a few days, with complete resolution in 10 to 14 days. Six had recurrent attacks over 1 to 12 months, with resolution upon repeat dosing with potassium iodide. Of those who did not respond well, most received treatment two to 14 months after the onset of symptoms, indicating that earlier treatment is better. All patients with positive C-reactive protein responded well, and those with high fevers and arthralgias also responded well.

Potassium iodide may be a reasonable choice for those patients who cannot tolerate NSAIDs or corticosteroids. A saturated solution of potassium iodide (SSKI) may be made more palatable by adding the solution to orange juice.

Second-line therapies

imageColchicine E
imageHydroxychloroquine E
imagePrednisone E

Third-line therapies

imageDapsone E
imageExtracorporeal monocyte granulocytapheresis E
imageErythromycin E
imageMycophenolate mofetil E
imageEtanercept E
imageAdalimumab E
imageInfliximab E
imageProphylactic penicillin E
imageVitamin B12 (if levels low) E
imageTetracycline E

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Erythema nodosum

Robert A. Allen

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

(Courtesy of Herbert B. Allen, MD, Drexel University, Philadelphia, PA, USA.)

Erythema nodosum (EN) is a septal panniculitis that presents as tender, erythematous nodules and plaques located primarily on the extensor surfaces of the lower extremities. There is a predilection for females. Numerous etiologies have been implicated, including chronic inflammatory states, infections, reactions to medications, and, rarely, malignancies. There is a tendency towards spontaneous regression, which usually occurs within 6 months after the onset of the first lesions.

Management strategies

Treatment of EN depends on the suspected or documented etiology, if known. Common causes include infections, chronic inflammatory states, and drug reactions. Unfortunately, even after extensive evaluations, many cases are classified as idiopathic.

Infectious agents include, but are not limited to, multiple bacteria, viruses, and fungi. Bacterial and protozoan causes include Streptococcus, Yersinia enterocolitica, Salmonella enteritidis, Giardia lamblia, Shigella, Klebsiella spp., tuberculosis, brucellosis, psittacosis, cat scratch disease, chancroid, tularemia, rickettsiosis, and Campylobacter. Viral causes include hepatitis B, hepatitis C, HIV, and Crimean-Congo hemorrhagic fever. Fungal infectious agents causing blastomycosis, sporotrichosis, coccidioidomycosis, histoplasmosis, nocardiosis, and fungal kerions have also been implicated. Although all these infectious agents have been implicated in various reports, the streptococcus remains the most likely causative agent.

Patients with certain diseases that are characterized by chronic inflammation may develop EN. The most common disease is sarcoidosis but inflammatory bowel disease (Crohn disease and ulcerative colitis), Behçet syndrome, Sweet syndrome, pyoderma faciale, and chronic abscesses have been associated.

Medications are common inciting agents. The most likely cause is oral contraceptive use, but medicines such as iodides, bromides, quinolones, and sulfonamides have been implicated. Lidocaine injections, aromatase inhibitors, all-trans-retinoic acid, propylthiouracil, granulocyte colony-stimulating factor, echinacea supplements, and glatiramer acetate are thought to be causative.

Malignancies such as leukemias, lymphomas, myelodysplastic syndrome, and parathyroid carcinoma have been implicated. In cancer patients it may be difficult to determine the definitive cause of the EN because of the multiple treatments and possible chronic inflammation that can occur.

Skin biopsy is generally not necessary if the history and physical signs are suggestive of EN. The pathology should demonstrate inflammation in the septae between fat lobules of the subcutis. The type of inflammation may vary between acute and chronic inflammation, including multinucleated giant cells. Other findings can include fibrosis, increased thickness of the intralobular septae, and radial arrays of macrophages around blood vessels. A biopsy is usually helpful in ruling out other forms of panniculitis, and if an infectious cause is in the differential diagnosis, some tissue may be sent for culture and stains to look for organisms.

Treatment consists primarily of bed rest, activity reduction, non-steroidal anti-inflammatory agents (NSAIDs), and potassium iodide. Various NSAIDs have been used successfully, including naproxen and indomethacin. Potassium iodide has recently regained popularity but may be difficult to obtain because of stockpiling by national governments. We recommend a supersaturated solution of potassium iodide of five drops three times a day in orange juice to mask the taste. One drop per dose is added each day until clinical effectiveness is achieved. Hypothyroidism can result from long-term use of potassium iodide. Hydroxychloroquine 200 mg twice a day has been used with limited success in EN. Dapsone was successful in a patient who developed EN after starting isotretinoin for acne fulminans. Systemic corticosteroids may also be helpful in refractory cases, or to ‘jump start’ therapy.

Specific investigations

Erythema nodosum: an evaluation of 100 cases.

Mert A, Kumbasar H, Ozaras R, Erten S, Tasli L, Tabak F, et al. Clin Exp Rheumatol 2007; 25: 563–70.

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