Published on 18/03/2015 by admin
Filed under Dermatology
Last modified 22/04/2025
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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
(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.
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.
Anti-streptolysin O (ASO) titer, throat culture
Chest radiograph
Purified protein derivative standard tuberculosis skin test
Skin biopsy
Soderstrom RM, Krull EA. Cutis 1978; 21: 806–10.
Streptococcal infection is the most common etiologic agent, and sarcoidosis is the most common disease associated with EN.
All patients should have a chest radiograph, ASO titer, throat culture, and PPD (purified protein derivative standard).
Cribier B, Caille A, Heid E, Grosshans E. Int J Dermatol 1998; 37: 667–72.
Streptococcal infection was the most common cause of EN and sarcoidosis the second most common.
Atanes A, Gomez N, de Toro J, de Toro J, Graña J, Sánchez JM, et al. Med Clin (Barc) 1996; 9: 169–72.
Of 160 cases reviewed, the majority were due to sarcoidosis, followed by drugs, streptococcal infection, and tuberculosis.
Mert A, Kumbasar H, Ozaras R, Erten S, Tasli L, Tabak F, et al. Clin Exp Rheumatol 2007; 25: 563–70.
The results showed a 6:1 female predominance; 53% of cases were idiopathic and 11% related to streptococcal infections, 10% tuberculosis, 10% sarcoidosis, 6% Behçet’s, 5% drug reactions, 3% inflammatory bowel disease, and 2% pregnancy induced.
Ubogy Z, Persellin RH. Acta Derm Venereol 1982; 62: 265–7.
Three patients with EN secondary to streptococcal pharyngitis were treated with indomethacin 100–150 mg orally for 2 weeks with excellent results, after having failed to respond to treatment with erythromycin, penicillin, and aspirin.
Barr WG, Robinson JA. Ann Intern Med 1981; 95: 659.
Idiopathic EN in a 32-year-old woman who had been unsuccessfully treated with aspirin, resolved with indomethacin 25 mg three times daily for 1 month.
Lehman CW. Cutis 1980; 26: 66–7.
A 28-year-old woman with recurrent EN refractory to phenylbutazone and aspirin was treated with naproxen 250 mg orally twice daily for 1 month, with cessation of symptoms within 96 hours and clearing in 14 days. Relapses occurred after stopping therapy, but cleared promptly with re-institution of naproxen.
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.
Schultz EJ, Whiting DA. Br J Dermatol 1976; 94: 75–8.
Twenty-four of 28 patients with EN experienced improvement within 48 hours, and resolution within 2 weeks with 300–900 mg daily of potassium iodide.
Sterling JB, Heymann WR. J Am Acad Dermatol 2000; 43: 691–7.
An excellent review article.
De Coninck P, Baclet JL, Di Bernardo C, Büschges B, Plouvier B. Presse Med 1984; 13: 680.
Five women were treated with colchicine (2 mg daily for 3 days, then 1 mg daily for 2 to 4 weeks). Improvement was seen within 72 hours, with no recurrences once colchicine was stopped.
Wallace S. JAMA 1967; 202: 144.
One patient with EN was successfully treated with colchicine.
Alloway JA, Franks LK. Br J Dermatol 1995; 132: 661–70.
A 38-year-old woman with a 24-year history of EN with almost monthly flares was treated with hydroxychloroquine 200 mg orally twice daily. Within 3 months she had a dramatic reduction in lesions and remained stable for at least 6 months. Previously she had occasionally responded to acetaminophen (paracetamol), but not to aspirin or indomethacin. One previous flare had responded to prednisone.
Jarrett P, Goodfield MJD. Br J Dermatol 1996; 134: 373.
A 52-year-old with idiopathic EN was treated with hydroxychloroquine 200 mg orally twice a day and prednisone 15 mg four times a day for 8 weeks, with improvement. Prednisone was stopped and 8 weeks later the hydroxychloroquine dose was cut by half, but the patient experienced a flare and the original dose was restarted. After 3 more months the hydroxychloroquine was stopped, although intermittent dosing was required. The patient had previously been unresponsive to NSAIDs and prednisone.
Tan B, Lear J, Smith A. Clin Exp Dermatol 1997; 22: 26–7.
Acne fulminans and EN that occurred in a patient 3 weeks after starting isotretinoin responded to dapsone without oral prednisone.
Prior to the use of isotretinoin for acne fulminans, dapsone was frequently used because it may help control both the acne and the EN. The improvement of EN may be secondary to the improvement of acne fulminans.
Fukunaga K, Sawada K, Fukuda Y, Matoba Y, Natsuaki M, Ohnishi K, et al. Ther Apher Dial 2003; 7: 122–6.
A patient with ulcerative colitis and EN that failed to respond to high-dose corticosteroids recovered from both conditions after monocyte granulocytapheresis once a week for 5 weeks. He was also on 2250 mg of 5-aminosalicylic acid daily.
Kaya TI, Tursen U, Baz K, Ikizoglu G, Dusmez D. J Dermatol Treat 2003; 14: 124–7.
A patient with refractory Behçet disease and EN responded to coincidental treatment with erythromycin for erythrasma.
Boyd AS. J Am Acad Dermatol 2002; 47: 968–669.
A patient taking estrogen replacement developed EN that was unresponsive to many treatments, including discontinuing hormone therapy and azathioprine. The EN cleared with an increasing dose of mycophenolate mofetil to 750 mg twice a day, and remained clear after a slow taper.
Kugathasan S, Miranda A, Nocton J, Drolet BA, Raasch C, Binion DG. J Pediatr Gastroenterol Nutr 2003; 37: 150–4.
One child in a series of four patients with Crohn disease had resistant concurrent EN. The patient cleared with infliximab 5 mg/kg (anti-tumor necrosis factor-a antibody) and was maintained on 6-mercaptopurine. The conditions associated with Crohn disease in the other children (pyoderma gangrenosum, orofacial Crohn, and lymphedema) also cleared.
Clayton TH, Walker BP, Stables GI. Clin Exp Dermatol 2006; 31: 823–4.
A 26-year-old woman with inflammatory bowel disease and EN was treated with infliximab as a steroid-sparing agent. She received doses at 0, 2, and 6 weeks, and then every 3 months. Both the EN and gastrointestinal symptoms improved.
Boyd AS. Skinmed 2007; 6: 197–9.
One patient with a 5-year history of EN was treated with etanercept 25 mg subcutaneously twice weekly after failing prednisone, indomethacin, SSKI, dapsone, and methotrexate. She was clear after 4 months. After 6 months the etanercept dose was reduced to 25 mg subcutaneously weekly for the rest of the year.
Bhalla M, Thami GP. Dermatology 2007; 215: 363–4.
Three patients with recurrent EN were treated with monthly doses of intramuscular benzathine penicillin 2.4 million units. One patient had high ASO titers, and the other two had idiopathic biopsy-proven EN. All patients were clear at 6 months’ follow-up.
Ortego-Centeno N, Callejas-Rubio JL, Sanchez-Cano D, Caballero-Morales T. J Eur Acad Dermatol Venereol 2007; 21: 408–10.
A 79-year-old patient with EN of many years’ duration was initially responsive only to steroids. She was switched to adalimumab 40 mg subcutaneously every 2 weeks, and was clear after 7 months of follow-up.
Volkov I, Rudoy I, Press Y. J Am Board Fam Pract 2005; 18: 567–9.
One patient had EN resolve after being treated for a low serum B12 level. She was treated with twice-weekly injections of 1000 µg of B12.
Davis MD. J Am Acad Dermatol 2011; 64: 1211–2112.
One patient with a renal transplant and recalcitrant EN had resolution with minocycline 100 mg twice daily. Within 1 month lesions resolved and minocycline was discontinued because of hyperpigmentation. EN recurred within a week and resolved again with tetracycline 500 mg twice a day.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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NSAIDs
Potassium iodide
Colchicine
Hydroxychloroquine
Prednisone
Dapsone
Extracorporeal monocyte granulocytapheresis
Erythromycin
Mycophenolate mofetil
Etanercept
Adalimumab
Infliximab
Prophylactic penicillin
Vitamin B12 (if levels low)
Tetracycline
