INTRODUCTION
Erythema nodosum (EN) is the most common form of panniculitis, classically presenting as tender, erythematous subcutaneous nodules on the extensor surfaces of the lower extremities. Systemic symptoms, including fevers, chills, and arthralgias, may also accompany the cutaneous manifestations.1 EN typically occurs between the second and fourth decades of life, and is up to six times more common in females.2 EN is thought to be a delayed hypersensitivity reaction, and there is an extensive list of triggers, including infectious agents, medications, underlying inflammatory diseases, malignancy, and hormonal states. Nevertheless, the trigger remains unidentified in up to 50% of cases.1 EN is often selflimited, with symptoms typically peaking in 1-2 weeks and resolving over 1-12 weeks. However, there is also a subset of patients who experience chronic, recurrent EN, which can last for several years.3 While treatment should be directed toward the trigger in cases with a known etiology, in all cases, additional treatments are often warranted, given the exquisitely tender nature of EN lesions. Herein, we will discuss the current landscape of therapeutic interventions for EN.
MANAGEMENT STRATEGIES
Non-pharmacological Interventions
Bed rest, leg elevation, and leg compression are commonly recommended adjuvant therapies for EN.1,3 The pain in EN is thought to be in part caused by edema-induced pressure on surrounding tissues, and bed rest with elevation of the legs reduces this pressure by increasing venous return.1 While there are no guidelines regarding duration and frequency, some authors have recommended elevating the legs for at least 30 minutes twice daily.1 For the same reason, patients should also wear support stockings or pressure bandages during periods of activity.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs are a first-line therapy for EN, relieving pain and inflammation by inhibiting cyclooxygenase production. Specifically, naproxen 1000 mg daily for 2-3 weeks, oxyphenbutazone 400 mg daily, and indomethacin 100-150 mg daily, the latter two for unspecified durations, have all demonstrated efficacy in alleviating discomfort.3 Comparative studies are lacking, though the authors of one article recommended starting with indomethacin and using ibuprofen or naproxen secondarily.1 NSAIDs are cost-effective and accessible, though they should be avoided in those with renal disease and used cautiously in patients with gastritis and esophagitis.
Potassium Iodide (KI)
KI has been used to successfully treat many dermatologic conditions, although its mechanism of action remains poorly understood. Studies demonstrate that it inhibits neutrophil chemotaxis and interferes with neutrophil oxidative burst.1 Additionally, KI causes mast cells to release heparin, which may play a role in EN management by suppressing delayed hypersensitivity reactions.2 In a study of 15 EN patients treated with KI, 300 mg three times daily, 11 experienced an ‘excellent’ response, with subjective symptom improvement within 24 hours and complete lesion resolution after 10-14 days.4 Patients who were administered KI closest to EN onset had the best responses. While effective in managing EN, KI can be accompanied by rare but serious side effects, thus, it must be avoided or used with extreme caution in certain patient populations. Patients with a history of thyroid disease or taking medications such as lithium and amiodarone can be at risk of hypothyroidism and goiter. Additionally, prolonged use of KI may result in potassium toxicity, especially in patients on potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, or those with chronic renal disease.1
Colchicine
Colchicine is an anti-inflammatory agent that functions by arresting microtubule polymerization, interfering with neutrophil chemotaxis. In a retrospective case series of 12 patients with long-standing EN treated with colchicine 0.6 mg twice daily for a mean duration of 8 months, 8 patients experienced improvement, 6 of whom completely cleared.5 Colchicine has also been found to be particularly effective in managing EN in patients with Behcet’s syndrome, particularly females. In a double-blind trial of colchicine vs. placebo in 116 patients with Behcet’s syndrome, 79% of female patients taking colchicine 1-2 mg daily versus 39% of females taking placebo were clear of EN lesions after 24 months (P=0.004).6 These data suggest that colchicine may be useful in patients with chronic, recalcitrant EN or co-existing Behcet’s syndrome.
Bed rest, leg elevation, and leg compression are commonly recommended adjuvant therapies for EN.1,3 The pain in EN is thought to be in part caused by edema-induced pressure on surrounding tissues, and bed rest with elevation of the legs reduces this pressure by increasing venous return.1 While there are no guidelines regarding duration and frequency, some authors have recommended elevating the legs for at least 30 minutes twice daily.1 For the same reason, patients should also wear support stockings or pressure bandages during periods of activity.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs are a first-line therapy for EN, relieving pain and inflammation by inhibiting cyclooxygenase production. Specifically, naproxen 1000 mg daily for 2-3 weeks, oxyphenbutazone 400 mg daily, and indomethacin 100-150 mg daily, the latter two for unspecified durations, have all demonstrated efficacy in alleviating discomfort.3 Comparative studies are lacking, though the authors of one article recommended starting with indomethacin and using ibuprofen or naproxen secondarily.1 NSAIDs are cost-effective and accessible, though they should be avoided in those with renal disease and used cautiously in patients with gastritis and esophagitis.
Potassium Iodide (KI)
KI has been used to successfully treat many dermatologic conditions, although its mechanism of action remains poorly understood. Studies demonstrate that it inhibits neutrophil chemotaxis and interferes with neutrophil oxidative burst.1 Additionally, KI causes mast cells to release heparin, which may play a role in EN management by suppressing delayed hypersensitivity reactions.2 In a study of 15 EN patients treated with KI, 300 mg three times daily, 11 experienced an ‘excellent’ response, with subjective symptom improvement within 24 hours and complete lesion resolution after 10-14 days.4 Patients who were administered KI closest to EN onset had the best responses. While effective in managing EN, KI can be accompanied by rare but serious side effects, thus, it must be avoided or used with extreme caution in certain patient populations. Patients with a history of thyroid disease or taking medications such as lithium and amiodarone can be at risk of hypothyroidism and goiter. Additionally, prolonged use of KI may result in potassium toxicity, especially in patients on potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, or those with chronic renal disease.1
Colchicine
Colchicine is an anti-inflammatory agent that functions by arresting microtubule polymerization, interfering with neutrophil chemotaxis. In a retrospective case series of 12 patients with long-standing EN treated with colchicine 0.6 mg twice daily for a mean duration of 8 months, 8 patients experienced improvement, 6 of whom completely cleared.5 Colchicine has also been found to be particularly effective in managing EN in patients with Behcet’s syndrome, particularly females. In a double-blind trial of colchicine vs. placebo in 116 patients with Behcet’s syndrome, 79% of female patients taking colchicine 1-2 mg daily versus 39% of females taking placebo were clear of EN lesions after 24 months (P=0.004).6 These data suggest that colchicine may be useful in patients with chronic, recalcitrant EN or co-existing Behcet’s syndrome.
