Erythema nodosum – clinical manifestations, diagnosis, associated diseases, treatment & prognosis
Michael D. Fox
Erythema nodosum is a relatively common dermatologic disease characterized by exquisitely tender, erythematous nodules on the lower extremities. Occasionally, the hands, fingers or other areas of the body are involved. Although malignant changes do not occur in the lesions, erythema nodosum may be a marker for internal malignancy or may clinically resemble a leukemic infiltrate of fat. Erythema nodosum may also be a marker for other systemic diseases, such as tuberculosis, sarcoidosis and inflammatory bowel disease.
Erythema nodosum is an excellent example of a septal panniculitis.[1,2] The earliest pathologic alteration occurring in the disease is mild infiltration of neutrophils around proliferating capillaries and venules in a swollen fibrous septum (Figure 1). Eosinophils may appear as well, but the infiltrate gradually becomes predominantly lymphocytic and histiocytic. Ultimately, the infiltrate becomes granulomatous, with dense clusters of lymphocytes and histiocytes.
Chronic erythema nodosum is characterized by mild septal alteration, with little fibrosis and only focal granuloma formation. In contrast, erythema nodosum migrans is characterized by a markedly widened and fibrotic septum, with granulation tissue-like capillary proliferation and many giant cells lining the septal borders. When hyaline fat necrosis or changes consistent with lupus panniculitis are found in an otherwise typical histologic pattern of erythema nodosum, the presence of underlying connective tissue disease should be considered.
Tender, bright-red subcutaneous nodules of the lower extremites are the hallmark of erythema nodosum (Figure 2). However, nodules may appear elsewhere, such as on the upper extremities. In bedridden patients, dependent areas may be affected. In the traditional form of erythema nodosum, lesions generally are bilaterally symmetric with no tendency to spread locally.
Acute nodules are round and poorly demarcated, with diameters ranging from 1 to 10 cm. New nodules may appear as others fade, and older nodules often resemble bruises. Ulceration is rare. Complete healing of a lesion usually occurs within a month or two of its appearance. Erythema nodosum migrans and chronic erythema nodosum are the two principal variants of the disease. In erythema nodosum migrans, the nodules are usually unilateral and only minimally symptomatic, and they tend to spread locally by coalescence or extension into plaques up to 20 cm in diameter (Figure 3). With chronic erythema nodosum, the nodules tend to spread by peripheral extension, and they are less inflammatory and less symptomatic than those in classic acute erythema nodosum.
Most patients with traditional and chronic erythema nodosum have significant associated systemic signs and symptoms, such as fever, malaise, leukocytosis, arthralgias and arthritis, whereas patients with erythema nodosum migrans often do not have systemic symptoms. Bilateral hilar adenopathy may occur in association with erythema nodosum alone and
Types of Panniculitis
Disorders of the subcutaneous septal panniculus
Subcutaneous granuloma annulare
Disorders of the subcutaneous fat lobules
Systemic lupus erythematosus
Nodular fat necrosis[Alpha.sub.1]-antitrypsin deficiency
Panniculitis associated with steroid use, cold and
infection, and other idiopathic forms
Behcet’s syndrome (erythema nodosum-like
Subcutaneous fat necrosis of the newborn
does not necessarily imply a diagnosis of sarcoidosis.
Diagnosis of erythema nodosum usually requires a deep elliptical skin biopsy, rather than a punch biopsy, because a specimen containing subcutaneous fat must be obtained. Then, the most common underlying etiologies should be considered, including streptococcal pharyngitis, sarcoidosis and medications, as well as tuberculosis and coccidioidomycosis in high-risk groups.
A careful history must be obtained, and a thorough physical examination must be performed. The selection of laboratory tests depends on the specific clinical situation. A complete blood count, a chest radiograph and a tuberculin skin test help screen for lymphoma, leukemia, tuberculosis and sarcoidosis. A specific search for lymphadenopathy and hepatosplenomegaly should be conducted.
Any type of panniculitis may clinically resemble erythema nodosum. The basic types of panniculitis, divided according to whether their primary involvement is the septa between the fat lobules or the lobules themselves, are listed in Table 1.[1,4] To these disorders might be added inflammatory processes of blood vessels, including periarteritis nodosum, migratory thrombophlebitis and superficial varicose thrombophlebitis. Inflammation of the subcutaneous fat blood vessels may be involved in erythema nodosum leprosum, nodular vasculitis and cutaneous Crohn’s disease.
Erythema nodosum is considered an immunologic response (Table 2). The three most common causes of erythema nodosum are streptococcal pharyngitis, sarcoidosis and medications. In children, streptococcal pharyngitis is the most likely etiology.
In the past, the infectious disease most commonly associated with erythema nodosum was tuberculosis. Erythema nodosum often appears in primary tuberculosis, usually at the same time or after the tuberculin skin test converts to positive. The tuberculin skin test itself, as well as the bacille Calmette-Guerin (BCG) vaccine, has been associated with the development of erythema nodosum. In one study, the lesions of erythema nodosum were the first sign of tuberculosis in four patients with human immunodeficiency virus (HIV) infection. Thus, the presence of erythema nodosum mandates consideration of tuberculosis and, possibly, HIV infection.
Atypical mycobacterial infections may also be associated with erythema nodosum. The skin eruption of erythema nodosum may be the first sign of infection with Mycobacterium marinum, the agent that causes “swimming pool” granulomas in humans.
Systemic fungal infections may be associated with erythema nodosum. In the southwestern United States, the most frequent cause of erythema nodosum is coccidioidomycosis. Erythema nodosum tends to develop at the same time that the skin test for coccidioidomycosis converts to positive. The presence of erythema nodosum is usually associated with a good prognosis, since extrapulmonary coccidioidomycosis is unlikely.
Beta-hemolytic streptococcal infection, usually manifesting as a pharyngitis, is a common cause of erythema nodosum, which typically appears two to three weeks after the onset of pharyngitis. One recent study found that 11 percent of patients with chronic erythema nodosum and 36 percent of patients with erythema nodosum migrans had associated streptococcal infection.
Other infections that have been associated with erythema nodosum include viral, spirochetal (syphilis), chlamydial and rickettsial infections. Asymptomatic Campylobacter colitis has been associated with erythema nodosum, which may also be linked to Yersinia enterocolitica infection, Salmonella enteritidis serotype typhimurium infection, psittacosis, TABLE 2 Underlying Diseases or Conditions Associated with Erythema Nodosum Idiopathic Infections
Mycobacterium tuberculosis and atypical
Systemic fungal infections (e.g.,
Viruses (e.g., hepatitis)
Spirochetes (e.g., syphilis)
Parasites (e.g., amebiasis, giardiasis) Sarcoidosis Drug reactions
Antibiotics (especially sulfonamides) Endocrine-hormonal conditions
Pregnancy Inflammatory and autoimmune disorders
Systemic lupus erythematosus Malignancy Lymphoma Leukemia
hepatitis, vaccines (including those for hepatitis), amebiasis and giardiasis.[10-12]
Medications are a common cause of erythema nodosum. In one study, 25 percent of the cases of chronic erythema nodosum were linked to medications, with oral contraceptives being a common offender. Antibiotics, especially the sulfonamides, are also frequently associated with erythema nodosum, although it is not clear whether the infection or the antibiotic used to treat it is responsible for the disease.
Sarcoidosis often presents with erythema nodosum and bilateral hilar adenopathy. This triad is associated with a favorable prognosis.
The increased incidence of erythema nodosum during pregnancy has long been recognized. One study found a 3 percent association between pregnancy and chronic erythema nodosum. The same study reported a 21 percent association between erythema nodosum migrans and thyroid disease.
Ulcerative colitis, Crohn’s disease and, possibly, diverticulitis are also associated with erythema nodosum. Inflammatory bowel disorders are usually active when erythema nodosum appears. Erythema nodosum may also be associated with a wide variety of collagen vascular diseases, including systemic lupus erythematosus. It has also been reported in patients with immunoglobulin A nephropathy and fulminant acne vulgaris with hepatosplenomegaly. Erythema nodosum may be the presenting sign in a number of malignancies, especially lymphomas and leukemias.[17,18]
Patients with erythema nodosum are often classified as having idiopathic disease, because no underlying disorder can be found. One study noted that 28 percent of patients with chronic erythema nodosum and 42 percent of patients with erythema nodosum migrans had idiopathic disease.
Treatment and Prognosis
Only supportive treatment, such as bed rest, is necessary for some patients with erythema nodosum. Patients with extremely tender nodules usually require salicylates or other nonsteroidal anti-inflammatory agents for pain control. Oral potassium iodide is a therapeutic option worth considering. Systemic corticosteroids, when not contraindicated, are also effective. Underlying infections such as tuberculosis and coccidioidomycosis need to be excluded to avoid dissemination after steroid use.
Patients with erythema nodosum must be carefully evaluated for associated disorders, because treatment of the underlying disease usually assures disappearance of the skin lesions in a month or two. In idiopathic erythema nodosum, the prognosis for complete recovery without recurrence is excellent. Children and young adults seem to do better than older persons, although erythema nodosum may persist for years in some young patients.
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