Erythema Nodosum

Back

Background

Erythema nodosum (EN) is an acute, nodular, erythematous eruption that usually is limited to the extensor aspects of the lower legs. Chronic or recurrent erythema nodosum is rare but may occur. Erythema nodosum is presumed to be a hypersensitivity reaction and may occur in association with several systemic diseases or drug therapies, or it may be idiopathic. The inflammatory reaction occurs in the panniculus.

Pathophysiology

Erythema nodosum probably is a delayed hypersensitivity reaction to a variety of antigens; circulating immune complexes have not been found in idiopathic or uncomplicated cases but may be demonstrated in patients with inflammatory bowel disease.[1]

Etiology

Currently, the most common cause of erythema nodosum is streptococcal infection in children and streptococcal infection and sarcoidosis in adults.[2] Numerous other causes have been reported.[3] The causes reported most often in the literature are described below.

Bacterial infections

Streptococcal infections are one of the most common causes of erythema nodosum.[4] Tuberculosis was an important cause in the past, but it has decreased dramatically as a cause for erythema nodosum; however, it still must be excluded, especially in developing countries.[5, 6] Yersinia enterocolitica is a gram-negative bacillus that causes acute diarrhea and abdominal pain; it is a common cause of erythema nodosum in France and Finland.[7, 8, 9] Mycoplasma pneumoniae infection may cause erythema nodosum. Erythema nodosum leprosum clinically resembles erythema nodosum, but the histologic picture is that of leukocytoclastic vasculitis. Lymphogranuloma venereum may cause erythema nodosum. Salmonella infection may cause erythema nodosum. Campylobacter infection may cause erythema nodosum.

Fungal infections

Coccidioidomycosis (San Joaquin Valley fever) is the most common cause of erythema nodosum in the American Southwest. In approximately 4% of males and 10% of females, the primary fungal infection (which may be asymptomatic or involve symptoms of upper respiratory infection) is followed by the development of erythema nodosum. Lesions appear 3 days to 3 weeks after the end of the fever caused by the fungal infection. Histoplasmosis may cause erythema nodosum. Blastomycosis may cause erythema nodosum.

Drugs

Sulfonamides and halide agents are an important cause of erythema nodosum. Drugs more recently described to cause erythema nodosum include gold and sulfonylureas. Oral contraceptive pills are implicated in an increasing number of reports.[10]  

Enteropathies

Ulcerative colitis and Crohn disease may trigger erythema nodosum. Erythema nodosum associated with enteropathies correlates with flares of the disease. The mean duration of chronic ulcerative colitis before the onset of erythema nodosum is 5 years, and erythema nodosum is controlled with adequate therapy of the colitis. Erythema nodosum is the most frequent dermatologic symptom in inflammatory bowel diseases, and it is strongly associated with Crohn disease.[11, 12]

Hodgkin disease and lymphoma

Erythema nodosum associated with non-Hodgkin lymphoma may precede the diagnosis of lymphoma by months. Reports of erythema nodosum preceding the onset of acute myelogenous leukemia have been published.[13, 14]

Sarcoidosis

Approximately 10-22% of all erythema nodosum cases are caused by sarcoidosis.[15]  The most common cutaneous manifestation of sarcoidosis is erythema nodosum.[16] A characteristic form of acute sarcoidosis involves the association of erythema nodosum, hilar lymphadenopathy, fever, arthritis, and uveitis, which has been termed Löfgren syndrome. This presentation has a good prognosis, with complete resolution within several months in most patients. HLA-DRB1*03 is associated with Löfgren syndrome. Most DRB1*03-positive patients have resolution of their symptoms within 2 years; however, nearly half of DRB1*03-negative patients have an unremitting course.[17]

Behçet disease

This condition is associated with erythema nodosum.

Pregnancy

Some patients develop erythema nodosum during pregnancy, most frequently during the second trimester. Repeated episodes occur with subsequent pregnancies or with the use of oral contraceptives.

Epidemiology

Frequency

United States

Peak incidence occurs at age 18-34 years. Age and sex distributions vary according to etiology and geographic location.[18]

International

Rates of erythema nodosum vary according to country. In England, the rate is 2.4 cases per 10,000 per year.

Sex

Women are affected more often than men, with a male-to-female ratio of 1:4.

Age

Erythema nodosum may occur in children and in patients older than 70 years, but it is more common in young adults aged 18-34 years. Age distribution varies with geographic location and etiology.

Prognosis

In patients with erythema nodosum, the prognosis is excellent. In most patients, erythema nodosum resolves without any adverse reactions.

Patient Education

Instruct patients that the restriction of physical activities may help shorten the course of erythema nodosum.

History

The eruptive phase of erythema nodosum begins with flulike symptoms of fever and generalized aching. Arthralgia may occur and precedes the eruption or appears during the eruptive phase. Most lesions in infection-induced erythema nodosum heal within 7 weeks, but active disease may last up to 18 weeks. In contrast, 30% of idiopathic erythema nodosum cases may last more than 6 months. Febrile illness with dermatologic findings includes abrupt onset of illness with initial fever, followed by a painful rash within 1-2 days.

Physical Examination

Pertinent physical findings are limited to the skin and joints.

Primary skin lesions

Lesions begin as red tender nodules (see the image below). Lesion borders are poorly defined, and lesions vary from 2-6 cm. During the first week, lesions become tense, hard, and painful; during the second week, they may become fluctuant, as in an abscess, but do not suppurate or ulcerate. Individual lesions last approximately 2 weeks, but occasionally, new lesions continue to appear for 3-6 weeks. Aching legs and swelling ankles may persist for weeks.



View Image

Classic presentation of erythema nodosum with nodular red swellings over the shins.

Distribution of skin lesions

Characteristically, lesions appear on the anterior leg; however, they may appear on any surface.

Color of skin lesions

Lesions change color in the second week from bright red to bluish or livid. As absorption progresses, the color gradually fades to a yellowish hue, resembling a bruise. This disappears in 1 or 2 weeks as the overlying skin desquamates.

Hilar lymph nodes

Hilar adenopathy may develop as part of the hypersensitivity reaction of erythema nodosum. Bilateral hilar lymphadenopathy is associated with sarcoidosis, while unilateral changes may occur with infections and malignancy.

Joints

Arthralgia occurs in more than 50% of patients and begins during the eruptive phase or precedes the eruption by 2-4 weeks. Erythema, swelling, and tenderness occur over the joint, sometimes with effusions. Joint tenderness and morning stiffness may occur. Any joint may be involved, but the ankles, knees, and wrist are affected most commonly. Synovitis resolves within a few weeks, but joint pain and stiffness may last up to 6 months. No destructive joint changes occur. Synovial fluid is acellular, and the rheumatoid factor is negative.

Laboratory Studies

Perform throat culture as part of the initial workup to exclude group A beta-hemolytic streptococcal infection.

Perform erythrocyte sedimentation rates often as part of the initial workup. The rate often is very high.

Antistreptolysin titer is elevated in some patients with streptococcal disease, but normal values do not exclude streptococcal infection. Evaluate titer levels during the initial workup, since streptococcal disease is a common cause of erythema nodosum.

Order stool examination, since along with the appropriate history of gastrointestinal complaints, a stool examination can exclude infection by Yersinia, Salmonella, and Campylobacter organisms.

Order blood cultures according to preliminary indications and findings.

Imaging Studies

Order chest radiographs as part of the initial workup to exclude sarcoidosis and tuberculosis and to document hilar adenopathy.

Other Tests

Intradermal skin tests can be used to exclude tuberculosis and coccidioidomycosis.

Procedures

Because the diagnosis of erythema nodosum often is clinical, biopsy is reserved for diagnostically difficult cases. Punch biopsies usually are not adequate. Deep skin incisional biopsies are required to sample the subcutaneous tissue adequately. Findings are localized to the subcutaneous tissue.

Histologic Findings

The classic features of erythema nodosum on histopathology include a septal panniculitis with slight superficial and deep perivascular inflammatory lymphocytic infiltrate.[19, 20] The septa of subcutaneous fat usually are thickened. Early-stage lesions demonstrate vascular damage in the septae with neutrophils and eosinophils similar to a leukocytoclastic vasculitis.[21] As lesions evolve, periseptal fibrosis, giant cells, and granulation tissue appear. Miescher granulomas are a hallmark feature of erythema nodosum. Small well-defined nodular aggregates of histiocytes around a central stellate cleft are scattered throughout the lesions. A lymphohistiocytic infiltrate is noted in the septum and in small and medium-sized vessels.

Medical Care

In most patients, erythema nodosum is a self-limited disease and requires only symptomatic relief using nonsteroidal anti-inflammatory drugs (NSAIDs), cool wet compresses, elevation, and bed rest.

Consultations

Consultations with a dermatologist and/or internist may be necessary for evaluation of the underlying cause of erythema nodosum.

Activity

Patient mobility is restricted in the acute stages if pain and swelling are significant.

Compression stockings may be beneficial to decrease swelling and allow patients to maintain their normal activity level.[22]

Prevention

Restriction of physical activities while erythema nodosum is active may prevent exacerbations of the disease.

Long-Term Monitoring

The course of erythema nodosum is benign and self-limited. Bed rest and restriction of physical activities is encouraged during the active phase.

Medication Summary

If the underlying disease or drug is identified, it should be eliminated. Since erythema nodosum often regresses spontaneously, symptomatic relief using NSAIDs (eg, acetyl salicylic acid, ibuprofen, naproxen, indomethacin) usually is all that is required. Corticosteroids are effective but seldom necessary in self-limited disease. Recurrence of erythema nodosum following discontinuation of treatment is common, and underlying infectious disease may be worsened. Potassium iodide may relieve lesional tenderness, arthralgia, and fever.[23] Colchicine has been used in a few refractory cases with good results. Note that some of the medications used to treat erythema nodosum have been implicated as rare causes of erythema nodosum in individuals with hypersensitivity to the drugs.[24]

Aspirin (Anacin, Ascriptin, Bayer Aspirin)

Clinical Context:  Aspirin is a salicylate used for anti-inflammatory, analgesic, and antipyretic properties. It treats mild-to-moderate pain and headache. Aspirin inhibits prostaglandin synthesis, which prevents the formation of platelet-aggregating thromboxane A2. It acts on the heat-regulating center of the hypothalamus, and it vasodilates peripheral vessels to reduce fever. Enteric-coated and extended-release tablets are available.

Naproxen (Naprelan, Naprosyn, Aleve, Anaprox)

Clinical Context:  Naproxen has analgesic, anti-inflammatory, and antipyretic properties. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

Indomethacin (Indocin, Indochron E-R)

Clinical Context:  Indomethacin is rapidly absorbed; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation; it inhibits prostaglandin synthesis.

Colchicine

Clinical Context:  Colchicine reduces the formation of uric acid crystals in affected joints, thereby reducing the amount of acute inflammation and pain; it also decreases uric acid levels in the blood.

Colchicine can be used in combination with probenecid on a long-term basis to prevent gout or it can be used alone to treat the pain and inflammation of acute gout attacks. Discontinue usage when the pain of a gout attack begins to subside, when the maximum dose is reached, or when GI tract symptoms (eg, nausea, vomiting, diarrhea) indicate cellular poisoning.

Class Summary

Anti-inflammatory agents provide symptomatic relief for lesional tenderness, arthralgia, and fever.

Potassium iodide (Pima, SSKI)

Clinical Context:  The mechanism of action for potassium iodide in erythema nodosum is unknown, but it is known to enhance response by potentiating neutrophil activity.

Class Summary

Antithyroid agents relieve lesional tenderness, arthralgia, and fever. Relief may occur within 24 hours. Most lesions completely subside within 10-14 days. Potassium iodide is not effective for all patients with erythema nodosum. Patients who receive medication shortly after the initial onset of erythema nodosum respond more satisfactorily than patients with chronic erythema nodosum.

What is erythema nodosum (EN)?What is the pathogenesis of erythema nodosum (EN)?What is the most likely cause of erythema nodosum (EN)?Which bacterial agents cause erythema nodosum (EN)?Which fungal infections cause erythema nodosum (EN)?Which drugs cause erythema nodosum (EN)?What is the relationship between inflammatory bowel diseases (IBD) and erythema nodosum (EN)?What is the relationship between erythema nodosum (EN) and malignancies?What is the role of sarcoidosis in erythema nodosum (EN)?Is erythema nodosum (EN) a symptom of Behcet disease?When in a pregnancy is erythema nodosum (EN) most likely to occur?In what age group is erythema nodosum (EN) most common?What is the incidence of erythema nodosum (EN)?Is erythema nodosum (EN) more common in males or females?Does the incidence of erythema nodosum (EN) vary among age groups?What is the prognosis of erythema nodosum (EN)?Should physical activity be restricted for patients with erythema nodosum (EN)?What is the disease course for erythema nodosum (EN)?Which physical findings suggest erythema nodosum (EN)?Where do skin lesions appear in erythema nodosum (EN)?What color are skin lesions in erythema nodosum (EN)?What is the role of hilar lymph nodes in erythema nodosum (EN)?What are the physical findings of the joints in erythema nodosum (EN)?What are the differential diagnoses for Erythema Nodosum?Which lab studies are performed in the diagnosis of erythema nodosum (EN)?What is the role of stool testing in the diagnosis of erythema nodosum (EN)?What is the role of chest radiography in the diagnosis of erythema nodosum (EN)?What is the role of skin testing in the diagnosis of erythema nodosum (EN)?When is a biopsy indicated in suspected erythema nodosum (EN)?Which histologic findings suggest erythema nodosum (EN)?What is the treatment for erythema nodosum (EN)?When is specialist consultation indicated for patients with erythema nodosum (EN)?When is activity restricted in patients with erythema nodosum (EN)?How is exacerbation of erythema nodosum (EN) prevented?Is long-term monitoring necessary in patients with erythema nodosum (EN)?Which medications are used for the treatment of erythema nodosum (EN)?Which medications in the drug class Anti-inflammatory agents are used in the treatment of Erythema Nodosum?Which medications in the drug class Antithyroid agents are used in the treatment of Erythema Nodosum?

Author

Jeanette L Hebel, MD, Dermatologist, Dermatology Associates of Lancaster; Dermatologist, Department of Dermatology, Lancaster General Hospital

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.

Additional Contributors

Timothy McCalmont, MD, Director, UCSF Dermatopathology Service, Professor of Clinical Pathology and Dermatology, Departments of Pathology and Dermatology, University of California at San Francisco; Editor-in-Chief, Journal of Cutaneous Pathology

Disclosure: Received consulting fee from Apsara for independent contractor.

Acknowledgements

Thomas Habif, MD Adjunct Professor, Department of Internal Medicine, Section of Dermatology, Dartmouth Medical School

Thomas Habif, MD is a member of the following medical societies: American Academy of Dermatology and New Hampshire Medical Society

Disclosure: Nothing to disclose.

References

  1. Nguyen GC, Torres EA, Regueiro M, et al. Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort. Am J Gastroenterol. 2006 May. 101(5):1012-23. [View Abstract]
  2. Psychos DN, Voulgari PV, Skopouli FN, Drosos AA, Moutsopoulos HM. Erythema nodosum: the underlying conditions. Clin Rheumatol. 2000. 19(3):212-6. [View Abstract]
  3. Mert A, Ozaras R, Tabak F, Ozturk R. Primary tuberculosis cases presenting with erythema nodosum. J Dermatol. 2004 Jan. 31(1):66-8. [View Abstract]
  4. Wheeler DJ, Cascino T, Sharpe BA, Connor DM. When the Script Doesn't Fit: An Exercise in Clinical Reasoning. J Gen Intern Med. 2017 Mar 23. [View Abstract]
  5. Kakourou T, Drosatou P, Psychou F, Aroni K, Nicolaidou P. Erythema nodosum in children: a prospective study. J Am Acad Dermatol. 2001 Jan. 44(1):17-21. [View Abstract]
  6. Requena L, Yus ES. Erythema nodosum. Dermatol Clin. 2008 Oct. 26(4):425-38, v. [View Abstract]
  7. Bottone EJ. Yersinia enterocolitica: the charisma continues. Clin Microbiol Rev. 1997 Apr. 10(2):257-76. [View Abstract]
  8. Polcari IC, Stein SL. Panniculitis in childhood. Dermatol Ther. 2010 Jul-Aug. 23(4):356-67. [View Abstract]
  9. García-Porrúa C, González-Gay MA, Vázquez-Caruncho M, López-Lazaro L, Lueiro M, Fernández ML, et al. Erythema nodosum: etiologic and predictive factors in a defined population. Arthritis Rheum. 2000 Mar. 43(3):584-92. [View Abstract]
  10. Min MS, Fischer R, Fournier JB. Unilateral Erythema Nodosum following Norethindrone Acetate, Ethinyl Estradiol, and Ferrous Fumarate Combination Therapy. Case Rep Obstet Gynecol. 2016. 2016:5726416. [View Abstract]
  11. Farhi D, Cosnes J, Zizi N, et al. Significance of erythema nodosum and pyoderma gangrenosum in inflammatory bowel diseases: a cohort study of 2402 patients. Medicine (Baltimore). 2008 Sep. 87(5):281-93. [View Abstract]
  12. Richter L, Rappersberger K. [Cutaneous involvement in chronic inflammatory bowel disease : Crohn's disease and ulcerative colitis]. Hautarzt. 2016 Dec. 67 (12):940-947. [View Abstract]
  13. Sullivan R, Clowers-Webb H, Davis MD. Erythema nodosum: a presenting sign of acute myelogenous leukemia. Cutis. 2005 Aug. 76(2):114-6. [View Abstract]
  14. Polat A, Dinulescu M, Fraitag S, Nimubona S, Toutain F, Jouneau S, et al. Skin manifestations among GATA2-deficient patients. Br J Dermatol. 2017 Apr 25. [View Abstract]
  15. Wanat KA, Rosenbach M. Cutaneous Sarcoidosis. Clin Chest Med. 2015 Dec. 36 (4):685-702. [View Abstract]
  16. Amschler K, Seitz CS. [Cutaneous manifestations of sarcoidosis]. Z Rheumatol. 2017 Jun. 76 (5):382-390. [View Abstract]
  17. Grunewald J, Eklund A. Lofgren's syndrome: human leukocyte antigen strongly influences the disease course. Am J Respir Crit Care Med. 2009 Feb 15. 179(4):307-12. [View Abstract]
  18. Mert A, Ozaras R, Tabak F, Pekmezci S, Demirkesen C, Ozturk R. Erythema nodosum: an experience of 10 years. Scand J Infect Dis. 2004. 36(6-7):424-7. [View Abstract]
  19. Moraes AJ, Soares PM, Zapata AL, Lotito AP, Sallum AM, Silva CA. Panniculitis in childhood and adolescence. Pediatr Int. 2006 Feb. 48(1):48-53. [View Abstract]
  20. Requena L, Yus ES. Panniculitis. Part I. Mostly septal panniculitis. J Am Acad Dermatol. 2001 Aug. 45(2):163-83; quiz 184-6. [View Abstract]
  21. Wilk M, Zelger BG, Hayani K, Zelger B. Erythema Nodosum, Early Stage-A Subcutaneous Variant of Leukocytoclastic Vasculitis? Clinicopathological Correlation in a Series of 13 Patients. Am J Dermatopathol. 2019 Aug 12. [View Abstract]
  22. Golisch KB, Gottesman SP, Segal RJ. Compression stockings as an effective treatment for erythema nodosum: Case series. Int J Womens Dermatol. 2017 Dec. 3 (4):231-233. [View Abstract]
  23. Sterling JB, Heymann WR. Potassium iodide in dermatology: a 19th century drug for the 21st century-uses, pharmacology, adverse effects, and contraindications. J Am Acad Dermatol. 2000 Oct. 43(4):691-7. [View Abstract]
  24. Gilchrist H, Patterson JW. Erythema nodosum and erythema induratum (nodular vasculitis): diagnosis and management. Dermatol Ther. 2010 Jul-Aug. 23(4):320-7. [View Abstract]

Classic presentation of erythema nodosum with nodular red swellings over the shins.

Classic presentation of erythema nodosum with nodular red swellings over the shins.