Erythema nodosum

OVERVIEW: What every practitioner needs to know

Are you sure your patient has erythema nodosum? What are the typical findings for this disease?

Typical Findings for Erythema Nodosum in Children

The key features of erythema nodosum (EN) typically include sudden onset of bilateral, 1-5 cm tender, erythematous, subcutaneous nodules arising in crops, most commonly on the pretibial areas. In children, lesions can also be found less commonly on the knees, ankles, extensor aspects of arms, face neck, anterior thighs, and trunk. Lesions are rarely found on the palms and soles although they appear to be more often encountered there in children (Figure 1 and Figure 2).

Figure 1.

Figure 2.

After a few days, lesions may develop a brownish red or purple bruise-like appearance (
Figure 3). The eruption usually lasts 3-6 weeks and lesions do not ulcerate or leave scars. Lesions may be accompanied by fever of 38-39 °C , arthralgias, cough, diarrhea, and malaise. Joint pains may precede, coincide, or follow the eruption in as many as 90% of cases. In contrast to adults, arthralgias are found less commonly in children and appear to be related to associated underlying diseases.

Figure 3.

EN has a much shorter duration in children, and fever is an accompanying manifestation in fewer than half of the cases. Although EN can be associated with a wide variety of systemic disorders, despite investigation, no underlying cause is found in most pediatric patients.

What other disease/condition shares some of these symptoms?

Differential Diagnosis

Although diagnosis is not usually difficult, other conditions that can mimic EN include the following:

Cellulitis: often unilateral with prominent inflammatory symptoms

Common bruises

Erysipelas

Deep fungal infections: for example, sporotrichosis or Majocchi granuloma

Insect bites: itching can be a major clue

Deep thrombophlebitis

Cutaneous forms of periarteritis nodosa

Eccrine hidradenitis: can be confused with this disorder if lesions are on palms and soles

Battered child syndrome: important to note distribution

Cold-induced panniculitis: classically involves the face and upper limbs, evolving into depressed scars

Lupus panniculitis: commonly involves upper limbs and generally heals with atrophic scars

Deep granuloma annulare: lesions are deep subcutaneous nodules with little to no modification of overlying skin

Henoch-Schönlein purpura: palpable purpura and associated extracutaneous findings may be helpful for diagnosis

When lesions are few in number, are of longer duration, and are located in sites that are not the most common, EN can be difficult to distinguish from other forms of panniculitis, including erythema induratum and pancreatic panniculitis. Erythema induratum tends to occur on the posterior aspect of the lower legs and may ulcerate. Pancreatic panniculitis may also ulcerate and is more likely to be accompanied by arthritis and serositis and is associated with elevated serum lipase and amylase levels.

A clinical clue to the diagnosis is the predictable change in color over time from red to purple to yellow-green, resulting in bruise-like changes (Figure 3). When the diagnosis is in doubt, a skin biopsy can aid in diagnosis.

What caused this disease to develop at this time?

Etiologic causes of erythema nodosum

Most pediatric cases are idiopathic (up to 40%) and no underlying cause is found despite investigation. Although there are numerous causes, the most common in pediatric patients is β-hemolytic streptococcal infection, especially pharyngitis, followed by gastrointestinal infections, particularly Yersinia enterocolitica. The cutaneous lesions generally appear 2-3 weeks after the throat infection. Infections generally account for one third or more of the cases.

Common infections: β-hemolytic streptococcal infections,
Mycoplasma pneumoniae, upper respiratory viruses (Epstein-Barr virus), coccidiomycosis in endemic areas, tuberculosis,
Yersinia entercolitica

Less common infections: hepatitis B; brucellosis; meningococcosis; neisserial infection; cat-scratch disease; infection with HIV, Chlamydia, Campylobacter, Shigella;blastomycosis; histoplasmosis; sporotrichosis; syphilis; pertussis; Escherichia coli infection; leprosy; parvovirus

Inflammatory conditions: Sarcoidosis, inflammatory bowel disease (Crohn disease has a stronger association than does ulcerative colitis), Behçet disease, Sweet syndrome

Medications: Many medications have been implicated as a cause of EN, but the most common associated with EN in children include oral contraceptives, macrolide antibiotics, sulfonamides, and penicillin.

Pregnancy

Rare causes: EN has been described in a girl with tinea capitis caused by Trichophyton mentagrophytes. Leukemia masquerading as EN is exceptional but may be diagnosed with biopsy. Recently, there has been an extremely rare case of EN with acute myeloid leukemia.

Although drugs and chronic conditions (i.e., sarcoidosis, autoimmune conditions, and inflammatory bowel disease) account for most of the adults cases, these are less often implicated in the pediatric population.

The presence of EN in patients with coccidiomycosis suggests a positive prognostic sign with a decreased risk of dissemination. This is in contrast to a worse prognosis in children with primary tuberculosis who present with lesions of EN.

How to make the diagnosis of erythema nodosum

EN is generally diagnosed with history and physical examination, as it has a characteristic clinical picture. A clinical clue to diagnosis is the predictable evolution in color over time resulting in bruise-like changes (Figure 3).

If needed, skin punch biopsy can help confirm the diagnosis. It is usually needed only when patients have an atypical presentation or protracted course. Histologically, erythema nodosum is the prototypical septal panniculitis. Early lesions show edematous septa and mild lymphocytic infiltrates. Neutrophils may predominate in early lesions (Figure 4).

Figure 4.

Miescher microgranulomas are a pathognomonic feature seen in early lesions. These microgranulomas are small collections of histiocytes found within the septa or at the septa/lobule interface that tend to surround neutrophils or small cleft-like spaces. As lesions progess, the septa become widened and contain a mixed partly granulomatous infiltrate (Figure 5).

Figure 5.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Suggested laboratory testing that may aid in elucidating underlying systemic causes

Complete blood count with differential (white blood cell count is normal or only slightly increased)

Erythrocyte sedimentation rate (correlated more with EN rather than with the underlying disease)

C-Reactive protein determination (correlated more with EN rather than with the underlying disease)

Liver function tests

Chest radiography to rule out pulmonary diseases

Pregnancy test if applicable

Bacterial cultures

Fungal cultures

Urinalysis

Pharyngeal culture

Antistreptolysin O (ASO) titer

A high ASO titer usually is seen in cases associated with streptococcal infections. A significant change, at least 30%, in ASO titer in two consecutive tests performed in a 2- to 4-week interval usually indicates a recent streptococcal infection.

In children, the elevation of the erythrocyte sedimentation rate correlates significantly with the number of cutaneous lesions and is often very high, returning to normal when the eruption fades.

The remainder of testing should be directed based on suspicion for underlying causes.

Stepwise approach to patient suspected of having erythema nodosum

Careful review of all medications (prescription and nonprescription) is essential, especially asking about oral contraceptives.

Careful history taking regarding previous diseases, foreign travel, pets, and hobbies, as well as familial cases is carried out.

Screening for streptococcal infections by throat culture or ASO titer is recommended even in asymptomatic individuals. A positive intradermal test to streptococcal antigen is often found in patients with EN secondary to streptococcal infections. It is important to keep in mind that when cutaneous nodules develop, the cultures of routine throat swabs usually do not detect microorganisms, thus necessitating obtaining ASO titers.

Cough or upper respiratory symptoms warrant obtaining Mycoplasma pneumoniae antibody titers. Repeat testing in 10 days to look for a seroconversion or fivefold rise of titers.

Stool for culture and serum Yersinia titers should be obtained in patients with diarrhea, based on history. Consider stool culture for Campylobacter, Salmonella, and Shigella.

When the cause is doubtful, a sample of blood should be serologically investigated based on the bacterial, viral, fungal, or protozoal infections that are more prevalent in the area.

Consider purified protein derivative testing in children with risk factors, although tuberculosis is a rare cause of EN in children.

Additional testing that may be considered based on suspicion includes rheumatoid factor and alpha-2 globulin.

If you are able to confirm that the patient has erythema nodosum, what treatment should be initiated?

Management is directed at identification and treatment of the underlying cause if one can be identified. The condition is generally self-limited in idiopathic cases.

Pain, inflammation, or arthralgias can be treated with strict bed rest, elevation of legs, and restriction of physical activity until resolution of lesions (a few weeks). These efforts can help prevent exacerbations. Salicylates and nonsteroidal antiinflammatory drugs (NSAIDS) such as ibuprofen or naproxen can also be used to alleviate symptoms.

If needed, small volumes (0.1 mL) of intralesional corticosteroids (intralesional triamcinolone acetonide in a dosage of 5 mg/mL) can be injected into the center of the nodule and frequently leads to rapid involution of individual lesions. If lesions become persistent or recurrent, oral corticosteroids may be beneficial. A dose of 0.5 mg/kg of prednisone per day for a period of 1-2 months had variable success in one pediatric case series.

There have been case reports of the use of etanercept and infliximab in adults with chronic or recurrent cases of EN.

These treatments have not been reported in children with EN.

Other treatments more commonly used in adults include potassium iodide, colchicine, hydroxychloroquine, cyclosporin A, and thalidomide. Mainly these treatment modalities are targeted at treating the underlying systemic cause.

What are the adverse effects associated with each treatment option?

NSAIDS should be avoided in the treatment of EN associated with inflammatory bowel disease, as it may trigger a flare of the bowel disease or compromise maintenance therapy. Gastrointestinal effects are one of the most common adverse effects of NSAIDS and include dyspepsia, peptic ulcer disease, and bleeding. Other potential adverse effects include, but are not limited to, nephrotoxicity, hepatoxicity, and skin reactions such as toxic epidermal necrolysis, and Stevens-Johnson syndrome.

Salicylates should be used with caution in children, given the link to Reye syndrome. Adverse effects from salicylate toxicity include nausea, vomiting, confusion, dizziness, psychosis, stupor, coma, death, hypoglycemia, and tinnitus.

Before oral steroids are administered, an underlying infection should be excluded. Prolonged oral corticosteroids (>4 weeks) can cause multiple adverse effects, including suppression of the hypothalamic-pituitary axis, growth suppression in children, hypertension, hyperglycemia, behavior and personality changes, delayed wound healing, hypertrichosis, glaucoma, increased risk of infections, alterations in appetite and sleep, and ocular effects.

Routine H2-receptor antagonists or proton pump inhibitors are of value to prevent or ameliorate the frequency of gastrointestinal complaints in children.

Patients must be cautioned that intralesional steroids may cause atrophy of the skin.

Prognosis

EN tends to resolve spontaneously over 3-4 weeks and the course is generally benign. More severe cases resolve over 6 weeks. Lesions heal without scarring, atrophy, or ulceration. Recrudescences may appear over a period of weeks to months, but attacks are seldom recurrent. In 10% of patients who have recurring disease, these recurrences are frequently associated with repeated streptococcal infection.

Epidemiology

EN is considered to be a delayed hypersensitivity response to a variety of antigenic stimuli, including infections, medications, pregnancy, and inflammatory and malignant disease.

EN is the most common type of panniculitis is all ages. Its peak incidence is between 20 and 30 years of age, with a smaller peak in adolescence, particularly in children older than 10 years of age. Although there is a clear female predominance in adults with EN, during childhood, girls are affected only slightly more than boys, and most studies and reviews report an equal sex incidence. It is rare in children younger than the age of 2 years. The greatest incidence is seen in the spring and fall. Although seen in the summer, it is less common during that season.

In the past, tuberculosis was the most common cause associated with EN. In the United States and Europe, β-hemolytic streptococcal infection is now the most common inciting agent. In cases of EN with undefined causes, it is often reported that a respiratory tract infection occurred before skin manifestations.

Racial and geographic differences of incidence vary depending on the prevalence of diseases that are causative factors. In areas where certain causes of EN are prevalent (e.g.,
Coccidioides immitis, Behçet disease), EN may be seen in greater numbers

Pathogenesis

EN has long been considered a hypersensitivity response to a wide variety of inciting factors. The large variability of potential antigenic triggers that can induce EN suggests that this disorder is a cutaneous reactive process.

A delayed type of hypersensitivity reaction is suggested based on histopathologic features and despite the fact that direct immunofluorescence studies have shown the very occasional finding of immunoglobulin/immunoreactant deposits in the blood vessel walls of the septa in the subcutaneous fat, an immune complex–mediated vasculitis is not considered likely. It is probable that EN represents a nonspecific hypersensitivity reaction that involves a delayed type of hypersensitivity mechanism in addition to a type 3 component.

Neutrophils are numerous in early lesions and produce reactive oxygen intermediates; these intermediates are suspected to provoke inflammation and tissue damage. Regardless of the exact mechanism, a wide variety of triggering factors has been linked to erythema nodosum.

The reason that the anterior aspects of the legs are so susceptible for lesions is unknown. Some authors have proposed that there is no other site on the skin surface that has a combination of a relatively sparse arterial supply associated with a venous system subject to gravitational effects and cooling as well as a lymphatic system that is hardly efficient enough to meet the requirements of any increase in fluid load. In addition, the skin in this location has no mechanical stimulus and no underlying muscle pump; this area receives little in the way of massage.

What complications might you expect from the disease or treatment of the disease?

The complications associated with EN are those expected from the underlying systemic disease that may be the cause. In most idiopathic causes, EN resolves spontaneously with no serious sequelae.

What is the evidence?

Below are listed the texbooks, clinical studies, case reports and reviews of erythema nodosum in the literature. These are some of the most relevant studies and references because they focus on EN and its management in the pediatric population.

Morin, D, Zini, R, Urien, S. “Labelling of rat brain beta-adrenoceptors: (3H)CGP-12177 or (125I) iodocyanopindolol?”. J Recept Res. vol. 12. 1992. pp. 369-87.

Requena, L, Yus, ES. “Erythema nodosum”. Dermatol Clin. vol. 26. 2008. pp. 425-38.

Modgil, G, Bridges, S. “Erythema nodosum associated with Shigella colitis in a 7-year-old boy”. Int J Infect Dis. vol. 11. 2007. pp. 556-7.

Polcari, IC, Stein, SL. “Panniculitis in childhood”. Dermatol Ther. vol. 23. 2010. pp. 356-67.

Kakourou, T, Drosatou, P, Psychou, F. “Erythema nodosum in children: a prospective study”. J Am Acad Dermatol. vol. 44. 2001. pp. 17-21.

Hassink, RI, Pasquinelli-Egli, CE, Jacomella, V. “Conditions currently associated with erythema nodosum in Swiss children”. Eur J Pediatr. vol. 156. 1997. pp. 851-3.

Labbé, L, Perel, Y, Maleville, J, Taïb, A. “Erythema nodosum in children: a study of 27 patients”. Pediatr Dermatol. vol. 13. 1996. pp. 447-50.

Yi, SW, Kim, EH, Kang, HY. “Erythema nodosum: clinicopathologic correlations and their use in differential diagnosis”. Yonsei Med J. vol. 48. 2007. pp. 601-8.

Garty, BZ, Poznanski, O. “Erythema nodosum in Israeli children”. Isr Med Assoc J. vol. 2. 2000. pp. 145-6.

Moraes, A, Soares, PM, Zapata, AL. “Panniculitis in childhood and adolescence”. Pediatr Int. vol. 48. 2006. pp. 48-53.

Bassi, N, Kersey, P. “Erythema nodosum complicating a case of kerion celsi of the scalp due to Trichophyton mentagrophytes”. Clin Exp Dermatol. vol. 34. 2009. pp. 621-2.

La Spina, M, Russo, G. “Presentation of childhood acute myeloid leukemia with erythema nodosum”. J Clin Oncol. vol. 25. 2007. pp. 4011-2.

Cenqiz, AB, Kara, A, Kanra, G. “Erythema nodosum in childhood: evaluation of ten patients”. Turk J Pediatr. vol. 48. 2006. pp. 38-42.

Boyd, AS. “Etanercept treatment of erythema nodosum”. Skinmed. vol. 6. 2007. pp. 197-9.

Clayton, TH, Walker, BP, Stables, GI. “Treatment of chronic erythema nodosum with infliximab”. Clin Exp Dermatol. vol. 31. 2006. pp. 823-4.

“Aetiology of erythema nodosum in children. A study by a group of paediatricians”. Lancet. vol. 2. 1961. pp. 14-6.

Bolognia, JL, Jorizzo, JL, Rapini, RP. Dermatology. 2003.

Wolverton, SE. “Comprehensive Dermatologic Drug Therapy”. 2007.

Paller, AS, Mancini, AJ. “Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescents”. 2006.

McKee, PH, Calonje, E, Granter, SR. “Pathology of the Skin with Clinical Correlations”. 2005.

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