Erythema Nodus: Causes, Symptoms, Diagnosis, Treatment, Prognosis and Complications

It is the most common type of panniculitis (inflammation of the layer of fat on the skin).

It leads to the formation of raised, red nodules that are usually seen over the area of ​​the shins, ankles, and knees.

Erythema nodosum can occur at any age, but it is most commonly seen in patients between 20 and 40 and is most common in women.

Erythema nodosum has long been considered a hypersensitive response to many inciting factors.

The significant variability of possible antigenic triggers that can induce erythema nodosum suggests this disorder is a reactive skin process.

A type of delayed hypersensitivity reaction is suggested based on histopathological characteristics.

Although direct immunofluorescence studies have shown the occasional finding of immunoglobulin and immunoreaction deposits on the septa blood vessel walls in subcutaneous fat, immune complex-mediated vasculitis is not considered likely.


Erythema nodosum is likely to represent a nonspecific hypersensitivity reaction involving a type of delayed hypersensitivity mechanism and a type 3 component.

Neutrophils are numerous in early lesions and produce reactive oxygen intermediates; these intermediates are suspected of causing inflammation and tissue damage.

Regardless of the exact mechanism, many triggers have been associated with erythema nodosum.

The reason why the legs are so susceptible to injury is unknown.

Some authors have proposed that no other site on the surface of the skin has a combination of a relatively poor arterial supply associated with a venous system subject to gravitational effects and cooling.

This area has a lymphatic system that is not efficient enough to meet the requirements of any increased fluid load.

Also, the skin at this location has no mechanical stimuli or underlying muscle pump.

Causas del eritema nodoso

Erythema nodosum is considered a hypersensitivity response to different provoking agents.

This leads to activation of the immune system and inflammation of the fatty layer on the skin.

Most pediatric cases are idiopathic (up to 40%), and no underlying cause is found despite investigation.

Among the most common causes of erythema nodosum we have:


The condition can be triggered by various stimuli, with infections generally accounting for a third or more of cases.

Common infections

It has been associated with β-hemolytic streptococcal infections, Mycoplasma pneumonia, upper respiratory tract virus (Epstein-Barr virus), coccydiomycosis in endemic areas, tuberculosis, and Yersinia enterocolitis, among others.

Less common infections

There are other less common infections such as hepatitis B, brucellosis, meningococcus, Neisseria infection, cat scratch disease, HIV infection, Chlamydia campylobacter, Shigella, blastomycosis, histoplasmosis, sporotrichosis, syphilis, pertussis, Escherichia coli infection, leprosy, parvovirus, which can also cause the appearance of erythema todos os.

Inflammatory conditions

It has also been reported that some inflammatory conditions lead to the appearance of this type of erythema, such as Sarcoidosis, inflammatory bowel disease (Crohn’s disease has a stronger association than ulcerative colitis), Behcet’s disease, and Sweet’s syndrome.


Many medications have been implicated as a cause of erythema nodosum, but the most common ones associated with erythema nodosum in children include:

  • Oral contraceptives.
  • Macrolide antibiotics.
  • Sulfonamides.
  • Penicillin.
  • Iodine.
  • Bromide.
  • Non-steroidal anti-inflammatory drugs.

The pregnancy

Pregnancy has been associated with the appearance of erythema nodosum.

Uncommon causes

Erythema nodosum has been described in a patient with tinea capitis caused by Trichophyton mentagrophytes.

Leukemia masked as erythema nodosum is rare but can be diagnosed with a biopsy.

Recently, there has been a sporadic case of erythema nodosum with acute myeloid leukemia.

Erythema nodosum symptoms

Skin lesions usually appear 2 to 3 weeks after a throat infection.

The key features of erythema nodosum are usually the sudden appearance of bilateral, sensitive, erythematous, subcutaneous nodules that arise 1–5 cm, most commonly in the pretibial areas.

In children, lesions can also be found less frequently on the knees, ankles, extensor aspects of the arms, the face of the neck, the front thighs, and the trunk.

Lesions are rarely found on the palms and soles of the feet, although they appear to be more common in children.

Initially, the lesions are bright red and rise above the skin. After 1 to 2 weeks, they flatten and take on a reddish-purple or purple appearance. The rash usually lasts 3 to 6 weeks.

The nodules usually do not form pus and do not ulcerate. They usually heal without leaving scars.

Leg pain and ankle swelling are joint in the initial phase.

The lesions may be accompanied by a 38 to 39 ° C fever.

Other symptoms can include lethargy, abdominal pain, cough, diarrhea, and general malaise.

Joint pain can precede, coincide or follow the rash in up to 90% of cases.

Unlike in adults, arthralgias are found less frequently in children and are related to associated underlying conditions.

Diagnóstico del eritema nodoso

Erythema nodosum is generally diagnosed with a history and physical examination since it has a characteristic clinical picture.

A careful history of the patient is carried out on previous illnesses, trips abroad, pets and hobbies, and family cases.

A clinical clue to the diagnosis is the predictable evolution of color over time that produces changes similar to bruises.

Sometimes a biopsy of the fat layer may be needed to confirm the diagnosis.

It is generally needed only when patients have an atypical presentation or a long course.

The classic finding on biopsy is septal panniculitis (inflammation of the septa that divides fat into lobules).

Early lesions show edematous septa, and mild lymphocytic infiltrates. Neutrophils may predominate in early lesions.

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/lobe interface that tend to surround neutrophils or small cleft-like spaces.

The septa widen and contain a partially mixed granulomatous infiltrate as the lesions progress.

Several tests may also be needed to determine the underlying cause.

  • A complete blood count with differential (white blood cell count is average or only slightly increased).
  • An erythrocyte sedimentation rate (correlated more with erythema nodosum than with underlying disease).
  • In children, elevated erythrocyte sedimentation rate is significantly correlated with the number of skin lesions and is usually very high, returning to normal when the rash subsides.
  • Determination of C-Reactive protein (more correlated with erythema nodosum than with the underlying disease).
  • Chest x-ray and active tuberculosis test.

Testing of purified protein derivatives should be considered in children with risk factors, although tuberculosis is a rare cause of erythema nodosum in children.

It is important to note that when skin nodules develop, routine throat swab cultures generally do not detect microorganisms, requiring angiotensin-converting enzyme titers.

A positive intradermal test for streptococcal antigen is often found in patients with erythema nodosum secondary to streptococcal infections.

Detection of streptococcal infections by throat culture or angiotensin-converting enzyme level titer is recommended even in asymptomatic individuals.

A high titer of antistreptolysin is generally seen in cases associated with streptococcal infections.

Cough or upper respiratory symptoms warrant obtaining antibody titers against Mycoplasma pneumoniae.

At least 30%, a significant change in the antistreptolysin titer in two consecutive tests performed at an interval of 2 to 4 weeks generally indicates a recent streptococcal infection.

The doctor may also order a urine test.

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

The rest of the tests should be directed based on suspicion of underlying causes.

In the approach to the patient with suspected erythema nodosum, a careful review of all prescription and non-prescription drugs should be made; it is essential to know about oral contraceptives.

Treatment of erythema nodosum

Management is aimed at identifying and treating the underlying cause. The condition is generally self-limited in idiopathic cases.

If no underlying cause is found, treatment usually consists of strict bed rest, leg elevation, restriction of physical activity, and wearing compression stockings.

These efforts can help prevent flare-ups and decrease pain, inflammation, or joint pain.

Treatment of the underlying condition or removal of the offending medication will usually lead to the resolution of symptoms.

Salicylates and nonsteroidal anti-inflammatory drugs, such as ibuprofen or naproxen, can also be used to relieve symptoms.

If necessary, small volumes (0.1 ml) of intralesional corticosteroids (intralesional triamcinolone acetonide at a dose of 5 mg per ml) can be injected into the center of the nodule and often leads to rapid involution of individual lesions.

If the lesions become persistent or recurrent, oral corticosteroids may be beneficial. A dose of 0.5 mg per kg of prednisone per day for 1 to 2 months had variable success in a series of pediatric cases.

Cases of etanercept and infliximab have been reported in adults with chronic or recurrent issues of erythema nodosum.

Other more commonly used treatments in adults include potassium iodide, colchicine, hydroxychloroquine, cyclosporine A, and thalidomide; these treatment modalities aim to treat the underlying systemic cause.

Adverse effects associated with the treatment of erythema nodosum

Nonsteroidal anti-inflammatory drugs should be avoided in treating erythema nodosum associated with inflammatory bowel disease, as it may trigger a flare of bowel disease or compromise maintenance therapy.

Gastrointestinal effects are among the most common adverse effects of nonsteroidal anti-inflammatory drugs and include dyspepsia, diseases such as peptic ulcers, and bleeding.

Other potential adverse effects include but are not limited to nephrotoxicity, hepatotoxicity, and skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome.

Given the link to Reye’s syndrome, salicylates should be used with caution in children.

Adverse effects of salicylate toxicity include nausea, vomiting, confusion, dizziness, psychosis, stupor, coma, death, hypoglycemia, and tinnitus.

Before administering oral steroids, an underlying infection must be excluded.

Long-term oral corticosteroids (for more than four weeks) can cause multiple adverse effects, including:

  • Suppression of the hypothalamic-pituitary axis.
  • Growth suppression in children.
  • Hypertension and hyperglycemia.
  • Changes in the behavior and personality of the individual.
  • Delayed wound healing.
  • Hypertrichosis
  • Glaucoma.
  • Increased risk of infections.
  • Appetite and sleep disturbances.
  • Eye effects.

Routine H2 receptor antagonists or proton pump inhibitors are of value in preventing or improving the frequency of gastrointestinal conditions in children.

Patients should be advised that intralesional steroids can cause skin atrophy.


Erythema nodosum tends to resolve spontaneously after 3 to 4 weeks, and the course is generally benign.

The most severe cases resolve in 6 weeks. Lesions heal without scarring, atrophy, or ulceration.

However, leg pain and ankle swelling can persist for weeks after this. Children tend to have a shorter illness than adults.

In the 10 percent of patients who have recurrent disease, these recurrences are frequently associated with a repeat streptococcal infection.

Flare-ups can appear over weeks to months, but attacks are rarely recurrent.

Relapses are more common in people with erythema nodosum of unknown cause and erythema nodosum not associated with respiratory tract infections.

Complications of erythema nodosum

Complications of erythema nodosum are infrequent.

Complications associated with erythema nodosum are those expected from the underlying systemic disease that may cause the condition.

In most idiopathic causes, erythema nodosum resolves spontaneously without serious sequelae.