Erythema nodosum
Classification of panniculitis depends upon
multiple factors, including clinical characteristics such as location and
ulceration as well as histopathology and etiology.
Overview
|
Clinical ·
Symmetric, tender, erythematous, warm nodules and plaques on the
anterior aspects of the lower extremities. May become confluent. ·
Acute onset; no ulceration or scarring; more common in women. ·
May be accompanied by fever, malaise, arthralgias and
headache. ·
Lasts from 3–6 weeks, with new lesions appearing for up to 6 weeks. ·
Associated with a wide variety of systemic disorders. Histopathology ·
Mostly septal panniculitis without vasculitis. ·
Thickened septa with inflammatory cells. ·
Neutrophils in early lesions and histiocytes and Miescher granulomas
in late-stage lesions. ·
Treatment of the associated disorder. ·
Bed rest, aspirin, non steroidal anti-inflammatory drugs. ·
Systemic corticosteroids are rarely indicated. |
Introduction
Erythema nodosum is the most common panniculitis. The
process usually shows an acute onset and self‐limited course. It is clinically
characterized by the sudden eruption of several erythematous, tender, non‐ulcerating nodules and
plaques, typically located on the shins. The condition normally resolves
spontaneously without ulceration, scarring or atrophy, but recurrent episodes
are common.
Epidemiology
Age
Erythema nodosum may occur at any age, but
most cases appear between the second and fourth decades of life, with the peak
between 20 and 30 years of age, probably due to the high incidence of
sarcoidosis at this age. It may occur in children and in patients older than 70
years. Age distribution varies with geographic location and etiology.
Sex
Erythema nodosum occurs three to six times more frequently
in women than in men, although the incidence before puberty is approximately
equal in both genders.
Etiology and Pathogenesis
Erythema nodosum has been
considered a delayed hypersensitivity response to a variety of antigenic
stimuli, including infections
(bacteria, viruses, fungi, and protozoa),
medications (sulfonamides,
bromides and oral contraceptive pills), malignancies
(most often leukemias or lymphomas), autoimmune diseases, and other
inflammatory disorders, especially sarcoidosis and inflammatory bowel disease. Half
of all EN cases are idiopathic, without specific etiology, but the most common
triggers are bacterial infections, sarcoidosis and inflammatory bowel disease.
Bacterial infections
Geographical variations in infectious etiology occur, but
a previous episode of upper respiratory infection by group A β‐haemolytic streptococcus is
a frequent cause for erythema nodosum in children and young adults.
Erythematous subcutaneous nodules usually develop 2–3 weeks after the throat
infection and are accompanied by an elevation of the antistreptolysin O (ASO) titer;
by the time cutaneous lesions appear, the cultures from throat swabs usually
fail to detect microorganisms. Tuberculosis is a common cause of erythema nodosum
in areas of high endemicity. Erythema nodosum, when triggered by tuberculosis,
presents mainly in children at the time of primary pulmonary infection and
concomitant with the conversion of the tuberculin test.
Drugs
Sulfonamides, NSAIDs and halide
agents (bromides, iodides) are an important cause of erythema nodosum. Drugs more
recently described to cause erythema nodosum include gold, omeprazole,
leukotriene inhibitors and sulfonylureas. The prevalence of oral contraceptive
pills induced EN has decreased since the introduction of low dose estrogen
therapy.
Inflammatory bowel disease
Ulcerative colitis and Crohn
disease may trigger erythema nodosum. In adults, erythema nodosum is often
associated with a flare of inflammatory bowel disease, although the cutaneous
eruption may sometimes precede the bowel 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. Crohn
disease
has a stronger association with EN than does ulcerative
colitis.
Hodgkin disease and
lymphoma
Erythema nodosum associated
with non-Hodgkin lymphoma may precede the diagnosis of lymphoma by months. Erythema
nodosum may precede the onset of acute myelogenous leukemia.
Sarcoidosis
In adults approximately one
third of all erythema nodosum cases are caused by sarcoidosis. The
most common cutaneous manifestation of sarcoidosis is erythema nodosum. 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.
Clinical features
Clinically, the eruption is quite
characteristic and consists of a sudden onset of symmetrical, bilateral,
tender, painful, erythematous, warm nodules and raised plaques
on the anterior and at times the lateral aspect of
both lower legs and ankles. Other locations are occasionally involved,
particularly the thighs and forearms. Nodules may also appear on the trunk,
neck and face, but this is sufficiently rare that development of lesions in
these locations should prompt consideration of other diagnoses. The nodules range
from 1 to 5 cm or more in diameter. Early lesions show a bright red color and
are raised slightly above the skin. In the second
week, they become flat, with a change in
color from bright red to livid red or purplish color. Finally, they show
a yellow or greenish appearance, often taking on the look of a deep bruise, and
for that reason the process is classically named ‘erythema contusiformis’ if hemorrhage is present in the adipose tissue. This disappears as
the overlying skin desquamates. Individual lesions last approximately 2 weeks, with new lesions appearing for up to 6 weeks, but it may persist
longer and may recur.
Aching legs and swelling ankles may persist for weeks. Nodules of erythema
nodosum never ulcerate and the lesions regress without atrophy or scarring. Up to one-third of cases of erythema nodosum recur. Annual
recurrences are particularly common among idiopathic cases.
Often, acute bouts of erythema nodosum are associated
with a fever of 38–39°C, fatigue, malaise, arthralgia, headache, and more
rarely, abdominal pain, vomiting, cough or diarrhea. Episcleral lesions and
phlyctenular conjunctivitis may also accompany the cutaneous lesions. Rare
clinical manifestations associated with erythema nodosum include
lymphadenopathy, hepatomegaly, splenomegaly and pleuritis. Duration of erythema
nodosum in children is shorter than in adults and arthralgias and fever are less
frequent in pediatric cases.
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.
|
FINDINGS SUGGESTIVE
OF A SYSTEMIC CAUSE FOR ERYTHEMA NODOSUM |
|
·
Synovitis ·
Diarrhea* ·
Abnormal
chest X-ray ·
Preceding
upper respiratory tract infection ·
Elevated
antistreptolysin O and/or anti-DNase B titers ·
Positive
tuberculin skin test or interferon-gamma release assay (e.g. QuantiFERON®-TB Gold In-Tube test, T-SPOT®.TB test) |
* Check
for fecal white blood cells and stool culture for bacteria and, if indicated,
ova and parasites.
Additional evaluation can include viral
hepatitis panel and in women of child-bearing age, serum β-human chorionic
gonadotropin.
Investigations
Laboratory abnormalities may include a high ESR, positive throat
culture, or high ASO titer in those with a streptococcal etiology and
leukocytosis. A positive PPD must be evaluated in the context of prevalence of
tuberculosis in the geographical area. A stronger relationship with
tuberculosis may be established using an IFN‐γ
release assay. Chest X-ray will rule out pulmonary infectious or
noninfectious disease (sarcoidosis). When the etiology is
unclear, serological tests for those bacterial, viral, fungal or protozoal
infections most prevalent in the area should be undertaken.
When the clinical and laboratory findings are
characteristic, a tentative diagnosis of erythema nodosum may be established,
but diagnostic confirmation requires biopsy.
Histopathology
Histopathologically, erythema nodosum is
considered the prototype of septal panniculitis without vasculitis.
The connective tissue septa of the subcutis appear thickened and edematous and
are infiltrated by inflammatory cells that involve mainly the interface between
the septa and the fat lobule. Usually, a superficial and deep perivascular
inflammatory infiltrate composed predominantly of lymphocytes is also present
in the overlying dermis.
As with other panniculitides, erythema nodosum is a
dynamic process and the composition of the inflammatory cells involving the
septa varies with the stage of the condition. Early lesions of less than 48 h
duration show edema and hemorrhage at the septa and numerous neutrophils
arranged interstitially between collagen bundles.
A histopathological hallmark of erythema nodosum is the
presence of so‐called
Miescher microgranulomas. These are small well‐defined nodular aggregates
of macrophages, found within septa or at a
septal–lobular interface, that tend to surround a central stellate or
banana‐shaped cleft-like spaces. They can be found in almost all stages of
erythema nodosum lesions and such a search should always be undertaken to
establish a specific diagnosis. In older lesions,
Miescher microgranulomas may feature epithelioid and multinucleated giant cells.
Late‐stage
lesions of erythema nodosum show septal fibrosis and periseptal granulation
tissue, partially replacing the fat lobules, with an infiltrate composed of
lymphocytes, histiocytes and multinucleated giant cells. Despite this fibrotic
process involving the septa, it is striking that erythema nodosum resolves
completely after some weeks or months.
Vasculitis is not normally seen at any stage in the
course of erythema nodosum.
Differential
diagnosis
The clinical scenario of an acute eruption of
tender subcutaneous nodules over both shins of a young person is highly
characteristic of erythema nodosum. However, when lesions are few in number,
are located in sites other than the lower legs, or are of longer duration
(>6 weeks), erythema nodosum can be difficult to distinguish from other
forms of panniculitis. Lesions of erythema induratum (nodular vasculitis) can
resemble those of erythema nodosum, but they tend to occur on the posterior
aspect of the lower legs and may ulcerate. Ulceration is also a feature of
pancreatic panniculitis, which occurs more frequently in other locations
(although still favoring the lower legs), is more likely to be accompanied by
arthritis and serositis, and is associated with elevated serum amylase and
lipase levels.
Prognosis and clinical course
EN is a benign self-limited subcutaneous disease that resolves
a few weeks after initial presentation; the course, however, varies based on
the etiology. Medication-induced EN may improve after discontinuation of the
drug with the reappearance of the clinical findings when the drug is
reintroduced. New lesions of EN are uncommon after 6 weeks, with persistent and
recurrent cases reported. EN secondary to a malignancy, a severe systemic
disease, or infection may have a more complicated course as a result of the
prognosis of the primary disease. Patient with EN secondary to sarcoidosis have
an improved prognosis. Patients with Crohn disease and EN are more likely to
have colonic involvement of IBD. While
recurrence of EN is rare, it is more frequent when associated with sarcoidosis,
hormonal therapy and pregnancy, streptococcal infection and in patients with
idiopathic erythema nodosum.
Treatment
Treatment of EN primarily focuses on treatment or removal of the
etiologic factor. Suspected medications should be discontinued, underlying
infections sought and treated if possible, and associated inflammatory
disorders or malignancies sought and appropriately treated. During the acute stages
if pain and swelling are significant, management options include limiting
physical exercise, cool wet compresses, bed rest
and leg elevation. Aspirin, as well as several other non steroidal
anti‐inflammatory drugs, such as
indometacin 100–150 mg daily or naproxen 500 mg daily are helpful for pain and
for hastening resolution. Non‐steroidal
anti‐inflammatory drugs are
contraindicated in patients with inflammatory bowel disease.
In more persistent cases, Supersaturated potassium iodide solution
(SSKI), 2–10 drops (1 drops = 0.03 mL = 30 mg) in water or orange
juice three times per day, may be administered. Improvement
can be seen within 2 weeks. The
mechanism of action of potassium iodide in erythema nodosum is unknown, but it
probably induces mast cells to release heparin, which suppresses delayed hypersensitivity
reactions. In addition, potassium iodide inhibits neutrophil chemotaxis and suppresses neutrophil-generated oxygen intermediates.
It should be remembered that potassium iodide is contraindicated during
pregnancy, because it may induce goitre in the fetus. Severe hypothyroidism
secondary to exogenous intake of iodide has also been described in patients
with erythema nodosum treated with potassium iodide.
Treatment of erythema nodosum is influenced
by underlying conditions. Thus, colchicine is useful in management of erythema
nodosum that accompanies Behçet disease. Various treatments for inflammatory
bowel disease are also effective in managing coexistent erythema nodosum. Both
etanercept and infliximab have been reported to be effective in treating
erythema nodosum, but paradoxically both have been noted to produce erythema
nodosum as a cutaneous side effect. In case reports, adalimumab has led to
improvement of refractory chronic erythema nodosum.
Systemic corticosteroids are not usually indicated in
erythema nodosum and they should not be commenced unless an infectious etiology
has been excluded. When administered, prednisolone in a dosage of 40 mg/day is
followed by resolution of the nodules in few days. Intralesional injection of
triamcinolone acetonide at a concentration of 10 mg/mL into the center of the
nodules may also be helpful in solitary persistent lesions.
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TREATMENT RECOMMENDATIONS
FOR ERYTHEMA NODOSUM |
|
|
In all patients |
1.
Discontinue possible causative medications 2.
Diagnose and treat underlying cause 3.
Bed rest and leg elevation 4.
Compression |
|
First-line |
1.
Non steroidal anti-inflammatory medications
(3)* 2.
Salicylates 3.
Potassium iodide (2) |
|
Second-line** |
1.
Colchicine (3)# 0.6–1.2 mg twice a
day 2.
Infliximab (3)## Hydroxychloroquine (3) ^ 200 mg twice a day. 3.
4.
Adalimumab (3)^ 5.
Etanercept 6.
Mycophenolate mofetil (3) |
|
Third-line** |
1.
Systemic corticosteroids (3) 2.
Thalidomide (3)^^ 3.
Cyclosporine (3) 4.
Dapsone (3) |
Key
to evidence-based support: (1) prospective controlled trial; (2) retrospective
study or large case series; (3) small case series or individual case reports.
* May trigger a flare of inflammatory bowel
disease.
** Immunosuppressives to be used only if
underlying infection has been excluded and/or treated.
# Helpful for erythema nodosum associated
with Behçet disease.
## Helpful for erythema nodosum associated
with inflammatory bowel disease.
^ Helpful for chronic erythema nodosum.
^^ May transiently exacerbate erythema
nodosum associated with Behçet disease.
|
USE OF POTASSIUM IODIDE (KI) |
|
Saturated solution of potassium iodide (SSKI) |
|
·
1000 mg/ml ·
Droppers are supplied with calibrations
for: o 0.3 ml
(300 mg)* o 0.6 ml
(600 mg) ·
In adults and older children, common dose =
300 mg TID po with starting dose = 150–300 mg TID ·
In infants and young children, common dose
= 150 mg TID po ·
SSKI should be diluted in water or juice to
try to minimize the bitter aftertaste ·
Crystallization may occur with cold
temperatures, but rewarming and shaking dissolves the crystals; discard if solution
turns yellow–brown * 0.3 ml = 10 drops from the calibrated
dropper supplied with SSKI. |
|
Side effects of SSKI |
|
·
Acute – nausea, bitter eructation,
excessive salivation, urticaria, angioedema, cutaneous small vessel
vasculitis ·
Chronic – enlargement of salivary and
lacrimal glands, acneiform eruption, iododerma, hypothyroidism, hyperkalemia,
occasionally hyperthyroidism |
Prevention
Restriction of physical activities while
erythema nodosum is active may prevent exacerbations of the disease.
