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Dermatologic Therapy, Vol. 23, 2010, 320–327
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© 2010 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY
ISSN 1396-0296
Erythema nodosum and
erythema induratum (nodular
vasculitis): diagnosis
and management
dth_1332
320..327
Heidi Gilchrist & James W. Patterson
Department of Pathology, University of Virginia Health System,
Charlottesville, Virginia
ABSTRACT: Erythema nodosum is the most common type of panniculitis; it may be due to a variety of
underlying infectious or otherwise antigenic stimuli. The pathogenesis remains to be elucidated, but
both neutrophilic inflammation and granulomatous inflammation are implicated. Beyond treating
underlying triggers, therapeutic options consist mainly of nonsteroidal anti-inflammatory drugs,
symptomatic care, potassium iodide, and colchicine. Erythema induratum (nodular vasculitis) is a
related but distinctly different clinicopathologic reaction pattern of the subcutaneous fat. It is classically caused by an antigenic stimulus from Mycobacterium tuberculosis but may be associated with
several other underlying disorders. After appropriate antimicrobial treatment in tuberculous cases,
therapy for erythema induratum is similar to options for erythema nodosum.
KEYWORDS: erythema induratum, erythema nodosum, management, nodular vasculitis, treatment
Introduction
EN
Erythema nodosum (EN) and erythema induratum
(EI; nodular vasculitis) are classic forms of panniculitis, and both may represent manifestations of
various disease processes. Classification of the
clinicopathologic reaction pattern and identification of underlying infection or other disorders may
be an exacting task, as the subcutaneous adipose
tissue displays a limited variety of responses to
inflammatory stimuli, and there may be some
overlap in clinical presentation and in histological
features on biopsy. After treatment of any identified
potential etiologies, therapeutic options are similar
for both forms of panniculitis.
Diagnosis
Address correspondence and reprint requests to: Heidi
Gilchrist, MD, Department of Pathology, UVA Health System,
Box 800214, 1215 Lee Street, Hospital Expansion, 3rd Floor,
Charlottesville, VA 22908, or email: [email protected].
320
EN is the most common form of panniculitis. It
classically presents as tender, warm, erythematous
subcutaneous nodules on the bilateral pretibial
areas. Although it can occur in both sexes and at
any age, it has a predilection for young women,
particularly during the second through the fourth
decades of life. In a study of 129 patients, the mean
age was 31 years, but ages ranged from 9 to 70 years
with 10 patients younger than 15 years (1). The
female to male ratio has been reported as 4–5 : 1
(2). EN has also been reported to occur in anatomic
locations other than the shins, especially on the
thighs and extensor forearms (1). Rarely, the head,
neck, or trunk may be involved (3).
Ulceration or suppuration of lesions of EN is
exceedingly rare, although it has been reported in a
case associated with Crohn’s disease (4). More
Erythema nodosum and erythema induratum
usually, individual nodules last approximately 2
weeks and then slowly involute without scarring.
New crops of lesions can continue to arise for as
long as 6 weeks. Occasionally, if subcutaneous
hemorrhage has occurred, the lesions of EN resolve
with a bruise-like hyperpigmentation and are then
sometimes termed erythema contusiforme. There
are also chronic variants of EN; lesions are more
likely to be unilateral and migratory, or undergo
centrifugal spread with central clearing. These
variants are known as erythema nodosum migrans
or subacute nodular migratory panniculitis (5).
EN is often accompanied by systemic symptoms
including fever, malaise, arthritis, and arthralgias.
These symptoms can comprise a prodrome as early
as 1–3 weeks before the lesions appear (4). Arthralgias and rheumatoid factor-negative arthritis have
been reported to persist for up to 2 years after the
resolution of EN lesions. Abnormal laboratory
studies can include leukocytosis greater than
10,000 per mm3 and elevated erythrocyte sedimentation rate and C-reactive protein levels (6).
Pathophysiology
A word about the pathogenesis of EN is required in
order to logically discuss the therapeutic options.
EN is generally regarded as a type IV delayed hypersensitivity response to a variety of antigens,
although this is likely an oversimplification (7).
This nonspecific subcutaneous reaction pattern is
commonly idiopathic; a trigger is not identified in
one third to one half of cases (2,8,9). Table 1 lists
common and uncommon known causes of EN
(1,6,10–12). The most common infectious cause
and the most common cause in children is streptococcal upper respiratory infections (Lancefield
Group A, Streptococcus pyogenes), accounting for
28–44% of cases (1,13). In some instances, EN
denotes a favorable prognosis for the underlying
condition, predicting a lower likelihood of disseminated disease in coccidioidomycosis (14) and a less
protracted disease course with spontaneous resolution of sarcoidosis (1).
Given the broad variety of possible triggers for
EN, a thorough history and physical examination
are essential to narrowing the list of possible etiologies. Depending on the patient’s signs and symptoms, a reasonable laboratory and radiologic
workup might include antistreptolysin O or antiDNase B levels, a chest X-ray, stool cultures, a
tuberculin skin test, and a urine pregnancy test.
In the absence of specific symptoms or positive
findings, further studies are probably not cost–
effective (1).
Skin biopsy may be of great benefit in diagnosing clinically atypical cases of EN. As for all panniculitides, a deep incisional biopsy with a
generous sample of the subcutaneous fat gives the
greatest chance of a definitive diagnosis. Histopathologically, EN is the prototypical septal panniculitis. Neutrophils frequently predominate in
Table 1. Etiologies of erythema nodosum
Common causes
Uncommon causes
Infectious agents
Lancefield Group A Streptococcus
Coccidioides immitis
Gastroenteritis due to Yersinia,
Salmonella, and Campylobacter
Chlamydia pneumoniae
Chlamydia trachomatis
Mycoplasma pneumoniae
Mycobacterium tuberculosis
Brucella melitensis
Hepatitis B (infection or vaccine)
Epstein–Barr virus
Medications
Estrogens/oral contraceptive pills
Sulfonamides
Penicillins
Halogens (bromides, iodides)
Cabergoline
Underlying disease processes
Crohn’s disease
Sarcoidosis (Lofgren’s syndrome)
Ulcerative colitis
Behçet’s disease
Sweet’s syndrome
Hormonal states
Malignancy
Pregnancy
Acute myelogenous leukemia
Hodgkin’s disease
Carcinoid tumor
Pancreatic carcinoma
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Gilchrist & Patterson
early lesions, and increased circulating neutrophils
in the peripheral blood may promote production of
reactive oxygen intermediates and resulting tissue
damage (15,16). Indeed, many of the therapeutic
options discussed below may be effective through
their actions on neutrophils. There is also growing
evidence for the role of other inflammatory cells
and biochemical mediators (15–17).
Both early and late lesions of EN can show
granulomatous features, ranging from Miescher’s
microgranulomas accompanying the early acute
inflammation to widened, fibrotic subcutaneous
septa with multinucleate giant cells in late lesions.
Granulomatous diseases have been closely linked
to deregulated tumor necrosis factor (TNF)-alpha
production, and a strong correlation between a
TNF-alpha gene promoter polymorphism and
sarcoidosis-associated EN has been described (18).
This postulates a role for therapies that inhibit
TNF-alpha as well as for other treatments that are
antigranulomatous.
Therapeutic options
The primary treatment for EN is to remove the
underlying trigger, if possible. Potential causative
drugs should be discontinued based on risk–
benefit assessment and consultation with the prescribing physician. Underlying infections or
malignancies should receive appropriate treatment. Beyond these steps, the mainstay of treatment is symptomatic, as most cases are self-limited
and will resolve spontaneously. Patients should be
cautioned that up to 2 months may elapse before
they stop developing new lesions. Recurrences
occur in 33–41% of cases and are more likely if the
etiology is unknown (6,19).
Nonsteroidal anti-inflammatory drugs. The firstline therapy is nonsteroidal anti-inflammatory
drugs (NSAIDs), including salicylic acid derivatives
(20). Of note, NSAIDs should be avoided in patients
with acute and chronic renal disease as these medications cause renal artery constriction and a
decrease in renal perfusion. NSAIDs also increase
the risk of gastrointestinal bleeding in patients on
hemodialysis (21). In addition, NSAIDs should be
used with caution in patients with cardiovascular
disease, as they have been reported to be associated with an increased incidence of both nonfatal
and fatal myocardial infarctions and strokes (22).
Further caution should be exercised in patients
with known gastritis or esophagitis because
NSAIDs can aggravate these conditions; addition of
a proton pump inhibitor at standard doses may
allow these patients to tolerate the therapy. Finally,
NSAID use is contraindicated after the fifth month
of gestation because of the risk of premature
closure or constriction of the ductus arteriosus,
persistent fetal pulmonary hypertension, intracranial hemorrhage, and fetal renal toxicity (23). In
the absence of the above contraindications, most
healthy adults with EN can be treated with NSAIDs
at standard doses (see Table 2) with good success.
Based on anecdotal experience, the present
authors usually begin therapy with indomethacin
and use ibuprofen and naproxen as second-line
agents, but individual patients may respond
differently, and the clinician should be comfortable
prescribing a variety of NSAIDs as monotherapy.
Rest, elevation, and compression. Bed rest and
regular elevation of the legs are highly recommended adjuvant treatments. Some of the pain of
Table 2. Adult dosing of oral nonsteroidal anti-inflammatory drugs for the treatment of erythema nodosuma
Drug
Dose
Frequency
(hours)
Daily maximum
dose (mg)
Aspirin
Celecoxib
Diclofenac
Ibuprofen
Indomethacin
325–650 mg
100–200 mg
50–75 mg
200–800 mg
25–75 mg
q4
q12
q12
q6–8
q8–12
4000
400
150
3200
150
Ketoprofen
Naproxen
Salsalate
Sulindac
25–75 mg
250–500 mg
1–1.5 g
150–200 mg
q6–8
q8–12
q8–12
q12
300
1000
3000
400
a
Physician’s Desk Reference, 63rd edition, 2009.
LFTs, liver function tests; q, every.
322
Comments
May aggravate asthma
Contraindicated with sulfonamide allergy
Check LFTs at baseline and periodically
May aggravate depression or psychiatric
disturbances
Rare pancreatitis and potentially fatal
hypersensitivity syndrome
Erythema nodosum and erythema induratum
EN is likely caused by the pressure of edema on
surrounding tissues. In the present authors’ experience, raising the legs above the level of the heart
for at least 30 minutes twice daily can mitigate the
discomfort. It should be emphasized that placing
the legs high enough to maximize venous return
(i.e., ankles above the chest) is essential. The
patient should be instructed to lie supine on the
floor or a piece of furniture, and place the legs in
a vertical position on an adjoining wall. Gentle
flexion and extension of the ankles while in this
position can create a muscular pumping action,
further encouraging lymphatic and venous
drainage.
In addition, gradient support stockings or pressure bandages can help to decrease edema and discomfort while the patient is active. The present
authors instruct the patient to purchase knee-high
hosiery with a 15–20 mmHg pressure gradient.
Longer and tighter hose may be difficult to
don and uncomfortable to wear, decreasing patient
compliance.
Potassium iodide. Potassium iodide (KI) is a timehonored therapy in the arsenal of the dermatologist. First discovered in the 19th century as a
treatment for thyroid disease, today, it is used to
treat a variety of dermatologic conditions, including EN and nodular vasculitis (24). The mechanism
of action of KI is not entirely known, but there is
evidence that it inhibits neutrophil chemotaxis (25)
as well as significantly suppresses neutrophils’
ability to generate toxic oxygen intermediates (26).
Also, given the reported successes of KI used to
treat Wegener’s granulomatosis (27), disseminated
granuloma annulare (28,29), and lymphocutaneous sporotrichosis (30,31), an antigranulomatous
effect can also be postulated, although the basic
science of such a potential mechanism remains to
be elucidated.
Practically, KI is administered as a saturated
solution of KI (SSKI), which, in the United States
Pharmacopeia generic formulation, contains
1000 mg/mL. Available from Upsher-Smith Laboratories, Inc. of Minneapolis, Minnesota, the solution is supplied in 30 and 237-mL bottles with
calibrated droppers (10 drops delivers 0.3 mL or
300 mg) (32). A common starting dose for adults is
300 mg three times daily, with weekly titration up
to 500 mg three times daily if needed. Improvement may be seen after 2 weeks (33,34). Nausea,
dysgeusia, bitter eructation, excessive salivation,
and gastrointestinal irritation are common. To
mitigate these side effects, the clinician can opt to
start at a lower dose: 100–150 mg three times daily
with upward titration as tolerated. The taste of
SSKI can be made more tolerable to the patient by
diluting it with water, milk, or juice. In the present
authors’ experience, the sweetness and acidity of
orange juice or cola has shown the best results
with rendering the solution palatable and increasing patient compliance. The manufacturer advises
that SSKI should be stored at a controlled temperature, tightly closed, and protected from
light. When exposed to cold temperatures, the
solution may crystallize, but warming and shaking
should dissolve the crystals. The solution should
be discarded if the color changes to brownishyellow (32).
In addition to the common, unpleasant, minor
side effects described above, KI can also cause
more rare but serious adverse effects. The Wolff–
Chaikoff effect occurs when the thyroid gland stops
producing thyroid hormone in the presence of
excess levels of iodine. Healthy patients with intact
thyroid autoregulatory mechanisms are generally
not affected; however, patients with Hashimoto’s
disease, patients with a history of Graves’ disease
previously treated with surgery or radioactive
iodide, and patients receiving certain medications (i.e., lithium, amiodarone, sulfonamides,
phenazone) can be at risk for hypothyroidism and
goiter (24). Dermatologists who prescribe SSKI
should obtain a thorough history regarding preexisting thyroid disease and current medications. If
SSKI therapy extends beyond 1 month, screening
thyroid-stimulating hormone level is recommended (24). If iodide-induced hypothyroidism is
detected, KI should be discontinued, and thyroid
hormone levels are expected to return to normal
within 1 month (35).
Additional rare but serious adverse effects of
KI include potentially fatal pulmonary edema
with associated cardiac failure (36) and, after prolonged use, potassium toxicity with symptoms of
confusion, hand numbness, generalized weakness, and cardiac arrhythmias. Patients receiving
potassium-sparing diuretics or angiotensinconverting enzyme inhibitors, or who have
chronic renal disease are at most risk for potassium toxicity (37). Table 3 lists other side effects of
KI (24).
Colchicine. Colchicine has proved to be useful in
the treatment of EN, particularly for lesions that
occur in the setting of Behçet’s disease (15).
Reported successful doses are between 1 and 2 mg
per day, divided into twice daily dosing. For unclear
reasons, women are more likely to respond to
colchicine than men (38).
323
Gilchrist & Patterson
Table 3. Potential side effects of potassium iodide
administration
Well known
Rare reports
Acneiform eruptions
Dermatitis herpetiformis,
exacerbations
Gastrointestinal
effects (see text)
Hypothyroidism
Angioedema
Bullous pemphigoid
Cardiac irritability
Hyperthyroidism
Iododerma
Lymphadenopathy
Metabolic acidosis
Myalgias
Periarteritis nodosa
Potassium toxicity
Pulmonary edema
Pustular psoriasis
Urticaria
Vasculitis (granulomatous)
A plant-derived alkaloid, colchicine’s antiinflammatory activity is thought to partly derive
from its ability to arrest microtubule polymerization, resulting in impaired neutrophil chemotaxis
(39). There is also new evidence that colchicine
suppresses inflammasome-driven caspase-1 activation, blocks adhesion of neutrophils to endothelium by decreasing expression of L-selectin, and
inhibits neutrophilic production of superoxide
anions (40).
Common side effects of colchicine are gastrointestinal (diarrhea, abdominal pain) and can
be ameliorated by starting with a once daily low
dose (e.g., 0.6 mg daily) and increasing to twice
daily dosing as the patient builds gastrointestinal
tolerance. Bone marrow suppression with pancytopenia is a rare, dose-dependent side effect of
colchicine, occurring 3–5 days after a high
dose (mainly reported with accidental colchicine
poisoning in children). Granulocyte colonystimulating factor can be administered if
necessary, but the bone marrow usually
recovers 7–10 days after discontinuation of
colchicine (41).
Other therapeutic options. EN associated with
inflammatory bowel disease, particularly cases in
which skin lesions parallel intestinal inflammation
in severity, may respond to infliximab (42,43).
However, EN has also paradoxically been reported
to occur in patients treated with infliximab with
resolution of the lesions upon discontinuation of
the medication (44,45).
Other therapeutic agents reported useful in the
treatment of EN include hydroxychloroquine
(particularly for chronic EN) (46,47), cyclosporin
324
A, thalidomide, and systemic corticosteroids
(7). As with the use of any immunosuppressive
medications, an underlying infectious cause of
the EN should be ruled out before therapy is
instituted.
EI/nodular vasculitis
Diagnosis
The term “erythema induratum” was coined by
Bazin in 1855, who described deep violaceous
nodules on the posterior lower legs of young
women. He classified it as an “erythematous benign
scrofulid,” presumed to be of tuberculous origin
because of its coexistence with pulmonary tuberculosis. In the early 20th century, there were reports of
a similar clinicopathologic entity that did not seem
to be associated with tuberculous disease, and the
terminology “erythema induratum of Whitfield”
arose to describe these nontuberculous cases. In
1945, Montgomery et al. introduced the concept of
“nodular vasculitis” as a new category for the presumably noninfectious variant of EI (48). Today,
most authors continue to use these terms interchangeably, and for simplicity, the present authors
choose to use the term EI to refer to a distinct clinical and histological reaction pattern regardless of
etiology.
EI presents clinically as recurrent crops of
tender, violaceous nodules and plaques on the
posterior lower legs. Lesions have also been
reported on the feet, thighs, buttocks, and forearms (48). The nodules tend to evolve over several
weeks, often developing focal ulceration and
drainage. The areas heal with scarring and postinflammatory hyperpigmentation. The age
of the patients in one review ranged from 13 to 66
years (mean 37 years) (49). Although EI can
occur in men, there is an overwhelming female
predominance.
Histopathological examination most commonly shows diffuse septolobular panniculitis
with primary neutrophilic vasculitis of nearby
vessels. The classic vessel involved is a large muscular artery, but a systematic microscopic review
of 101 biopsy specimens by Segura et al. showed
the most common pattern to be vasculitis involving the small venules of the fat lobule (47% of
cases) (50). When the vasculitis is less prominent,
serial sections may be required to identify it.
There are varying degrees of acute and chronic
inflammation, coagulative and caseation-like
necrosis, and poorly developed granulomas. The
Erythema nodosum and erythema induratum
simultaneous presence of both primary vasculitis
and granulomas suggests a role for both type III
and type IV hypersensitivities in the pathogenesis
of EI (51).
Pathogenesis
As previously noted, EI was historically causally
associated with tuberculosis because of frequent
co-occurrence of the two diseases, although no
mycobacterial organisms were ever identified on
histopathological examination. With the invention
of the polymerase chain reaction technique in
1984, detection of minute quantities of antigen
became possible. Beginning in the early 1990s with
the development of specific primers able to distinguish Mycobacterium tuberculosis DNA from that
of other species, there were several reports of
detection of such material in lesions classified as EI
or nodular vasculitis (52–55).
However, EI has also been associated with both
infectious nontuberculous and noninfectious
disorders. Infectious nontuberculous cases have
been associated with Nocardia, Pseudomonas, and
Fusarium (56). One case has also been described in
conjunction with “red fingers syndrome” (chronic,
painless erythematous macules and patches on the
distal fingers and toes associated with cryoglobulins and/or a vasculopathy) in a patient with
chronic hepatitis C (57). There may also be an association with hepatitis B virus (50). Noninfectious
associations may include previous episodes of
superficial thrombophlebitis of the lower legs,
hypothyroidism, chronic lymphocytic leukemia,
rheumatoid arthritis, and Crohn’s disease (50).
Finally, nodular vasculitis has been reported in
association with treatment with propylthiouracil,
with rapid resolution after the medication was discontinued (58).
As noted above, the vasculitic pathology of EI
suggests a type III hypersensitivity reaction or
immune complex-mediated vasculitis (51). Others
have suggested that the reaction pattern more
likely represents a type IV hypersensitivity reaction
or a specific T lymphocyte-mediated response to
an antigenic stimulus (mycobacterial or other)
(59). Indeed, patients with tuberculosis-associated
EI can have an exaggerated response to intradermal purified protein derivative (PPD)-simulating
cellulitis because of the extensive release of cytokines and chemokines by activated T lymphocytes
(60). Commercially available interferon-gamma
release assays specific to M. tuberculosis antigens
(QuantiFERON®-TB Gold test, Cellestis, Carnegie,
VIC, Australia, and T-SPOT.TB®, Oxford Immuno-
tech, Abingdon, UK) further demonstrate the
release of high levels of interferon-gamma by activated T cells in patients with EI. Such laboratory
tests may be valuable in avoiding uncomfortable
exaggerated hypersensitivities to intradermal PPD
testing when screening for M. tuberculosis infection in patients with EI (61).
Therapeutic options
Treatment of EI should target the underlying cause,
if possible. All patients with suspected EI should
receive a Mantoux skin test, an intradermal PPD
application, or an interferon-gamma release assay
as described above. Patients with positive tests
should receive a full 9-month course of triple-agent
antituberculous therapy under the care of an infectious disease specialist (62). Appropriate antimicrobial therapy should be provided for any other
underlying infections, potentially associated systemic conditions should be treated, and any suspected medications should be discontinued if
feasible.
KI has also been reported as an effective treatment for EI (63,64). Further therapies are similar
to the treatment of EN as described above: NSAIDs,
rest, elevation, compression, and, possibly (in
severe cases and once underlying infection has
been ruled out) systemic corticosteroids may all be
helpful. There are also isolated case reports of successful treatment of EI with mycophenolate mofetil
(65) and oral gold (66).
Conclusion
Although they share some similar clinical and histological features, EN and EI are distinctive pathologic entities that can be due to a variety of causes.
Treatment, especially for the chronic variants, may
be challenging for the clinician. The mainstays of
therapy include addressing any underlying disease,
prescribing anti-inflammatory medications, and
educating the patient about symptomatic adjuvant
care. In recalcitrant cases, a variety of immunosuppressive drugs have been tried with isolated reports
of successful treatment.
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