InrernationalJournal of Dermatology, Vol. 35, No, 6, J .
ine 1996
ERYTHEMA
MITCHELLS.
MEYERSONM,
Leprosy is a chronic, slowly progressive granuloma-
tous infectious disease, supposedly caused by the bacil-
lus Mycobacterium leprae, which has a predilection for
skin and nerves. The two main forms are tuberculoid
and lepromatous. Two other types are indeterminate
and borderline. Indeterminate lesions may progress to
either tuberculoid or-lepromatous. Borderline lesions
have clinical and histologic features of both main forms.
Borderline disease is unstable and tends to "downgrade"
towards lepromatous, especially if untreated, or "up-
grade" towards tuberculoid. The progression of the
disease is usually slow and indolent, but sometimes a
change in the immunologic status of the patient devel-
ops suddenly and a reactional state occurs. Lepra reac-
tions are divided into type I reactions that occur in
borderline disease and are associated with "upgrading"
or "downgrading," and type 2 reactions, or erythema
nodosum leprosum.
BACKGROUND
Erythema nodosum leprosum (ENL), occurs in a patient
with lepromatous leprosy or, occasionally, with border-
line lepromatous leprosy. Erythema nodosum leprosum
is usually associated with multi-drug therapy, but it can
be seen in untreated patients. I Pfaltzgraff et al.? report-
ed that over 50% of lepromatous leprosy patients and
25% of borderline lepromatous leprosy patients experi-
ence an ENL reaction. Within the first year of sulfone
therapy, more than one half of patients with leproma-
tous leprosy in Southeast Asia develop ENL.,lGenerally,
there have been reports of between 15 and 50% of lep-
romatous leprosy patients developing ENL within the
first year of trearrnent.t-' however, ENL can develop
later during therapy or even after discontinuation of
therapy." The reaction is not always related to therapy
and seems to be a manifestation of the disease." Precipi-
tating factors include surgical operations, pregnancy,
parturition, lactation, menstruation, trauma, intercur-
rent infection, vaccination (especially smallpox), physi-
calor mental stress, and sometimes therapy.4.8-12 Pre-
From the Department of Dermatology, New York Medical
College, Valhalla, New York.
Address for correspondence: Mitchell S. Meyerson, M.D., 18
The Hamlet, Pelham Manor, NY 10803.
REVIEW
NODOSUM LEPROSUM
.D.
cipitating drugs include iodides and bromides;'? di-
aminodiphenylsulfone (005),14 and chaulmoogra.l- One
study reported an increased incidence of ENLin glucose-
6-phosphate dehydrogenase-deficient patients." A sta-
tistically significant increase in the frequency of HLA-All
was found in ENLpatients as compared to patients with
lepromatous leprosy.'?
CLINICALANDHISTOLOGICPRESENTATION
Clinically, there are crops of tender, red-purple papules,
plaques, or nodules that appear in previously normal
skin between existing lepromatous lesions that remain
morphologically unchanged except for some edema
noted histologically." Less commonly, the lesions may
be hemorrhagic, vesicular, erythema multiforme-like,
pustular, or ulcerating.!" The lesions are most com-
monly located on the face and extensor surfaces of ex-
tremities and usually occur bilaterally and symmetri-
cally;'! Although specific lesions usually only last for 7
to 10 days, recurrences can continue to appear for
weeks, months, or years.' Repeated attacks can lead to
loss of elasticity of the skin.!" Erythema nodosum lep-
rosum can also involve the eyes, joints, viscera (e.g.,
the liver!"), nerves, and lymph nodes.'? A case of iso-
lated ENL-Iymphadenitis without skin lesions has been
reported recently.I"
Extracutaneous manifestations include fever, pain-
ful neuropathy, epididymoorchitis, immune complex
glomerulonephritis, synovitis, large joint arthritis,
lymphadenopathy, iridocyclitis.P uveitis, dactylitis,
arthralgias, myositis, malaise, weight loss," hepato-
splenornegaly.!'' leukocytosis, generalized or dependent
edema, epistaxis, iritis;' proteinuria, rhinitis, insomnia,
and depression." The severity of the reaction seems to
be related to the size of the bacterial load."? Sterility or
gynecomastia can result from testicular damage and
blindness can occur from iritis if the patient is not ade-
quately treared."
Histologically, there is classically an intense vasculi-
tis with a neutrophilic and lymphocytic infiltrate and
granulomas made up of foamy histiocytes, many filled
with Mycobacterium leprae? There is swelling of en-
dothelial cells and edema of vessel walls." Acute necro-
tizing vasculitis is a variable finding.f The ulcerating
form, called necrotizing ENLor ENLnecroticans, shows
the same histologic features but to a greater degree. In-
133
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 Illll-' 11.1(1'111.(1.1\)\1111,11 III 1.~""lJ'd"""b.'

filtrates are heavier, cell-mediated the changes in in ENL, there have been
the granuloma is mechanisms are in- ENLreactions ..16 reports of patients with
larger, and edema and volved in the Levels of soluble ENL who have an
vasculitis are more pathogenesis of interleukin-Z receptors increased ratio of
severe.P ENL.There is evidence have also been studied, helper/inducer T cells
As lesions age, the of an increased and although they were (CD4+) to
number of lymphocytes percentage of B shown to be sig- suppressor/cytotoxic T
and plas- ma cells lymphocytes with low nificantly higher in cells (CD8+) in their
increases and that of lev- els of complement leprosy patients blood,'9-41 which does
neutrophils and eosin- in one study.?" and of compared to con- trols, not seem to occur
ophils declines." The an increased number of especially multi bacillary during non- reactional
subcutaneous fat is helper T cells and a patients, there was no lepromatous disease.
variably in- volved with significant change in Skin lesions of ENLalso
higher helper-supressor
a lobular panniculitis ratio in the lesions of those for ENL-reactional show an increased CD4+
consisting of an acute ENLin other studies.29,1(l patients before or after to CD8+ ratio,29.30,42-
Various substances treatment. 37
neutrophilic infiltrate 44where- as the skin
or a chronic have been studied to lesions of nonreaction
lymphocytic and determine their lepromatous patients
histiocytic infiltrate significance in the course MANAGEMENT showed an excess of
with fibrosis." Direct of ENLreactions. Adeno- CD8+ Iymphocytes.i'v+"!
immunofluo- rescence sine deaminase is an The treatment of choice It has been suggested that
shows granular deposits enzyme that is found in for ENL is thalidomide, ENLis a disease of
of immunoglobulin and cells of the body actively It in- creases motor insufficient T-cell-
complement in the involved in nucleotide conduction velocities of mediated suppression.t"
metabolism;" and seems nerves involved in ENL.38
vessels of lesional resulting in the
to playa role in cellular Among theories on the
skin.23,24 exaggeration of Band T
immune function.V Lym- action of thalidomide
An Arthus reaction cell responses" I and in
involves deposition of phocyte adenosine enhanced mitogenic ac-
immune complexes with deaminase (L- tion ..l9-41,46Therefore, in
vasculitis and a ADA)activity was found the transition from
polymorphonuclear in- to be higher in leprosy quiescent lepromatous
filtrate, The concept patients compared to disease to ENL, there
that ENLis a form of healthy controls and was seems to be a shift from
Arthus reac- tion is 10-fold higher in leprosy CD8+ to CD4+
supported by the patients un- dergoing prevalence." Thalidomide
presence of circulating reactions, including caused
immune complexes, the ENL, than in those not a decrease in the CD4+
demonstration of in reacrion.P however, to CD8+ ratio in the
mycobacterial anti- there were no blood of healthy men,"?
significant differ- ences by reducing CD4+ cell
gens, complement, and
in L-ADAlevels between numbers and in- creasing
immunoglobulins around
the leprosy controls or those of CD8+ cells, It
blood vessels in some
re- action groups before is thought that thalido-
lesions and the
and after rreatment.P mide acts as a treatment
occurrence of an
Acute phase reactant for ENL by modulating
immune- complex
responses have been T cells in this
glomerulonephritis in
studied to assess their
some patients;23,25,26 fashion.4g,49 A similar
roles in leprosy reactions.
however, others suggest mechanism of inhihition
Alphar-antitrypsin levels
that the immune of T-helper cell function
have been studied as a
complexes are is observed with
possible indicator of
extravascular and in cyclosporine A that also
ENLre-
this way, ENLis different has been used to treat
action34,35 and C-reactive
from the Arthus "serum protein levels have been ENL.4g,50 A decrease in
sickness" reacrion.F shown the number of CD4+
Both humoral and to correlate better with cells is seen during

treatment. 50
Another possible
mechanism of
thalidomide action
relates to tumor
necrosis factor-alpha
(TNF-alpha) levels in
serum that are increased
in ENLpatients.'
1,52When in- tradermal
injections of
recombinant interferon-
gamma (INF-gamma)
were given, ENL was
induced in 6 of 10
borderline and
lepromatous leprosy
patients within 7
monrhs.P This is
significant because lFN-
gamma increas- es the
release of TNt-alpha
from monocytes.V
Improve- ment of
symptoms of ENLwith
thalidomide was associ-
ated with a reduction of
TNF-alpha levels.v':'
Initial dosages of
thalidomide are 100
mg, three to four times
daily. This usually will
control the reaction
within a couple of days
and the dose may then
be ta- pered.!'' Some
authors suggest
tapering to a mainte-
nance level of 100 mg
a day; however, other
protocols have opted for
a slow dose decrease
over a 3-week pe- riod.
Side effects of
thalidomide include
teratogenicity, neuropathy,
drowsiness, eosinophilia
and peripheral edema.l"
In the past, patients,
who had developed
neu- ropathy from
thalidomide, were for
the most part non-
leprosy patients. These
patients were taking
the drug as a sedative, …
Illll-' 11.1(1'111.(1.1\)\1111,11 III 1.~""lJ'd"""b.'
I or for the management
of chronic dis- coid
lupus erythernatosus.t"
prurigo nodularis, or
aph- thous stomaritisr'?
however, there are
those who have
questioned the previous
statement by
leprologists that
neuropathy does not
occur in patients with
ENL given the drug and
suggested that these
leprologists were
perhaps unable to
detect signs of nerve
damage. 58 It is also
difficult to differentiate
nerve damage caused
by thalidomide from
that caused by leprosy
itself.
If the patient is a
premenopausal woman
or if signs and symptoms
persist with thalidomide
therapy, corti- costeroids
can be administered.
Prednisone will control
ENL rapidly but
treatment for months
to years with high
doses are often
required. s At least 60
mg, and
Erythema Nodosum Leprosum
Meyerson
even as high as 120 h (Dapsone): reactional states
Avlosulfon, and their treat- ment.
mg, of prednisone per l
Br J Dermatol 1977;
day should be given as o Diasone
97:345-352.
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392