LITERATURE REVIEW

MANAGEMENT OF LEPROSY REACTION

Hengky Yoga Prasetya, Sitti Nur Rahmah, Sri Vitayani Muchtar
Department of Dermatovenereology Medical Faculty of Hasanuddin University / Wahidin
Sudirohusodo Hospital Makassar

ABSTRACT
Leprosy reaction can cause of disability in people with leprosy
and can occur before, during and after therapy. Reaction leprosy is a
disease that occurs due to episodes of immunological phenomenon.
There are two types of reactions in leprosy, the type I reaction or
reversal reaction (RR) and the type II reaction or erythema nodosum
leprosum (ENL).
There are various of management reaction. In type I reaction or
reversal reaction may be non pharmacologic and pharmacologic
management in which the reaction is no reaction to mild and severe
reaction. Reversal reactions can be given chloroquine, aspirin. While the
severe reversal reaction given corticosteroid, , dapsone, azathioprine,
cyclosporine A therapy or surgical decompression.
In type 2 reaction or ENL reaction in which its management is
distinguished by clinical picture, mild ENL reactions can be treated with
mild analgesics and NSAIDs. In the ENL reaction medium can be given
therapy antimonial, chlorpromazine, antimalarial, promethazin and
colchicine. While the severe ENL reaction treated with thalidomide,
which is the first-line therapy, while the second-line treatment given
corticosteroid therapy, pentoxifilin, azathioprine. Other therapies for the
treatment of ENL reactions are minocycline and prednisone combination
.
Keyword: reversal reaction, erythema nodosum leprosum,
management reaction

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management of leprosy reaction

reaction or erythema nodosum

leprosum (ENL) .2,4, 6 Severe reactions are
often difficult to handle, especially on the
practice field and the serious consequences of the reaction is irreversible
nerve damage and dissability.7

INTRODUCTION
Leprosy is a chronic infectious
disease caused by Mycobaacterium leprae
which attack peripheral nerves, skin and
other body tissue .1 Nervous system
disease can lead to many social problems
because of the disability.1 The clinical
manifestation of leprosy more various depending on the immune response patient
characterized by skin lesions hypopigmentation.1,2 Based on criteria that classify Ridley Jopling leprosy into 5 types,
from polar and borderline tuberculoid and
borderline lepromatous polar and borderline. Patients with different types of leprosy
showed different immunological respones
against M. Leprae. 1,2

Leprosy reactions are commonly

and have a highest prevalence based on
data.7, 8 Study in China found that the
prevalence of type I reactions was 2.5%
and the type II reaction was 4.3% .8 A
study in India reported that 39, 8% of
patients have experienced reactions
during and after the treatment of multi drug
treatment (MDT) and 23.3% of patients
with type I reactions and 28% of patients
with type II reaction have dissability.8
However, leprosy reactions can be monitored well and disabilities could be prevented if early diagnosis, because it required
the clinician to have an understanding of
the signs and symptoms and appropriate
treatment of leprosy reactions .6 In this
paper, we will discuss about definition and
clinical management of leprosy reaction
that is more easily understood. Leprosy
reactions can affect the type of leprosy PB
and MB type. There are two types of
reactions in leprosy, type I reaction or
reversal reaction (RR) and type II reaction
or erythema nodosum leprosum (ENL)
.2,4,6

Based on the WHO criteria for

leprosy were divided into 2 group based
on the number of the skin lesions and
smear examination of the skin lesion 1,2 :
a. Pausibasiler type (PB) consist of tuberkuloid (TT), borderline tuberculoid
(BT). The number of lesion 1 up to 5
skin lesions. The result of the acid-fast
bacilli (AFB) negative
b. Multibacillary type (MB) consist of the
type borderline (BB), borderline lepromatous (BL), Lepromatous (LL). The
number of lesions more than 5 skin
lesions. BTA examination is positive
In the course of leprosy, the patient have a severe situation known as
leprosy reactions. Leprosy reaction lead to
disability in people with leprosy and can
occur before, during and after reaction
therapy.3 Leprosy is a disease that occurs
because the episode immunological causes inflammatory response in the form of
acute or subacute occurring during course
of disease.4, 5 There are two types of
reactions in leprosy, the type I reaction or
reversal reaction (RR) and the type II

1. Reaction type I / Reaction Reversal

Reversal reaction is an acute episode of leprosy caused by increasing
responsiveness cell mediated immunety (CMI) against Mycobacterium leprae
are characterized by skin lesions or
nerve damage.8,9 Clinically, reversal reaction can be found in the patients with
increasing of CMI. Generally, it found
in people with PB and MB type which
have complaints of mild to severe de-

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pend on the presence or absence of

neuritis. This reaction can be distinguished on leprosy type 1 reactions.2
a. Pathogenesis
Reaction Type I is characterized by
increasing of inflammatory response in the skin lesions and nerves
or both. This reaction occurs because of the interaction between T
lymphocytes by antigens released
from M. leprae. Type I reaction is
type IV hypersensitivity reaction by
Gell and Coomb. Type I reactions
are commonly in borderline types
of leprosy.8

required in some patients.

Rested
in cases of
neuritis.
Physiotherapy
is
recommended in an
acute inflammatory process to restore muscle
function.
In cases of nerve
damage, such as claw
hand or foot drop, the
patient should be given
appropriate splint and
should be trained to do
simple exercise at home
to
improve
muscle
function. Physiotherapy
is very important in
case like this.

b. Clinical Manifestation
Clinical skin lesions include erythematous reactions were mild reversal active plus, thickening, palpable
heat and tenderness, macular
thickening can be up to form plaques. Here are no peripheral nerve
neuritis
(no
thickening
and
impaired nerve function) .2 Skin
lesions in severe reversal reaction
include swollen until the broken,
red, felt the heat and tenderness,
no new skin lesions, inflammation
on palms and soles, arthralgia.

2. Pharmacologic :
The main purpose of pharmacologic therapy to decrease
the amount of antigen by using
MDT
and
corticosteroids
(prednisolone) to suppress
cellular immunity.10
- Mild Reversal reaction
Some authors also recommend to use aspirin or hydroxychloroquine to treat
mild reversal reaction consist of skin lesion without
nerve impairment.

c. Management
In type I reactions, we can give
pharmacologic and nonpharmacologic management.2
1. Non-pharmacologic, such as: 2.4
Supportive treatment in type I reactions are the same
important as management
of type I reactions and neuritis, such as:
Pain management by
analgesics or nonsteroidal anti-inflammatory
drugs (NSAIDs) may be

Treatment2,7,10 :
1. Rest, outpatient
2. Taking analgesic (aspirin)
400-600 mg 4 time a daily
and dose is revaled when
sign and symptom have
controlled.

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management of leprosy reaction

3. We can take Cloroquine

150 mg 3x1 , 3-5 days
4. MDT ( leprosy drug) followed by a dose that is not
modified.
- Severe reversal reaction

state that
taking prednisolone
in 5
months better than in 3 months to decrease for steroid dependant to treatment
type 1 reaction . A study in Nepal compare using methylprednisolone by pulse
dose in taking prednisolone in 16 weeks
and found that 50% patient in regimen still
need taking steroid treatment in follow up.
18
Some expert suggest that taking
immunosuppressive in long time can reduce release antigen and then celluler
imunity response. Taking corticosteroid is
associated by leprosy type is 3-6 months
in BT type, 6-9 months in BB type and 1824 months in BL type.11,12 Early dose
prednisolone is 40 mg a daily (0,5-0,6
mg/kg a daily) and can be reduced 5 mg
every 2 week in 2-3 months up to 20-25
mg a daily. And then, prednisolone dose
is decreased 5 mg a month. Some expert
suggest that prednisolone 15-20 mg (
0,30-0,35 mg/kg a daily ) are appropriate
dose to suppress a 1 type rection in early
reaction. 11,12 Sensoris test and voluntary
motoric test is done for guidance to
decrease prednisolone doses. In severe
case, early dose of prednisolone is 60 mg
a daily.11 Maximal result can be seen in 3
months and to be continued to 6 months.
A good response is obtained in paralysis
patient (less than 6 months), BL and
medianus nervi paralysis. 11,12 There are
concensus suggest that corticosteroid
unusefull to repair impairment nerve which
have been in months. 17,19 Corticosteroids
have a variety of adverse effects on longterm use, because it is the long-term use
of corticosteroids in the treatment of
leprosy reactions need to consider several
things such as: 12

Corticosteroid
Systemic steroid is a choice treatment in Type 1 reaction, although evidence about effectiveness of corticosteroid is
limited. Action mechanism of corticosteroid
in reaction reversal is suppression of cell
T. Inflammation response in antigen of
Mycobacterium leprae in skin and nerve
are bloked by decreasing oedema, immunosuppressive and decrease scar post inflammation.11-13 Corticosteroid have known
as agent to repair nerve impairment in 3337% in Type 1 reaction.14-15. Study about
using of corticosteroid in type 1 reaction is
limited. Study by Cochrane conclude that
too little eveidence about doses or duration optimum of corticosteroid to prevent
nerve impairment.16
WHO, the treatment in almost reaction are corticosteriud topical in 12 weeks.
Early diagnosis are 40-60 mg a daily ( max
1 mg /kg bodyweight), and then decrease
every week or every 4 day and then
stopped. The treatment prednisone by
WHO on svere 1 type reaction are 1-2

40 mg in 2 weeks

35 mg in 2 weeks

30 mg in 2 weeks

25 mg in 2 weeks

20 mg in 2 weeks

15 mg in 2 weeks

10 mg in 2 weeks

5 mg in 2 weeks

Regimen therapy is associated by

individual condition. Corticosteroid more
than 12 weeks is recommended by World
Health Organization (WHO). A report

27

Getting rid of contraindications to

corticosteroid therapy such as
tuberculosis
Monitoring weight and blood
pressure at each visit, urinalysis

IJDV

Vol.1 No.3 2012

dose and was maintained for 2-4

weeks if after reducing the dose did
not show
clinical improvement.
Using drug is still controversial and
not useful in the acute phase reaction.2 Mechanism of action stabilizes lysosomes by inhibiting neutrophyl chemotaxis, reduce levels of
complement and inhibits the activity
of lymphocytes. 6
d. Dapsone is given in 50 mg up to
100 mg daily. Patients can be treated with a combination of dapsone
and corticosteroids. But if after a
few weeks still require high doses of
corticosteroids should be revised to
replace dapsone therapy with clofazimine .2 Mechanism of action inhibits the synthesis of folic acid. Dapsone is a bacteriostatic and baktericidal for Mycobacterium leprae.4

or measure blood sugar levels

on a regular basis
Prevent gastritis with antihistamine (AH) 2 and a proton pump
inhibitor
Prevent to osteoporosis

Others immunosuppressive drug

Immunosuppressive drugs may be
need to patients who cant tolerate or
dependent on corticosteroids. 19
a. Combination Azathioprin (3 mg / kg
/ day) with prednisone doses
reduced for 8 weeks more effective
than prednisone dose reduced for
12 weeks.19, 20.21 Mechanism of
action
azathioprine in reversal
reaction is inhibit the synthesis of
nucleic acids and has a very slow
effect. Azathioprin recommended as
a steroid sparing agent but its use
at high doses is still limited because
lack of toxicity data these drugs on
bone marrow. Another report says
the successfull in using of azathioprin 1 mg / kg daily as an adjuvant,
but the use of these drugs as monotherapy is not effective because it is
not able to reduce edema venostatic.22
b. Cyclosporine (7 mg / kg per day) is
useful in many case which no respond to corticosteroids. This drug is
a choice treatment in type I reaction, mechanism of action is inhibiting TH 1, however, it is very expensive.22 Cyclosporine has demonstrated efficacy in several pilot studies in Nepal and Ethiopia.23
c. Clofazimine be used in patients
with reversal reactions requiring
high-dose corticosteroid therapy
longer. The dose used is usually
300 mg daily, after 2-4 weeks
corticosteroid dose reduced gradually. Dose increased to the original

Surgical Decompression
Surgical decompression is recommended to reduce pressure of mechanical on cases of severe neuritis or neuritis
patients who dont respond to medication.
A Cochrane study can not prove superiority of surgery than prednisolone.24 Although data on surgical decompression is
still limited, there are some guidelines wich
recommended in this case, 25
Some patients may require surgical
decompression after administration
of drugs.
Surgery should not be done before
giving of drugs
There are several surgical techniques are not recommended such
as: complete fascicular neurolysis
and nerve decapsulation.
Surgery should not be done
without performing tests of nerve
function such as voluntary muscle
testing and sensory testing both
before and after surgery, to assess

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immune complex that continues

to circulate in the blood
circulation which can eventually
deposited in various organs
which
then
activate
the
complement system. Many
recent research studying the
role of tumor necrosis factoralpha (TNF-) in the pathogenesis of ENL. Patient LL show
ENL reaction after MDT treatment also showed high levels
of TNF-. These data show
about relationship between
TNF- and pathogenesis of
ENL. Tumor necrosis factor can
cause direct damage to cells
and tissues, activate macrophages, stimulate macrophages to produce IL-1 and IL-6
and stimulate liver cells produce reactive protein C (CRP).
Elevation of TNF- concentrations in serum and CRP ENL
patients were positively correlated approximately 95% when
compared to the lepromatous
leprosy non-reactions. Cellular
changes in the lesions was also
observed by other researchers.
In the new lesions were found
many lymphocytes CD4 + and
CD8 +; the next processes the
CD4 + increases more than
CD8+. Immunocompetent cells
revealed IL-2 receptor and then
appear neutrophils and natural
killer cells (NK cells). Immunopathology ENL also studied by
analyzing the pattern of cytokine mRNA using PCR. The
pattern of cytokine mRNA in
ENL showed an increase in the
amount of mRNA for IL-4, IL-5
and IL-10. This means that this
reaction shows a dominant Th2
response. Thus, ENL reactions

the efficacy of the procedure has been

done.
2. Reaction type II / ENL
ENL is a humoral reaction in
leprosy where bacilli of leprosy, both
of intact or not become antigen and
then produces antibodies, subsequently form immune complexes that
settle in vascular. Erythema nodosum
leprosum is a chronic disease with
systemic involvement and often have
recurrences .2.26
a. Pathogenesis
Immunopathogenesis mechanism is unclear. Although more
research is done, it is still difficult to conclude pathogenesis
of ENL. Erythema nodosum
leprosum is thought to be
manifestations
of
antigenantibody complex deposition in
blood
vessels.
ENL
is
hypersensitivitas type III by
Comb & Gell. Non-specific
stimulus by viral infections,
stress, pregnancy or more specific stimulus such as superinfection with tuberculosis. T
helper cell infiltration (Th2).
that produce a variety of cytokines, such as interleukin-4 (IL4) induces B cells to become
plasma cells then produce
antibodies to bond antibody
antigen M.leprae in tissue skin,
followed by complement activation. This can be seen by the
decrease in blood C3. Antigenantibody complex was also
found in the blood circulation.
In treatment, many leprosy
bacilli are dead and destroyed,
meaning there are many antigens are released and react
with the antibody to form an
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out fever or malaise.20, 22.28

Mild reactions can be treatted with mild analgesics and
NSAIDs. Aspirin, 400 mg
every 6 hours, the dose
reduced if signs and symptoms are controlled, reported beneficial in mild ENL.

can be imagined as a Th2 response that followed the formation of antibodies and immune
complexes. Accumulation of
Immune complexes in blood
vessels and lesions are characteristic reactions ENL.2
b. Clinical Manifestation
Manifestations of ENL can be
divided into mild, moderate and
severe. The clinical manifestation is nodules redness, pain,
and can develop within a few
hours or a few days. Distribution of lesions tend bilateral and
symmetrical. Lesions often on
the extensor surfaces along the
arms and legs, back, face but
can occur anywhere. ENL other
variants may be vesicular, bullous, pustular, and the rarely ulceration (type of severe ENL) .2

29

2. Moderate Erythema nodosum leprosum

Asymptomatic patients with
organ multiple involvement
without nerves, eyes and
testes is treated using Antimonial 2-3 ml per day IM for
3-5 days or 2-3 ml of IM
within a day to a total dose
does not exceed 30 ml with
prostaglandin inhibitor (indomethacin) .20 We know as
inhibitor of complement.
Promethazin works the
same way, which is inhibitted complement and can
also stabilize mast cells.
Colchicine has been used in
the reaction of type II with
the variant results.23 Chloroquine is given 3 x 150 mg
daily until there is improvement, it is considered beneficial because of its action
mechanism that stabilizes
lysosomal membranes, and
inhibits complement-activating antigen-antibody complexes .28

c. Management
Principle of ENL therapy to
treat acute inflammation in skin
and nerves, relieve pain, prevent eye damage and spread
of disease. Standard antileprosy therapy should be granted or
continued therapy along with
anti-reaction treatment. Clofazimine is a performance part of
the MDT, has been known to
be used in the treatment of
ENL.19, 21.27 Some drugs are
considered useful in the treatment ENL, although controlled
clinical studies proving its effectiveness is still limited.20, 22

3. Severe erythema nodosum leprosum

Patients which have experience severe ENL should
be admitted to hospital if
possible.
Corticosteroids
and thalidomide are medi-

1. Mild Erythema nodosum

leprosum
Type II reactions are characterized by a slightly lighter skin lesions with or with30

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management of leprosy reaction

cines that are beneficial in

the treatment of severe ENL
and characterized by ulceration, neuritis, uveitis or
epididimiorchitis.20, 22.28

with a dose of 300 mg per day in three

divided doses, to reduce discomfort in
the gastrointestinal tract. This dose
can be maintained for 3-4 months and
then reduced gradually to 100 mg a
daily. Total duration of administration
is 8-12 months or more. In controlled
ENL, prednisolone can be reduced if
clofazimin in combination with prednisolone (6-8 weeks). Dose may be increased in advance (before increasing
the dose of prednisolone) when ENL
experienced recurrence during the administration clofazimin.2, 30 Consider to
given clofazimin because many adverse effects such as skin pigmentation,
dry skin, abdominal pain, diarrhea, enteropathy crystals (rarely, but it can
threaten life)31

First Line Therapy

THALIDOMIDE
Thalidomide can be used in severe
ENL. Thalidomide is indicated in some
circumstances severe ENL .29-32 On
the other hand, thalidomide can cause
teratogenicity, neuropathy and sedation, so the use of thalidomide is a
limited. Mechanism of action inhibiting
TNF- m RNA that play a role in the
pathogenesis of ENL.33 It is also work
on lysosomal enzymes and inhibits the
chemotaxis of granulocytes. Thalidomide change the ratio of CD4: CD8
and increased levels of IL-2 and TNF.20, 22.28

Second Line Therapy

CORTICOSTEROID
Mechanism of action corticosteroids in
ENL reaction is suppress cellular immunity, inhibit the antigen-antibody complex,
inhibiting lysosomal complex, suppressing
neutrophils, inhibits prostag-landine and
reduce the leakage of fluid in the
inflammation area .20, 22.28 Until now there
has been no administration regimen
prednisolone are definitely on the ENL.
Although the dose and duration of corticosteroid administration should be tailored
to the patient, prednisolone following regimen may be used; 25

Thalidomide therapy given at a

dose of 400-600 mg (10-15 mg / kg)
daily, then reduced 25 mg every 2
days for 1-2 weeks. Therapeutic
response is obtained rapidly within 848 hours. Thalidomide should be given
to the lowest dose that may be given,
which is 50-100 mg daily to control
symptoms and should be maintained
for 2-3 months.32
CLOFAZIMIN
Clofazimin is a very useful drug in
the treatment of ENL. Mechanism of
action stabilize lysosomes by inhibiting neutrophil chemotaxis, reduce
levels of complement and inhibits the
activity of lymphocyte.6, 25 It has a slow
onset of action (4-6 weeks).30 These
drugs can be used as a steroid-sparing
agent in steroid-dependent patients or
patients who showed adverse effects
with the use of prednisolon.30 Started

Initial dose of 30-60 mg per day

Lower the dose of 10 mg per week
until the dose reached 20 mg prednisolone
Lower the dose of 5 mg per week up
to 10 mg
Maintain dose of 5-10 mg per day for
several weeks in patients with chronic
ENL

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Second-line drugs, others:

There are various reports about the use of
various drugs for the treatment of severe
and chronic ENL. A recent Cochrane study
states there is no strongly basis for the
use of the drugs.32-34 Pentoxifilin (1.2 to 2.4
grams a daily) is the drug most often used
as second-line therapy in ENL. Mechanism of action similar to thalidomide, which
inhibits the synthesis of TNF- and others
cytokine.2 Several studies have reported
that the effectiveness pentoxifilin lower
than thalidomide in overcoming the
symptoms ENL.32, 33 Other drugs used in
the treatment of ENL is azhatioprine.35-37 A
report declared an ENL treatment success
that do not respond to corticosteroids
during two years of treatment using 50 mg
azathioprine with prednisolone 35 mg and
300 mg per day. Therapy was given for
eight months, ENL improved since one
month therapy.36 Another report states that
nine cases of severe ENL successfully
treated using azhatioprin 2-3 mg / kg daily
as a steroid sparing agent that prednisolone dose could be lowered from 30-100
mg per days to 5-30 mg per day. These
cases give good results, considering the
previously experienced severe ENL
treated using prednisolone for 2-8 years
and have not experienced.37 Another
therapy is minocycline, drug is bactericidal
and bacteriostatic, as a broad-spectrum
antibiotic, works by inhibiting protein
synthesis of bacteria. Besides minocycline
also has anti-inflammatory effects in a
variety of circumstances dermatologic. A
study by Fajardo et al, 1995, and Siti
Musafirah, 2006, suggest effectiveness of
the combination of minocycline with prednisone in patients with ENL given for 3
months in which minocycline as an antichemotactic effect of neutrophils. Effective
in the treatment of ENL reactions. Prednisone given at a dose of 1 mg / kg / day

and then reduced the dose of 10 mg every

2 weeks, combined with minocycline were
given 100 mg / day for 1 month, and delivered within a day 1 next month and after
2 days 1 month .38, 39
Other drugs are reported to have
been used in the treatment of ENL is
methotrexate, 40 zinc orally 41 and infliximab, 42 but these drugs have not proven
their effectiveness.
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