Leprosy reactions are immunologically mediated
episodes of acute or subacute inflammation
which interrupt the relatively uneventful usual
chronic course of disease affecting the- skin,
nerves, mucous membrane and/or other sites.
May occur in any type of leprosy except the
3. LEPRA REACTIONS
Type 1 Reaction Type 2 Reaction The Lucio Phenomenon
Type 4 hypersensitivity
Borderline spectrum LL and BL leprosy
Type 3 hypersensitivity Type of reaction
observed in untreated,
uniformly diffuse shiny
infiltrative, non nodular
form of LL
5. Upgrading or Reversal Reaction
Increase in the immunity shift from borderline
spectrum towards tuberculoid pole.
‘Reversal reaction’ because of the natural
tendency for subpolar tuberculoid and borderline
leprosy to downgrade slowly toward the
lepromatous pole without treatment
6. Downgrading Reaction
Reduction of immunity sudden shift toward the
As the management is same, no distinction is
recommended to be made and all T1Rs are labeled
7. Risk Factors
BT, BB and BL- most vulnerable group
Who had one episode of reaction are more prone to develop a
Female gender - a higher risk than men (hormonal fluctuations,
pregnancy and postpartum)
Older age group
Multiple and disseminated patches involving larger body area
and multiple nerves
Large facial patches and lesions near eyes - risk of
8. Nerve enlargement, tenderness and paresthesia on
Skin lesions overlying major nerve trunks increase the
risk of nerve damage
Starting of treatment may precipitate reaction due to
increased antigens trigger the delayed- type
hypersensitivity (DTH) response.
Reaction may be present at the time of presentation or
develop during treatment and even after RFT
When MDT is combined with immunotherapy
Mycobacterium indicus pranii (MIP) as compared to
those under MDT alone
Hepatitis B or C
Increased cellular immune responses (DTH reaction) to
M. leprae antigens
Infiltration of activated CD4 T lymphocytes, especially of
Raised IL-2 receptor and INF-y
Autoimmunity : human nerve and skin have a number of
antigenic determinants in common with M. leprae
10. Histopathological Features
Epidermis- erosion of the granuloma into lower epidermis
Dermis- At initial stage - mild extracellular edemawith some influx of
Later stage- further increase in the edema
Upgrading reaction- Granulomas become more epitheloid with increased
Proliferation of fibrocytes
Langhans and multinucleated giant cells are common
AFB (upgrading reaction) while AFB (downgrading rxn)
Inflammatory edema and infiltration within nerves
12. Immunological Studies
In RRs, the cytokine responses are of Th1 type and in ENL the
responses are of Th2 type
Increased expression of proinflammatory cytokines, TNF-a, IL-
1b, IFN-y and IL-12, and immunoregulatory cytokines, TGF-b
and IL-10 in reactional skin lesions, and macrophage
13. Raised plasma levels of CXC-Chemokine-10
(CXCL10/1P10) and IL-6
High levels of antibodies against stress proteins in
patients with RRs
14. Clinical Features
Acute: Symptoms persisting up to or less than 1 month
Subacute: Symptoms persisting for more than 1 month up to 6
Chronic: Symptoms persisting for more than 6 months
Recent: Covers both acute and subacute types
Recurrent/Repeated reactions: Episodes recurring after 3
months of stopping antireaction treatment
Late reversal reaction (LRR): RR occurring any time after
completion of MDT
Pre-existing skin patches or plaques erythematous,
swollen and may be tender looking like erysipelas.
Necrosis and ulceration can occur
Crops of fresh inflamed skin lesions on previously clinically
uninvolved skin may occur
Edema of extremities or face, with nerve involvement.
Neuritis: Rapid swelling with severe pain/tenderness. Nerve
usually close to the inflamed skin lesion. Tinel sign may be
‘Silent neuritis', i.e. without apparent neuritis, producing claw
hand, foot drop and facial palsy.
20. Rare or Uncharacteristic Presentations
Tenosynovitis (over dorsum of hands and rarely over
dorsum of feet). Commonly associated in BT and BL
Very severe reaction - necrosis and deep ulceration
Systemic manifestations like fever, malaise, vomiting,
epistaxis and joint pain are unusual.
21. Grading of Reversal Reactions
Few skin lesions with features of reaction clinically; without any
nerve pain or loss of function.
Nerve pain or paresthesia
Increasing loss of nerve function
Fever or discomfort
Edema of hands, feet
Mild reaction persisting for more than 6 weeks
Reaction of skin lesion on the face
Ulcerative skin lesion.
Pre-existing and/or new skin lesions become inflamed,
red and swollen
One or more nerves become tender and may be swollen
Crops of new (painless) lesions appear
Sudden edema of face and extremities
Recent loss of sensation in hands and feet or signs of
recent nerve damage (loss of sweating, sensation,
muscle strength) in an area supplied by a particular
23. Lepromin Reaction
Due to strong DTH response in RR, the positivity of lepromin
will be stronger in BT and TTs and may become positive from
earlier negativity in BB and BL.
Other Laboratory Tests
Recently, Scollard et al. have shown that increased CXCL10 in
lesions and serum is characteristic of T1R.
A recent study has specified that serum circulatory levels of IL-
17F are elevated during T1Rs in the borderline spectrum of
26. Management of type 1 reaction
Multidrug therapy has to be started or continued
Specific Treatment of Reaction
Specific treatment has to be initiated depending on the severity
of the reaction (mild or severe type).
28. Severe Reaction
Corticosteroids are the cornerstone of therapy and
considered to be the drug of choice.
Starting dose: 1 mg/ kg body weight, given once in the
morning after breakfast, continued till improvement in
Dose cut by 5 mg every 1-2 weeks.
The crucial maintenance dose: around 15-20 mg for
In the follow-up period, the dose cut by 5 mg every 2-4
29. Dose and Duration of Prednisolone
The duration should be long enough to cover the period
during which the antigen (Ag) load is able to trigger the CMI
response (BT: 4-9 months, BB: 6-12 months, BL: 6-24
Duration of steroid treatment matters more than dose. Initial
dose of steroids does not affect the efficacy of the antileprosy
30. Other lmmunosuppressant drugs for
treatment of T1R
Methotrexate: Recently, low-dose methotrexate (5-7.5
mg/week) was reported to be successful
Cyclosporine A (CyA): 5 mg/kg/day followed by gradual
reduction of the dose.
Recently, topical tacrolimus 0.1% ointment was favorably
used to treat a case of BL leprosy with severe reversal reaction
without nerve involvement
31. Additional Measures for Neuritis/Nerve Function
Inflamed nerves must be kept in resting position.
Appropriate splinting and padding gives relief.
Involves exposing the affected nerve trunk at the point of
maximal thickness, and giving longitudinal incisions into
the nerve up to epineurium layers of nerve bundles
32. Treatment of late reversal reaction
Prednisolone (1 mg/kg body weight per day) for 4-6
weeks till complete subsidence of the lesions.
If no improvement seen within 3 months of steroid
therapy consider as relapse presenting in the form of
T1R, and MDT should be restarted for another course
and oral steroids gradually tapered off
34. Type 2 reaction, popularly known as ENL
Type III hypersensitivity reaction or Arthus
Major clinical lesions on the skin are erythema
nodosum type; hence the term "ENL” used as an
Occurs mostly in LL and sometimes in BL leprosy.
35. Risk Factors
Lepromatous leprosy with skin infiltration
Antileprosy drugs except clofazimine
Bacterial index (BI) of >4+
Patients with < 40 years of age
Intercurrent infections: Streptococcal, viral, intestinal parasites,
Physical and mental stress
A strongly positive Mantoux test
Pregnancy and parturition
Ingestion of potassium iodide
Initially, minimal increase in lymphocytes, especially
perivascularly. Majority of them are CD4+ Th2 cells.
IL-4, 1L-5, IL- 13 and IL-10 cytokines, which are indicative of a
Th2 type of reaction
Both immune-complex and T-cell reactivity are observed
During early phase in lepromatous granuloma in between the
foamy cells, smaller cells like monocytes become active
macrophages and destroy the inert foamy macrophages
Antigens released presented by fresh macrophages to
immune system stimulates CMI antigens which could not be
engulfed by macrophages, form immune complexes with locally
Within the lesions the plasma cells stimulated by IL-4
Antibodies + ubiquitous antigens immune complexes
M. leprae antigens, IgG, IgM antibodies, complement (C3d)
and IL-4 mRNA are all identified in ENL skin lesions
In ENL lesion, neutrophils dominate the picture
CMI involvement : increase in IL-2 receptors on the immune
38. Most prominent cytokines : IL-4, IL-5, TNF-a, and INF-y.
TNF-a (known pyrogen) rise of temperature and
Autoimmunity might also play a role in the tissue
Histopathological examination : increase in neural cell
adhesion molecules (NCAM) and NCAM-positive CD8+
cells in nerve tissue
Features of either LL or BL histopathology
Dense infiltration of the superficial or deep dermis or
subcutaneous tissue by neutrophils (superimposed on an
already existing lepromatous granuloma). Intense influx of
neutrophils - microabscesses.
Necrotising Vasculitis is a predominant feature in some
Damage to collagen and elastic fibers is common.
In some variants known as necrotizing ENL, there is also
necrosis and ulceration of skin
During healing phase, neutrophils are gradually replaced by
42. Mode of Onset
Cutaneous Onset :
Rheumatic Onset : (In one-third of the cases) pain and
swelling in the joints
Mixed Onset: Fever, joint pain and other constitutional
signs and symptoms; and skin lesions develop together.
43. Skin Lesions
Erythema Nodosum Leprosum
Usually no clinical change in the original clinical skin lesions.
these may appear anywhere[Except the hairy scalp, axillae,
groin and perineum (warmer areas)]
Sudden appearance of crops of evanescent (lasting for few
days) pink (rose) colored tender papules, nodules or plaques
and subcutaneous nodules.
Common sites : outer aspects of thighs, legs and face
44. May be few or multiple, if multiple distributed bilaterally and
Tender, warmer, and blanch with light finger pressure.
An individual ENL lesion after 24-48 hours changes from pink/red
to bluish and brownish and finally dark, in a week or 10 days.
May become vesicular, pustular, bullous and necrotic and break
down to produce ulceration erythema nodosum necroticans
Subside with desquamation or peeling of superficial skin
Edema of hands, feet or face may be present.
Inflammatory edema on the dorsum of the hand + SCN and arthritis
of interphalangeal (IP) joints reaction hand
47. Lazarine leprosy
Cochrane described it as a chronic progressive form of
ENL in which individual SCNs tend to break down and
ulcerate, and the patient’s condition is very distressing
48. Systemic Manifestations
In T2R, systemic manifestations like
muscle, joint and bone pain (usually confining to tibia)
Are common and may precede the appearance of ENL.
49. Nerve Involvement
Nerve damage may occur in T2R, but not as quickly as in
Due to inflammatory edema and cellular exudates in
perineurium nerve is unable to accommodate increase in
its bulk contents compression of vasa nervosum and nerve
fibers precipitation of acute symptoms.
Added compression is provided by points of entrapment of
50. Acute Myositis
Invaded by extension of the process of SCN formation, from
the subcutis to deep into the muscle through deep fascia.
Entire involved region feels woody hard.
In some cases painful, tender, firm nodular lesions occur in the
in one-third of the cases, T2R has rheumatic type of onset.
Joint swelling, pain, tenderness, with limitation of movements.
Synovial effusions and bursitis may be found
The joints commonly affected are knee,
metacarpophalangeal, IP, wrist and ankle joints
52. Involvement of Nose
Infiltration and nodules present in the nasal septum and inferior
turbinate may be swollen with blocking of the nose leading to
difficulty in breathing.
It may be associated with Pain and epistaxis.
May ulcerate and perforate
53. Palate and larynx
Soft Palate Involvement
Soft palate, fauces, base of the uvula may be hyperemic and may
ulcerate. Repeated ulceration may lead to complete destruction.
Hard Palate Involvement
Similarly be hyperemic and swollen during reactive states.
Erosion of these reacting lesions involves the bone with
destruction and eventually perforate the palate.
Involvement of Larynx
Edema of the epiglottis or of the false vocal cords lead to
54. Bone Changes
Severe bone pains and soft tender swelling of the anterior aspect
X-ray picture elevation of the periosteum at the site of swelling
with soft shadow underneath.
Repeated attacks may lead to laying down of new bone with
thickening of cortex and increased anterior curvature looking like
'sabre tibia' of syphilis.
May also involve the phalanges (dactylitis)
Phalanges and metacarpals
Demineralization or as punched out areas of rarefaction
55. Lymph Node Enlargement
Often acute and painful enlargement of inguinal, axillary,
cervical and epitrochlear lymph nodes along with constitutional
signs and symptoms.
Occasionally, large abscesses are formed which break
56. Involvement of Liver
Hepatic enlargement below the costal margin is sometimes
The liver is soft and tender.
Involvement of Kidneys
Acute glomerulonephritis due to the immune complex
Albuminuria from a trace to 1+.
Microscopic examination : plenty of red blood cells (RBCs),
pus cells, epithelial cells, casts (from RBC, pus cells) and
In few instances frank hematuria, and rarely oliguria.
57. Suprarenal Involvement
BP remains low due to hypofunction of the suprarenal
Acute pain, tenderness and swelling in scrotum due to
acute inflammation of the testes and epididymis.
Occasionally, a hemolytic crisis may be encountered with
dangerous fall in the RBC count and hemoglobin.
Sudden pallor and breathlessness may occur
58. Severity of Type 2 Reaction
Mild: temperature does not go above 100°F; and the
reacting skin lesions (ENLs) are few, confined to one or
Moderate: temperature goes up to 102°F, skin lesions
are more numerous, affecting all the four limbs, trunk,
face, occasionally vesiculation. Extracutaneous signs
may also be present.
Severe: temperature rises above 102°F, tends to be
remittent. Vesiculation and postulation are frequent.
Clinical and histopathological
Includes the major criterion or at least three minor criteria
Major: Sudden eruption of tender papules, nodules or plaques which
• Mild fever
• Tender enlarged nerves
• Loss of sensation or muscle power
• Edema of extremities or face
• Positive Ryrie or Ellis test
60. Clinical Tests
Certain clinical tests are used for diagnosis of T2R.
Stroking the sole of the foot with the back of a reflex
hammer elicits a burning pain
Squeezing the wrist during ENL elicits a painful reaction
61. Laboratory tests
ESR is markedly elevated
C-reactive proteins appear in the blood
Routine and microscopic urine examination is must
Liver function tests: In certain number of cases there is mild rise
of serum bilirubin of 1-2 mg/100 ml and rise in serum
62. Differential Diagnosis
However, acute EN can occur
due to other common causes
Also need to be excluded
Collagen disorders like
63. Type 1 reaction must be differentiated clinically from T2R
64. Management of type 2 reaction
Treat precipitating factors
Continue or Start Multidrug Therapy
65. Mild Type 2 Reaction
Managed with analgesics and anti-inflammatory drugs such
as aspirin and other NSAIDs.
Aspirin : 600 mg 6 hourly with meals. Dosage is reduced
slowly as signs and symptoms are controlled.
Dose : 0.5 mg, three times daily with a tapering course.
66. Severe Type 2 Reaction
First line of treatment in the management of severe T2R.
should be started in dose of 1 mg/kg/day till clinical
then tapered every week by 5-10 mg over 6-8 weeks.
maintenance dose of 20-30 mg may be needed for several
weeks to prevent recurrence of ENL
Acts by blocking the template function of DNA, by increasing
lysosomal enzyme synthesis and by increasing phagocytic
capacity of macrophages.
Binds preferentially to GC-rich region of mycobacterial (not
Stimulation of PGE2 synthesis, inhibition of neutrophil motility,
together with selective suppression of Th-1 subtype of T-helper
Inhibition of the calcineurin-nuclear factor of activated T-cells
(NFAT) signaling pathway.
300 mg daily, orally for a period of 1-3 months, followed by
200 mg daily for 3 months and
100 mg daily for as long as the symptoms remain.
The treatment of choice for management of severe T2R, but
kept as second option because of its teratogenic effects,
difficulty in monitoring at all healthcare levels, cost and
nonavailability at all places.
Suppresses all clinical manifestations of T2R within 48-72
Its action is faster and more effective than aspirin,
clofazimine and pentoxyphylline.
In severe ENL, start at a dose of 400 mg at bedtime or 100 mg
Then it is tapered to 200 mg BD or 100 mg QID
The dose is then reduced more slowly by 100 mg each month.
In rebound cases prolonged maintenance therapy is required. a
maintenance dose of 100 mg daily (with a range of 100 mg on
alternate days; to 100 mg two or more times, daily) should be
given for a sufficient period.
Attempts to discontinue the drug every 6 months after gradual
tapering of the dose.
If again there is recurrence of reaction, this drug can be restarted
for another period of 6 months.
This process is repeated until reaction no longer recurs when the
drug is discontinued.
70. For recurrent or chronic ENL: Combination treatment is always
Option 1: Clofazimine + Prednisolone
Clofazimine + Prednisolone: 1 mg/kg body weight OD till clinical
improvement followed by 5-10 mg reduction every 2 weeks
100 mg tds for 3 months
100 mg bd for 3 months
100 mg od as long as symptoms persist
Option 2: Thalidomide + Prednisolone
Thalidomide + Prednisolone in the same dose as above
200 mg bd for 3-7 days
100 mg morning + 200 mg evening for 4 weeks
200 mg evening for 4 weeks
100 mg evening for 4 weeks
50 mg daily evening or 100 mg every alternate day evening for 8-12
71. Alternate therapies for type 2 reaction
Betamethasone pulse therapy: Slow infusion of 40 mg
betamethasone daily in 5% dextrose for three consecutive
days and every 4 weeks
Dexamethasone pulse therapy with azathioprine given in a
dose of 100 mg dexamethasone in 500 mL glucose IV infusion
on three consecutive days, every month, along with 50 mg
Azathioprine 2 mg/kg/day given for 6-8 months
Pentoxifylline 1,200 mg daily good option for patients HIV
coinfection where long-term steroids are contraindicated
73. LUCIO PHENOMENON
Observed in Lucio leprosy, mainly reported from Mexico,
Costa Rica, USA, Hawaii, Brazil and recently from India.
Lucio leprosy is characterized by diffuse skin infiltration,
loss of facial skin creases (leading to youthful appearance-
beautiful leprosy) and absence of papules and nodular
Specific histopathological features:
ischemic epidermal necrosis, necrotizing vasculitis of small
blood vessels in the upper dermis, severe focal endothelial
proliferation of mid-dermal vessels, and by presence of large
number of AFB in endothelial cells
74. Classical clinical picture of Lucio
erythematous diffuse or plaque type lesions
Purpuric necrotic black eschar
The eschar falls off in a few days leaving
behind big ulcers of irregular shape.
The condition improves after starting MDT.
They respond to oral steroids
Thalidomide is of no value.
Unless promptly and adequately treated, they can result in deformity and disability.
Type 1 reactions as a part of immune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV) positive patients
To conclude, longer duration of treatment depending on the spectrum of the leprosy (longer duration of treatment in MB cases) with higher starting dose (1 mg/kg body weight) of steroid is the most ideal regimen for appropriate management as well as to prevent recurrence of TJR
Coomb and gell classification
crops of skin lesions in the form of painful/tender evanescent maculopapular, papular, nodular or plaque type of lesions before appearance of constitutional signs and symptoms.
Colchicine inhibits vascular injury by inhibiting neutrophil chemotaxis and may be helpful in mild to moderate type of ENL.25
This dose easily controls the reaction within 48 hours in most of the cases.