Two types 1 n 2

1. Leprosy reactions and their
management
Presentor- Dr Ketki
Moderator- Dr Amit Tiwari

2. Introduction
 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
indeterminate type.

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

4. Type 1 reaction

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
lepromatous pole
 As the management is same, no distinction is
recommended to be made and all T1Rs are labeled
as RRs.

7. Risk Factors
 BT, BB and BL- most vulnerable group
 Who had one episode of reaction are more prone to develop a
second episode
 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
lagophthalmos

8.  Nerve enlargement, tenderness and paresthesia on
palpation
 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

9. Immunopathomechanisms
 Increased cellular immune responses (DTH reaction) to
M. leprae antigens
 Infiltration of activated CD4 T lymphocytes, especially of
Th1 class
 Raised IL-2 receptor and INF-y
 Autoimmunity : human nerve and skin have a number of
antigenic determinants in common with M. leprae
(molecular mimicry)

10. Histopathological Features
 Epidermis- erosion of the granuloma into lower epidermis
 Dermis- At initial stage - mild extracellular edemawith some influx of
lymphocytes
 Later stage- further increase in the edema
 Upgrading reaction- Granulomas become more epitheloid with increased
lymphocytes
 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
activation.

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
Clinical Terms
 Acute: Symptoms persisting up to or less than 1 month
 Subacute: Symptoms persisting for more than 1 month up to 6
months
 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

15. Clinical Manifestations
Symptoms:
 Burning
 Stinging sensation
 Aches and pains in the extremities
 Loss of strength and/or sensory perception

16. Signs
 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
positive
 ‘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
Mild:
 Few skin lesions with features of reaction clinically; without any
nerve pain or loss of function.
Severe:
 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.

22. Criteria
Major
 Pre-existing and/or new skin lesions become inflamed,
red and swollen
Minor
 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
nerve

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
disease

24. Differential Diagnosis
 Relapse
 Acute urticaria
 Erysipelas
 Cellulitis
 Insect bite.

26. Management of type 1 reaction
Antileprosy Treatment
 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).

27. Mild Reaction
 Nonsteroidal anti-inflammatory drugs (NSAIDs, e.g.
aspirin or paracetamol)
 Reassurance.

28. Severe Reaction
Corticosteroids (Prednisolone)
 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
symptoms.
 Dose cut by 5 mg every 1-2 weeks.
 The crucial maintenance dose: around 15-20 mg for
several weeks/months.
 In the follow-up period, the dose cut by 5 mg every 2-4
months.

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
months).
 Duration of steroid treatment matters more than dose. Initial
dose of steroids does not affect the efficacy of the antileprosy
regimen.

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.
 Azathioprine
 Mycophenolate mofetil
 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
Impairment
 Inflamed nerves must be kept in resting position.
 Appropriate splinting and padding gives relief.
Surgical Decompression
 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

33. Type 2 reaction

34.  Type 2 reaction, popularly known as ENL
 Type III hypersensitivity reaction or Arthus
phenomenon.
 Major clinical lesions on the skin are erythema
nodosum type; hence the term "ENL” used as an
alternative term
 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,
filariasis, malaria
 Trauma
 Surgical intervention
 Physical and mental stress
 Protective immunizations
 A strongly positive Mantoux test
 Pregnancy and parturition
 Ingestion of potassium iodide

36. Immunopathomechanisms
 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
present antibodies.

37. Immunology
 Within the lesions the plasma cells  stimulated by IL-4 
produce antibodies.
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
competent cells

38.  Most prominent cytokines : IL-4, IL-5, TNF-a, and INF-y.
TNF-a (known pyrogen)  rise of temperature and
tissue damage
 Autoimmunity might also play a role in the tissue
damage.
 Histopathological examination : increase in neural cell
adhesion molecules (NCAM) and NCAM-positive CD8+
cells in nerve tissue

39. Histopathology
 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
cases.
 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
lymphocytes

41. MANIFESTATIONS OF T2R
• Tender and swollen
lymph nodes
• Acute epididymo-
orchitis
• Nephritis
• Proteinuria
• Renal failure
• Hepatosplenomegaly
• Anemia
• Amyloidosis
• Myositis
• Arthritis
• Synovitis
• Rhinitis
• Epistaxis
• Laryngitis
• Iridocyclitis
• Glaucoma
• Painful dactylitis
• Periosteal pain
SKIN NERVE SYSTEMIC INVOLVEMENT
ENL NEURITIS

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
symmetrically.
 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
 fever,
 malaise,
 prostration,
 headache,
 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
T1R.
 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
certain sites

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
muscle fibers

51. Arthritis
 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
respiratory embarrassment

54. Bone Changes
Osteoperiostitis:
 Severe bone pains and soft tender swelling of the anterior aspect
of tibia.
 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)
Osteoporosis
 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
producing sinuses

56. Involvement of Liver
 Hepatic enlargement below the costal margin is sometimes
observed.
 The liver is soft and tender.
Involvement of Kidneys
 Acute glomerulonephritis due to the immune complex
deposition
 Albuminuria from a trace to 1+.
 Microscopic examination : plenty of red blood cells (RBCs),
pus cells, epithelial cells, casts (from RBC, pus cells) and
granular casts.
 In few instances frank hematuria, and rarely oliguria.

57. Suprarenal Involvement
 BP remains low due to hypofunction of the suprarenal
gland
Acute Epididymo-orchitis
 Acute pain, tenderness and swelling in scrotum due to
acute inflammation of the testes and epididymis.
Hematological Changes
 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
two extremities.
 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.

59. Diagnosis
 Clinical and histopathological
 Includes the major criterion or at least three minor criteria
 Major: Sudden eruption of tender papules, nodules or plaques which
may ulcerate
 Minor
• Mild fever
• Tender enlarged nerves
• Loss of sensation or muscle power
• Arthritis
• Lymphadenitis
• Epididymo-orchitis
• Iridocyclitis
• Edema of extremities or face
• Positive Ryrie or Ellis test

60. Clinical Tests
Certain clinical tests are used for diagnosis of T2R.
 Ryrie Test
Stroking the sole of the foot with the back of a reflex
hammer elicits a burning pain
 Ellis Test
Squeezing the wrist during ENL elicits a painful reaction

61. Laboratory tests
 Hematological changes:
 leukocytosis
 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
transaminases

62. Differential Diagnosis
However, acute EN can occur
due to other common causes
like:
 Sarcoidosis,
 Tuberculosis,
 Streptococcal infections,
 Intestinal infections
 Drugs
Also need to be excluded
are:
 Rheumatic fever,
 Rheumatoid arthritis,
 Collagen disorders like
SLE
 Drug reactions

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.
 Colchicine
Dose : 0.5 mg, three times daily with a tapering course.

66. Severe Type 2 Reaction
Oral corticosteroids
 First line of treatment in the management of severe T2R.
Prednisolone
 should be started in dose of 1 mg/kg/day till clinical
improvement,
 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

67. Clofazimine:
 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
mammalian) DNA
 Stimulation of PGE2 synthesis, inhibition of neutrophil motility,
together with selective suppression of Th-1 subtype of T-helper
cells
 Inhibition of the calcineurin-nuclear factor of activated T-cells
(NFAT) signaling pathway.
 Dose:
 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.

68. Thalidomide:
 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
hours.
 Its action is faster and more effective than aspirin,
clofazimine and pentoxyphylline.

69. Dosage
 In severe ENL, start at a dose of 400 mg at bedtime or 100 mg
QID
 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
preferred
 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
weeks

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
daily azathioprine
 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

72.  Cyclosporine A
 Plasma exchange
 Methotrexate
 Mycophenolate mofetil
 Leukotriene Inhibitors (Zafirlukast, Montelukast)
 Thalidomide Derivatives-IMiDs [Lenalidomide(Revimid),
Pomalidomide (Actimid)]
 Anti-TNF-a Agents (Infliximab, Etanercept, Adalimumab)

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
lesions
 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
phenomenon:
Afebrile
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.
 Management:
The condition improves after starting MDT.
They respond to oral steroids
Thalidomide is of no value.

75. Thank you