Reactions in leprosy - Type 1 Type 2 reactions

Reactions In leprosy

1. REACTIONS IN LEPROSY Presenter : Dr. Abinaya S Moderator : Associate Prof Dr. Bobita Boro Commentator : Dr. Himakshi Uzir

2. INTRODUCTION Leprosy reactions are immunologically mediated episodes of acute or sub-acute inflammation which interrupt, the relatively uneventful usual chronic course of disease affecting the skin, nerves, mucous membrane and/or other sites. This may occur before, during or following MDT. It may affect any type of leprosy except the indeterminate type. Unless promptly and adequately treated, they can result in deformity and disability.

3. TYPES OF REACTION  There are three types of reaction recognized. 1. TYPE 1 REACTION 2. TYPE 2 REACTION OR ERYTHEMA NODOSUM LEPROSUM 3. LUCIO PHENOMENON

4. IMMUNOPATHOGENESIS OF REACTIONS Most reactional episodes occur while the patient is on multidrug therapy Antibiotic treatment Bacteria killed Antigen released Overactivation of immune system Attempts to clear bacterial antigen Inflammation 

5. GENETIC EXPRESSION (Genetic Polymorphism)                                      T1R                           T2R 1. TLR1 &2 Increase risk            Protection 2. NOD2         Protection             Increase risk 3. IL6                                           Increase risk

6. CELL TYPE                            Treg Increase. Controls the exacerbated CMI, with benefial consequenses to the host’. Depleted. Unregulated inflammation thus causes extensive clinical manifestations. Widespread tissue damage Th17 Increased/decreased or unchanged Increase , along with recruitment of neutrophils. T1R T2R

7. CYTOKINES               T1R                                 T2R 1.INF γ - Much higher             Hallmark Cytokine                  levels       Cause hyperimmune   Partial and transient        response                        augmentation of CMI       Clearing of bacilli &         Sufficient to result          concomitant tissue           in antibody and IC    damage                            formation but                                                                unable to clear bacilli                                               

8.                             T1R                       T2R 2.IL1β & TNFα - Increase                 Increase                   Initial increase in IL1β may indicate higher susceptibility of reactions after treatment initiation. TNFα  decreases with treatment of reaction with steriods and thalidomide.  In ENL its level correlated to disease activity. 3. IL6 - Significant increase in ENL, considered biomarker of ENL. Levels decline with treatment. 4.IL-17 - Th17 related cytokines, mainly found in ENL. IL-17F increases in T1R, while IL-17A increases in ENL.  

9. 5. OTHERS- TGFβ , Treg promoter cytokine expressed in ENL. IL10 levels decreases in T1R, increases in ENL. IL2 increase in both. IP10 increase in T1R. ACUTE PHASE REACTANT- CRP raised in T1R mainly while  Pentrexin family member PTX3 increases in ENL.

10. In T1R C aused by increase in CMI ,i.e. delayed hypersensitivity reaction to M.leprae antigen in skin (presented by macrophages) and nerves (presented by schwann cells). Activation of CD 4+ lymphocytes (Th1 type) and increased expression of adhesion molecules on endothelium, increased IL-2 and INF-γ leading to increased lymphocytic infiltration in skin and nerves (clinically manifesting as inflamed skin lesions, neuritis, nerve damage) Hypersensitivity is directed against –cytoplasmic antigens in nerves and surface antigens in skin

11. In T2R Both humoral and cell mediated mechanisms operate principal event–deposition of antigen-antibody complex in tissues. In LL-most are CD8+ cells, but when ENL starts           Macrophages present M. leprae antigens             Infiltration of CD4+ cells into dermis     Growth factors for mast cells, IL-4, IL-5, IL-10                 Stimulate antibody release           Immune complex deposition takes place                 Complement stimulation     Neutrophils chemotaxis, TNF- α levels increased                 Fever and tissue damage

12. IMMUNOPATHOGENESIS OF NERVE DAMAGE INNATE IMMUNITY-  Human Schwann cells express TLR2. (TLR2 positive leprosy lesions undergo apoptosis ultimately leading to nerve damage). ADAPTIVE IMMUNITY- TNF α alone does not have toxic effects on schwann cells but in combination with TGF β leads to significant schwann cell detachment and lysis. Infected schwann cells process and present antigen of M.leprae to antigen specific inflammatory Th1 cells which damage and lyse the infected schwann cells. (role of CD4cells is more important as compared to CD8)

13. MECHANISM OF NERVE DAMAGE IN T1R Edema     Perineurium(rigid layer)         A xonal compression    Pressure on venules     Interruption of intra-axonal flow Engorgement of capillaries by back pressure venostatic edema - Diffuse subacute and chronic segmental demyelination.

14. Mechanism of nerve damage due to local edema and granuloma in type I reaction and consequential fibrosis Fibrosis

15. TYPE 1 REACTION (T1R) T1R is a delayed hypersensitivity reaction associated with sudden alteration of cell mediated immunity associated with a shift in patient’s position on leprosy spectrum. Antigens from degenerating leprosy bacilli interact with T lymphocyte and this is associated with rapid change in cell mediated immunity. It is typically seen a borderline patients because of their immunological instability, rarely seen in LL.

16. Can be of two types- 1) UPGRADING OR REVERSAL REACTION: Reaction is associated with rapid increase in cell mediated immunity, as seen in patients under treatment. There is shift towards the tuberculoid pole. 2) DOWNGRADING REACTION: Reaction is associated with reduction in immunity. There is shift towards leprematous pole.

17. EPIDEMIOLOGY OF T1R Cumulative prevalence varies from 8%-33% for all leprosy patient. Likely time of occurrence of upgrading reaction-  BT & BB- 2weeks to 6months of treatment     BL-50% will get T1R, usually between 2-12months after starting chemotherapy. Untreated BT patients suffer from episodes of downgrading reactions reaching BL where the reaction ceases. But likely to occur during chemotherapy. Upgrading reaction occurs in subpolar LL  under treatment, with new skin lesions having features of BL. T1R can be seen even after treatment and recurrence is common.

18. RISK FACTORS FOR T1R During MDT and subsequent 6 months Positive BI (MB cases) Extensive disease indicated by the body area involved Borderline classification- BB & BL have higher risk Nerve function impairment Having a facial patch, high risk for lagophthalmos Pregnancy and delivery( esp 1 st 6months after delivery) Bactericidal drug regimens Enlarged ulnar nerve at diagnosis Attending as a self-reporting case Presence of anti PGL-1 ( Phenolic glycolipid -1) antibodies and lepromin test BCG vaccination

19. HISTOPATHOLOGY   1.PRODROMAL PHASE 2.ACTIVE STAGE 3.NECROSIS 4.SUBSIDENCE OEDEMA Mild oedema Severe oedema Profuse oedema Reduction in oedema GRANULOMA Dilated lymphatics and spaces around Dispersion by swelling and disruption Liquifactive necrosis Reformation CELLS Proliferation of fibroblast around granuloma Different type of giant cells inc. Langhans’ –type cells seen Local infiltation by neutrophils Resolving fibrosis

20. HISTOLOGICAL  CLASSIFICATION OF T1R   OEDEMA LYMPHO-CYTES MACRO-PHAGES GIANT-CELLS ACID FAST BACILLI UPGRADING REACTION Intense oedema  Markedly increase Old foamy macrophages Many Langhans’ giant cells Decrease or disappear in BL cases DOWN-GRADING REACTION  Present Decrease Increase Preexisting ones persist May increase if downgraded to LL 

21. A) F ocus of necrosis within epitheloid cell granuloma in BT leprosy with T1R. B) langhan giant cell and foreign body giant cell with beginning of necrosis.

22.                     CLINICAL FEATURES   Clinically the most prominent sign is rapidly developing change in the appearance of some or all skin lesions- Which becomes erythematous, edematous, more prominent ,shiny and warm to touch. Necrosis and ulceration may supervene. Crops of freshly inflamed skin lesions in the form of plaques over previously clinically uninvolved skin (as part of an upgrading reaction in borderline leprosy). New lesions may appear commonly in downgrading reaction. Edema of hands, feet and face. Systemic disturbance like fever and malaise are unusual .

23. Rapid swelling with severe pain/tenderness at the site of nerve swelling, and sometimes may be associated with abscess formation. Sensory nerve involvement could lead to pain in the region of the skin where it supplies ( eg. Pain at medial border of wrist or little finger in cases of ulanr nerve involvement). Motor disturbance : more serious. Nerves most at risk are ulnar nerve (claw hand), lateral popliteal nerve ( dropped foot) and facial nerve (facial palsy). These paralyses are likely to be permanent if neglected or incorrectly treated, but will recover with correct and prompt treatment.

24. Type I reaction in a case of borderline tuberculoid (BT) leprosy, In a case of borderline borderline (BB) leprosy

25. Type 1 reaction involving the facial plaque

26. Left- BT downgrading to BL with T1R Right- After treatment for 2 weeks

27.      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 paraesthesia Increasing loss of nerve function Fever or discomfort E dema of hands, feet Mild reaction persisting for more than 6 weeks Reaction of skin lesion on the face Ulcerative skin lesion

28. 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 oedema 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                          Diagnosis Clinical Criteria -Proposed by Naafs and his team     Requires presence of 1 major criterion, or atleast 2 minor criteria (without signs of ENL)

29.                 MANAGEMENT The principles of management of T1R are two folds-  1. Initiation of anti-mycobacterial therapy 2. Administering an effective and prolonged anti-inflammatory therapy with physical support during phase of active neuritis ( if present ) SPECIFIC TREATMENT- 1. CORTICOSTERIODS - Cornerstone of therapy and are considered the drug of choice. Initial dose of prednisolone- May vary from 40 to 60 mg ( 1mg/kg) Tapering of steriod - Once improvement is noted, dose is tapered by 5mg every 1-2 weeks until 20mg is reached.

30. This dose is continued for few months as gradual improvement in nerve function occurs. After this the steriod is withdrawn at 5mg per fortnight. Duration- BT- 4-9months                BB- 6-9 months                BL - 6-18 months, at times 24 months Response- patients with recent NFI <6 months, BL spectrum and medial nerve damage are predictive of favourable   response.

31. 2. Alternate drug-  Azathioprine : in combination with steroid, help reduce the dose of steroids. Methotrexate : Low dose (5-7.5 mg/week) helps in reducing the dose of steroid in patients with steroid intolerance.  Cyclosporine A : Useful in cases with chronic neuritis which do not respond well to prednisolone. Started at 5mg/kg/day followed by gradual reduction of the dose. Can be administered for upto 12 months without significant side effects. 3. Immunological drugs- IL-1inhibitor viz. anakinra, rilonacept, canakinumab. Tacrolimus and IL6 inhibiter tocilizumab are being efficacious in studies.

32. 4.Additional measures When acute phase over : Passive and active exercises Oil massage, Short wave diathermy, Ultrasonic therapy Surgical decompression : If despite all the above measures, pain and nerve function impairment continues. Involves exposing the affected nerve trunk at the point of maximal thickness, and giving longitudinal incisions into the nerve upto epineurium layers of nerve bundle.

33. NERVE ABSCESS IN T1R The inflammatory response in nerve due to rapid increase in CMI response leads to sudden influx of T lymphocytes into the intraneural granuloma. In severe reaction process, nerve abscess formation occurs in the affected nerve. This abscess is predominantly composed of lymphocytes hence, akin to ‘cold abscess’ of Tb, but extremely tender.  TREATMENT- MDT, steroids, Incision and drainage and nerve exploration, epineurotomy or neurectomy.

34. TYPE 2 REACTION Also known as Erythema Nodosum Leprosum (ENL). It is an immune complex syndrome (antigen-antibody reaction involving complement), causing inflammation of skin, nerves and other organs, and generally malaise. Occurs mostly in LL and sometimes in BL. Patients with high bacillary index are more prone. Time of onset : occurs mostly during the course of anti-leprosy treatment. Few cases may present for the first time with features of reaction.

35. RISK FACTORS Lepromatous leprosy spectrum with skin infiltration with Bacterial index of >4+ Anti-leprosy drugs except clofazimine Patients with <40years of age Coinfection ( like HIV , TB, Hep B &C, typhoid etc) Intercurrent infections Trauma or Surgical intervention Physical and mental stress Protective immunizations A strongly positive Mantoux test Pregnancy and parturition Decrease C4 and elevated anti M.leprae antibodies in newly diagnosed case Ingestion of potassium iodide

36. Epidemiology Average incidence of ENL in LL cases is about 15.4% ( 11.1 – 26%), and in BL 4.1% (2.7-5.1%) Most commonly occurs after 6 months of MDT, but in 1/3 rd patients appear as presenting symptoms without treatment. It may occur even after MDT ( upto 7-8 years) due to persistence of bacterial antigens.

37. Histology 1.Granuloma made of foamy macrophages, many of which are filled with M.leprae 2.Neutrophilic infiltrate 3.Swelling of endothelial cells and edema of vessel walls 4.Acute necrotizing vasculitis—variable finding 5.Necrotizing ENL—same findings but in greater degree—more severe and widespread 6.Bacilli are fragmented and granular. As reaction subsides—lymphocytes and plasma cells increase and neutrophils decrease Resolution occurs with fibrosis.

38. Macrophage granuloma in LL with T2R Higher magnification showing neutrophillic infiltation in macrophage garnuloma

39. CLINICAL FEATURES Type 2 reaction can cause inflammation in any organ invaded by lepra bacilli Cutaneous lesions -presents as crops of erythematous partially blanchable, warm, tender papules or nodules. These may be superficial or deep seated and have b/l symmetrical predilection. The lesions are evanecent lasting for 2-3 days and multiple in number. Usual sites are face, arms, thighs, palms and soles and may appear in any area except hairy scalp axilla, groin and perineum.

40. The fresh crops of ENL lesions  and intermittent fever usually appear in the evening when endogenous cortisol production is at its lowest. In SEVERE cases , skin lesions may become pustular, ulcerated, hemorrhagic, necrotic , vesicular, bullous, Sweet Syndrome like and erythema multiforme-like.  Generalized systemic illness , associated with fever, myalgia, edema of face, hands and feet and loss of protein in urine are present in T2R. Fever is considered the hallmark of ENL

41. Erythema nodosum leprosum (ENL) in a case of LL

42. Pustular ENL Necroticoulcerative lesion in ENL E rythema multiforme type of ENL

43. ORGANS  SIGNS AND SYMPTOMS JOINTS Polyathritis /polyarthalgia, with pain, tenderness and limitation of movement mainly affecting knee, MCP,IP, Wrist & ankle jt. LYMPH NODES Acute and tender lymphadenopathy esp femoral, inguinal, axillary, cervical and epitrochlear LN EYES Conjunctivitis, iritis, iridocyclitis, glaucoma and blindness LIVER Hepatomegaly , soft and tender GENITILIA Epididymo-orchitis- repeated reaction can lead to testicular atrophy and gynaecomastia KIDNEYS Glomerulonephitis, acute tubulointerstitial nephritis, amylodosis- which can progress to CKD BONE Dactylitis , periosteitis MUSCLES Myalgia, myositis NERVES Neuritis 

44. DIAGNOSIS Clinical Clinical tests :           - Ryrie test : stroking of sole of foot with the back of a reflex hammer elicits a burning pain.            - Ellis test : Squeezing the wrist during ENL elicits a painful reaction. Histopathology Laboratory tests           - Haematological changes : leucocytosis , increased ESR and CRP           -Urine may show presence of albumin, RBC, pus cells, epithelial cells and casts.            -LFT : there may be rise in serum bilirubin and transaminases (SGOT, SGPT)

45.   CRITERIA FOR DIAGNOSIS OF T2R Proposed by B Naafs and his team There should be presence of atleast 1 major criterion or 3 minor criteria Major criteria A sudden eruption of tender red papules, nodules or plaques which may ulcerate Minor criteria Mild fever , the patient is unwell Tender enlarged nerves Increased loss of sensation and muscle power Arthritis Lymphadenitis Epididymo -orchitis Iridocyclitis or episcleritis Edema of extermity or face Positive Ryrie’s test or Ellis’ test

46.        MANAGEMENT GENERAL MEASURES-  Treat precipitating factors :                           -Intercurrent infections                           -Psychological stress. Continue or start MDT. SPECIFIC MEASURES- MILD T2R-  analgesics such as aspirin, indomethacin, ibuprofen, diclofenac, paracetamol. Monitoring should be done every 2 weeks. If there is worsening and increase in symptoms, it is treated as severe. MODERATE T2R- steriod is used at a dose of 30-40mg prednisolone/day. RECURRENT T2R- increase and prolonged dose of steriods to control the inflammation and symptoms.

47. T REATMENT ALGORITHM FOR MANAGEMENT OF T2R

48. 1. CORTICOSTERIOD:  1 st line treatment in severe ENL Useful in-        1.neuritis when muscle paralysis threatened        2. iritis not responding to topical steriods        3. presence of epididymo -orchitis        4. in erythema necroticans ( vesicular/bullous ENL) Dose- 1-1.5mg/kg/day for 2-4 weeks            -then tapering by 10mg every 2weeks till 20mg per day.             -Then slow tapering of 5mg every 2weeks. Patient requires steriods for long time due to reccurent and chronic nature of ENL

49. 2. THALIDOMIDE : Treatment of choice,but kept as 2 nd choice due to its teratogenic effects, difficulty in monitoring , high cost and non availability at places MOA- 1. Inhibition of TNFα and neutrophil recruitment             2.polarization of immune response towards Th2 with production of IL2 , IL4 and 5.             3. suppresion of formation of IgM antibodies             4. decrease T helper cells and increased suppressor T cell production. DOSE- 3-4 tabs of 100mg daily in divided doses, tailing of as reaction subsides.              -continue 1tab daily or alternate day to avoid outbreaks

50. 3. CLOFAZIMINE :   High doses of clofazimine has anti inflammatory property. DOSE- 100 mg thrice daily along with standard course of prednisolone and to continue for a maximum of 12 weeks.          - tapering of dose is 100mg twice daily for 12 weeks then 100mg once daily for 12-24 weeks. It is slow to act and takes about 4-6 weeks to act. However it helps in reduction of dose of steriod . Management with clofazimine alone is indicated in patient where steriods are CI.

51. ALTERNATE OPTIONS- 1. Azathioprine – Good steriod sparing agent. It interferes with purine production , also has anti- TNF α action.                         - effective dose is 2mg/kg/day given for 6-8 months. 2. Methotrexate - useful in recalcitrant cases and chronic steriod resistant ENL. 3. TNF α Inhibitors - Infliximab and etanercept.                              - useful in resistant recurrent ENL cases which fail to respond to prednisolone.                              - DOSE - INFLIXIMAB  at a dose of 5mg/kg, repeated dosage given on week 2 and 6.                                            - ETANERCEPT at a dose of 50mg/week given sc

52. 4. Minocycline - has anti-inflammatory and anti- apoptotic properties. Useful in reccurent and/or chronic cases.                       - main advantage of using antibacterials like minocycline and clofazimine are additional immunomodulatory, anti-inflammatory and neuroprotective action. 5. Aprimilast - oral phosphodiesterase-4 inhibitor have immunomodulatory and anti-inflammatory actions. Inhibits proinflammatory cytokines involved in T2R. 6. Leprosy Vaccine

53. DIFFERENCES  BETWEEN   T1R  AND T2R FEATURES T1R T2R Type of immunological reaction Delayed type of HS reaction(type IV) Antigen antibody IC reaction (type III) Type of patient affected Borderline type (BT, BB, BL, rarely subpolar LL) LL, rarely BL Constitutional signs and symptoms None or rare Common  Type of skin lesions Existing skin lesions suddenly become reddish, swollen, warm, painful, tender Fresh red, painful, tender, subcutaneous nodules, plaques.Existing skin lesions remain unchanged Nerve involvement Nerves close to skin lesions may become enlarged, painful and tender due to acute neuritis with loss of nerve function Nerves may be affected but not as common or as severe as T1R Eye involvement Corneal anaesthesia and lagophthalmos may occur due to nerve involvement Internal eye diseases like iritis, iridocyclitis, glaucoma are common Other organs Not affected May be affected(lymphadenitis, epididymo -orchitis, arthritis)

54.    LUCIO PHENOMENON This is a unique form of leprosy reaction, which occurs due to massive proliferation of lepra bacilli inside endothelial cells resulting in vascular occlusion and vasculitis. It occurs 3-4 years after onset of disease.  It is more common in                    - untreated patients with diffuse LL                     -in those who received inadequate treatment. It presents with minimal systemic features and neuritis .

55. LESIONS Painful, tender, red patch, with a geographic margin Becomes purpuric           Center becomes necrotic and ulcerate       Develops brown or black crust (eschar) Falls off after few days to leave a superficial atrophic scar

56. ETIOPATHOGENESIS Patients in lucio phenomenon has a singularly deficient defense mechanism  Which permits unhindered multiplication of bacteria  Exposure of bacterial antigen to circulating antibody Vasculitis, thrombosis, infarction and skin necrosis HISTOLOGY - Ischaemic epidermal necrosis,  Fibrin thrombi in vessel lumen with wall infiltration, necrotising vasculitis of small and medium blood vessels in the upper dermis severe focal endothelial proliferation of mid-dermal vessels presence of large number of AFB in endothelial cells.

57.    CLINICAL FEATURE Patient is usually afebrile Appearance of erythematous diffuse or plaque type lesions which becomes purpuric, becomes necrotic followed by black eschar formation. The lesions mainly appear on the extremities and spreads in a characteristic ascending fashion. The lesions are frequently described as triangular, polygonal or angular ulcers. Occasionally hemorrhagic blisters and edema of hands, feet and ear conchae have been described Usually patient have lesions which are on different stages of evolution. TREATMENT MDT should be started. Respond well to oral steroids. Do not respond to thalidomide .

58. Lucio Phenomenon

59. LUCIO PHENOMENON Vs T2R WITH VASCULONECROTIC PHENOMENON FEATURES LUCIO PHENOMENON NECROTIZING ENL Seen in Diffuse LL  BL, LL Patient status Untreated Treated Clinical features Angular geographic necrotic lesions, ulcers,heals with scar Generalized Painful nodules with necrosis Histology Inv. of medium sized vessels of mid dermis with thrombosis and endothelial proliferation. Necrotizing vasculitis of small blood vessels of superficial dermis Panvasculitis starts in hypodermis with larger deep necrosis resulting in fibrotic scar. General symptoms No general symptoms Systemic features with fever seen Neuritis  Absent  Marked    Mainly vasculopathy Vasculitis 

60. LAZARINE LEPROSY It is ulcerating type 1 reaction Found in BT Hansen with spontaneous ulceration, occuring due to extreme hypersensitivity in type 1 reaction Factors implicated- breakdown of local immunity, increase proliferation of bacilli and severe tissue edema. Concomitant secondary infection due to protein malnutrition have also been implicated. There is no localized skin infiltrations. Systemic corticosteriods are necessary.

61. M ultiple non tender ulcers appearing on pre-existing lesion of chest and back

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