ppt

1. OM SAKTHI

2. History of Lupus
 Lupus means “wolf” in Latin
 10th century- case reports appeared in writings
 Late 1800s- Sir William Osler initially described the
systemic nature and linked rashes to organ involvement
 1949- LE cell described by Malcolm Hargraves at Mayo
Clinic
 1954- ANA described
 1971- First set of classification criteria proposed for Lupus
 1983- Antiphospholipid antibody syndrome described

3. History
 1948 – Malcolm Hargraves discovers the lupus
erythematosus (LE) cell.
 1957 – The first anti-DNA antibody is identified.

4. Mechanisms

5. Proposed Mechanisms of Autoimmunity

6. What exactly is Lupus?
 Autoimmune disease where one’s immune system
attacks itself
 Autoantibody production -> immune complex
deposition -> inflammation -> damage
 Chronic disease, characterized by flares and
remission
 Pleomorphic with different phenotypic expressions
 Multisystem involvement

7. Types Of Lupus
 Drug Induced Lupus
 Neonatal Lupus
 Cutaneous Lupus
 Systemic Lupus Erythematosus

8. Cutaneous
 Most common rash is photosensitive, raised
erythematous malar rash. 55-85% develop at
some point in disease
 Discoid Lupus Erythematosus (DLE): 15-30%
circular, scaly hyperpimented lesions with
erythematous rim, atrophic center—can be
disfiguring involving the bridge of the nose and
adjacent cheeks.
 Mouth/vaginal/nasal ulcers
 Alopecia: may be diffuse or patchy. Occurs
50%

9. Drug- Induced Lupus
 Approximately 80 offending agents can cause
lupus
 15,000- 30,000 cases reported annually
 Production of autoantibodies more common
than clinical symptoms
 99% disappear within 3 months of stopping
the medicine.

10. Neonatal Lupus
 Rare condition
 not true lupus, passively transferred autoimmune
disease
 Occurs when mother is SSA/SSB positive
 Transplacental transfer of IgG anti SSA or SSB
antibodies
 5-7% babies will have a transient rash, resolves by
6-8 months
 2% of babies will have cardiac complications with
congenital heart block

11. SYSTEMIC LUPUS
ERYTHEMATOSUS (SLE)
 Prevalence of 40 to 50 cases / 100,000
 Major causes of mortality
 Infections and nephritis (early)
 Athrosclerosis (late)
 Risk factors
 Genetics (HLA-A1, HLA-B8 and HLA-DR3)
 Race (AA, Hispanic, Asia > Caucasian)
 Hormones
 Chemicals
 Microorganisms

12. SYSTEMIC LUPUS
ERYTHEMATOSUS (SLE)
 Autoimmune disease affecting multiple organ
systems
 Relapsing (flares) and remitting course
 Protean clinical manifestations
 Etiology is unknown
 Female to male ratio is 9:1
 Age of onset
 16 to 55 years (65%)
 < 16 years (20%)

13. Who get’s Lupus?
 Prevalence is over 1.5 million Americans
 Incidence difficult due to lack of strict
definition
 Bimodal peak presentation: ages 20-40 and
again after age 60
 Prevalence is higher in African Americans,
Asians, Hispanics
 Female to male predominance

14. pathogenesis
 Immunologic factors;
 Inherited defect in B cells
 Stimulation of B cells by microorganisms
 T helper cell hyperactivity
 T suppressor cell defect

15. pathogenesis
 Genetic factors ;immunoregulatory
function of class II HLA genes
 Other factors
 Drugs ; pencillamineD
 Viral infections; EBV infection
 Hormones; oestrogen

16. pathogenesis
 Type II hypersensitivity ; formation of
autoantibodies against red blood
cell,platelets, leucocytes results in
haematologic derangement
 Type III hypersensitivity; Ag and Ab
complex and deposited at renal
glomeruli and walls of small blood
vessels

17. Does your sex really matter?
 90% of patients with lupus are female
 Before puberty F:M ratio is 2:1
 During reproductive years ratio 8:1
 Post-menopausal ratio 2.3:1
 Increased frequency in women attributed to
the hormonal effect of estrogen

18. Does your sex really matter?
 Nurses Health Study
 use of estrogen-containing contraceptive agents
associated with an 50 percent increase in risk of
developing SLE
 either early onset of menarche (age ≤ 10 years) or
administration of estrogen to postmenopausal
women doubles their risk
 Treatment of clinically stable SLE with oral
contraceptives for one year does not increase
disease flares

19. Overactive B-cells
 Estrogen is a stimulator of B-cell activity
 Lupus is much more prevalent in females of ages
15-45
 Height of Estrogen production
 IL-10, also a B-cell stimulator is in high
concentration in lupus patient serum.
 High concentration linked to cell damage caused by
inflammation

20. Genetic Associations
 HLA’s are loci on genes that code for
certain β chain on the MHC complex
 HLA-DR2
 HLA-DR3
 HLA-DQB1 – Involved in mediating
production of antibodies to ds-DNA

21. Genetics of Lupus
 High concordance in monozygotic twins
 5-12% or relatives with lupus have the disease
 No single lupus gene
 Disease is polygenic
 At least 30 susceptiblility genes identified
 HLADR2, HLADR3, HLADR4, HLADR8 (present
in 75%)
 Homozygous deficiency of C1q complement

22. Environmental Factors
 UVA and UVB light can stimulate/ up-regulate
autoimmunity
stimulating keratinocytes to produce cytokines -> activate B
cells to produce ab
 Viruses/Bacteria: molecular mimicry
SLE patients have higher titers of antibodies to Epstein-Barr
virus (EBV), increased circulating EBV viral loads; SSA ab
has a sequence similar to EBV nuclear ag 1
Parvovirus B19
 Drugs
 Silica exposure, tobacco smoke, emotional stress

23. Lupus
Genetically
susceptible
individual
Environmental
factors
Auto
antibody
production
Inflammation
Damage

24. Immune dysregulation
 Upregulation of innate immunity
 Delayed clearance of apoptotic cells, resulting in
antigenic stimulation
 Loss of tolerance via failed elimination of
autoreactive T lymphocytes
 Abnormalities in B cells
 Abnormalities in T regulatory cells (CD4+/CD25+
cells down regulate immune system responses)

26. Autoantibodies in Lupus
 Study of US army recruits revealed lupus autoab
present for up to 9 years prior to dx in 85%
 ANA
 dsDNA
 Anti-Smith
 Anti-RNP
 Anti-SSA, anti-SSB-ANTI RIBONUCLEOPROTEIN
 Anticardiolipin,ANTIPHOSPHOLIPID ,anti-histone
 Anti B2 glycoprotein,antiribosomal

27. Immunoglobulins
 Anti-dsDNA IgG: very specific, may
correlate with disease activity
 Anti-Sm: specific, but only present in
25% of cases, does not correlate with
activity
 APLA: not specific. Used to identify
patients at increased risk for clots,
thrombocytopenia and fetal loss

28. Activation of Complement
System
 Complement system is activated by the
binding of antibodies to foreign debris.
 In this case its over activation
 RBCs lack CR1 receptor
 Decreasing the effective removal of
complexes

31. How do patients present?
 Myriad of symptoms
 Symptoms are often non-specific
 No two patients are alike
 50% of patients have organ threatening
disease
 50% do not have organ threatening disease

32. CLINICAL
MANIFESTATIONS OF SLE
 General (Constitutional)
 Fever, chills, headache, fatigue, malaise and weight loss
 Renal
 Hematuria, proteinuria
 Skin
 Malar “Butterfly” rash
 Photosensitivity rash
 Cardiac
 Myocarditis, pericarditis, endocarditis

33. CLINICAL
MANIFESTATIONS OF SLE
 Central nervous system
 Cognitive dysfunction
 Pulmonary
 Pleurisy
 Musculoskeletal
 Myalgias, arthralgias and arthritis
 Hematologic
 Anemia, leukemia, thrombocytopenia
 Lymphatic system
 Lymphadenopathy

34. Symptoms
 Non-specific:
 Fatigue
 Weight loss
 Malaise = generally feeling ill
 Fever
 Anorexia (over time)
 Arthritis
 90% of patients experience arthritic symptoms
 Symmetrical
 Appears in hands, wrists, and knees mainly

35. CUTANEOUS LESIONS
 Butter fly area on nose and cheek
 LM shows liquefactive degeneration of
basal layer of epidermis ,oedema at
dermoepidermal junction, acute
necrotising vasculitis in dermis
 IF shows immune complex deposits
(IgG and C3) at dermoepidermal
junction.

36. Skin Manifestations
• Malar or Butterfly
Rash
• Discoid Rash –
Stimulated by UV
light
• Skin
manifestations
only appear in 30-
40% of lupus
patients.

38. Malar Rash

41. Malar rash

42. Malar rash

43. Discoid Lesions

44. Neonatal Lupus
 See erythematous,
 annular plaques
 tends to involve
 scalp, face,
 periorbital areas

46. Blood vessels
 Skin and muscles involved
 Light microscopy shows fibrinoid
deposits in the vessel wall ,perivascular
infiltrate of mononuclear cells.
 Acute necrotising vasculitis

47. Raynaud’s

48. Oral ulcerations

49. Jaccoud’s arthropathy

50. Arthritis

51. Serositis - Pulmonary
 Pleuritis with or without effusion
- if case is mild, tx: NSAIDS
- if case is severe, tx: steroids
 Life-threatening manifestations: interstitial
inflammation which can lead to fibrosis and
intra-alveolar hemorrhage.
 Also pneumothorax and pulmonary HTN can
occur

52. Other Manifestations
 Cardiac
 Central Nervous System
 Hematological

53. Serositis – Cardiac
 Pericarditis: most common cardiac manifestation
 Myocarditis (rare) and fibrinous endocarditis
(Libman-Sacks) may occur.
 MI due to atherosclerosis can occur in <35 y/o
 Vegetations on mitral and tricuspid valve
 Vegetations show fibrinoid material ,necrotic
debris, inflammatory cells.
 Endocardium and myocardium shows focal
inflammation and necrotising vasculitis

54. Neuro
 Cranial or peripheral neuropathy occurs in 10-15%, it is
probably secondary to vasculitis in small arteries
supplying nerves.
 Diffuse CNS dysfunction: memory and reasoning
difficulty
 Headache: if excruciating, often indicate acute flare
 Seizures of any type
 Psychosis: must distinguish from steroid-induced
psychosis (occurs in 1st weeks of tx at doses ≥40mg
prednisone and resolves after several days of reducing
or stopping tx)

55. Cont.
 TIA, Stroke: mostly increased among
patients that are APLA positive
 50-fold increase in risk of vascular events
in women under 45 compared to healthy
women
 Treatment for clotting event is long-term
anticoagulation

56. Heme
 Anemia: usually Normochromic,
normocytic
 Leukopenia: almost always consists of
lymphopenia, not granulocytopenia
 Thrombocytopenia

57. Renal
 Nephritis: usually asymptomatic, so
always check UA if patient has known or
suspected SLE
 Occurs early in course of disease-if not
present w/in 1 yr, probably will not occur.
 Histologic classification by renal biopsy is
useful to plan therapy

58. Histologic Classifications
 Class I is minimal mesangial glomerulonephritis which is
histologically normal on light microscopy but with
mesangial deposits on electron microscopy
class II is based on a finding of mesangial proliferative
lupus nephritis. Mesangial hypercellularity, subepithelial or
subendothelial deposits on electron microscopy.
Class III is focal lupus nephritis ;proliferation of
endothelial , mesangial and epithelial cells.
Focal sub endothelial deposits on electron
microscopy

59.  Class IV is diffuse proliferative nephritis.
Proliferation of endothelial,mesangial and
epithelial cells.diffuse subendothelial deposits
on electron microscopy.
 Class V is membranous nephritis and diffuse
basement membrane thickening electron
microscopy shows segmental subepithelial
deposits.
 Class VI Glomerulosclerosis- sclerosis of
90%glomeruli.

61. Laboratory Findings in SLE
 97% positive ANA
 61% low complement levels (C3, C4)
 50% dsDNA ab
 46% leukopenia
 42% anemia
 40% proteinuria, nephritis
 35% anticardiolipin antibodies
 25% sjogren’s syndrome with positive SSA, SSB
 12% pleural effusion
 Others: thrombocytopenia, anti SM, antiRNP, elevated
LFTs, splenomegaly, thrombophilia, miscarriages

62. Criteria
1. Butterfly rash
2. Discoid lupus
3. Photosensitivity
4. Oral ulcers
5. Arthritis
6. Serositis
7. Neurologic d/o
8. Hematologic d/o
9. Renal d/o
10.Immunologic: anti-
DNA, anti-Sm,
11.Anti-nuclear
antibody

63. AMERICAN COLLEGE OF RHEUMATOLOGY (ACR)
CRITERIA FOR DIAGNOSIS OF SLE
 Serositis (Pleurisy, pericarditis)
 Oral ulcers
 Arthritis
 Photosensitivity
 Blood disorders (Leukopenia, thrombocytopenia)
 Renal involvement
 Antinuclear antibodies (ANA)
 Immunologic phenomena [false-positive Rapid Plasma Reagin
(RPR)]
 Neurologic disorder
 Malar rash
 Discoid rash

64. ACR 1997 revised criteria
 1. malar rash
 2. discoid rash
 3. photosensitivity
 4. oral or nasal ulcers
 5. arthritis
 6. serositis: pleuritis or pericarditis
 7. renal disorder: proteinuria > 500mg/day, cells
 8. immunologic: anti SM, anti dsDNA, ACL, lupus ac
 9. hematologic: anemia, leukopenia, thrombocytopenia
 10. neurologic: seizures or psychosis
 11. positive ANA in absence of drugs

65. Diagnosis of SLE
 Initial criteria proposed by the ACR in 1971,
revised in 1982 and 1997
 Criteria designed for research purposes
 Need 4 of 11 criteria for diagnosis of SLE
 Not perfect, but have over 90% sensitivity
and specificity
 Currently two international groups are re-
evaluating the criteria

66. 2012 SLICC Classification Criteria
 Need at least 4 criteria (1 clinical and 1
lab)
 Or biopsy proven Lupus Nephritis with
Pos ANA or pos dsDNA

67. LE Cell
 The LE cell is a
neutrophil that has
engulfed the antibody-
coated nucleus of
another neutrophil.
 LE cells may appear in
rosettes where there are
several neutrophils vying
for an individual
complement covered
protein.

68. Autoantibodies in Lupus
 Study of US army recruits revealed lupus autoab
present for up to 9 years prior to dx in 85%
 ANA
 dsDNA
 Anti-Smith
 Anti-RNP
 Anti-SSA, anti-SSB
 Anticardiolipin
 Anti B2 glycoprotein

69. Meaning of ANAs
What exactly are they?
 Antibodies that bind to various antigens in
the nucleus of a cell
How is it measured?
 Indirect Immunofluorescence

70. ANTINUCLEAR
ANTIBODY (ANA)
TEST
 Diagnostic test for autoimmune diseases
 Detects autoantibodies against nuclear and cytoplasmic
antigens
 Nuclear and cytoplasmic antigens
 DS-DNA, SS-A, SS-B, Smith, RNP,
 Laboratory methods
 Enzyme immunoassay (EIA)
 Immunofluorescence assay (IFA)
 Indirect or direct

71. ANA in Lupus
 Sensitivity 93-99% in SLE
 Sensitivity 95-100% in drug induced Lupus
 Specificity is not great
 Higher the titer, higher the specificity
1:40- 30% normal population
1:160- seen in 5% of the population

72. ANA
 ANA: positive in 95% of cases. Pretest
probability affects interpretation. In PCP setting,
2% for SLE. In rheum: 30%
 Low Positive (1:160 or lower): SLE likelihood
<2% (<26% for rheumatologists)
 High Positive (1:320 or higher): SLE likelihood:
2-17% (32-81% for rheumatologists)
 SLE specific patterns: Rim and Homogenous

74. ANA and Aging
 For every year after age 50, percentage of
ANA positivity increases 1%/year
 For example
 Age 50 1%
 Age 55 5%
 Age 60 10%

75. ANA patterns

76. ANA patterns
Staining Patterns
 Observer dependent
 Not sensitive
 Not specific
 Only LOOSELY associated with certain
disease states

78. ANA measurement
Indirect Immunofluorescence Assay
1. Take patient serum and add it cells
2. If there are antibodies they will bind
3. Add a fluorochrome tag
4. View under a fluorescent microscope
5. If it lights up in the nucleus then it is positive
6. Dilute sample and repeat steps 1-5 until nuclear
fluorescence disappears

79. Clinical Indications for ANA
 ANA is NOT a good screening test given its low
specificity
 Presence of ANA does NOT mandate the presence
of rheumatologic illness
 A negative ANA is more useful and makes Lupus
very unlikely
 ANA titers correlate poorly with disease activity so
serial measurements are not recommended
 A positive ANA with anti-centromere pattern is
very specific for limited scleroderma

80. ANA associated Diseases
Rheumatic
Conditions
Rheumatic
Conditions
Auto-
Immune
Misc
Lupus Polymyositis Grave’s Aging
Drug-induced
Lupus
Dermato-
myositis
Primary Biliary
Cirrhosis
Primary
Pulmonary
HTN
Scleroderma RA Hashimoto
Thyroiditis
Sjogren’s Vasculitis Autoimmune
Hepatitis
MCTD MS

83. Poor Prognostic Factors
 Renal disease (esp DPGN)
 Hypertension
 Male sex
 Young age
 Older age at presentation
 Poor socioeconomic status
 Black race, which may primarily reflect low socioeconomic
status
 Presence of antiphospholipid antibodies
 Antiphospholipid syndrome
 High overall disease activity

84. Mortality
 Bimodal mortality
 Early deaths: infection and renal
involvement
 Later deaths: atherosclerotic disease
 Premenopausal women with lupus have
30-50x higher risk of CAD than their non-
lupus counterparts

89. THANKYOU