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Todays Quranic verse

And hold fast, all together, by the rope which God (stretches out for you), and be not divided among

yourselves; and remember with gratitude God's

favour on you; for ye were enemies and He joined your hearts in love, so that by His Grace, ye became brethren; and ye were on the brink of the pit of Fire, and He saved you from it. Thus dothGod make His Signs clear to you: That ye may be

guided. [003:103]

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Todays Quranic verse

And hold fast, all together, by the rope which God (stretches out for you), and be not divided among

yourselves; and remember with gratitude God's

favour on you; for ye were enemies and He joined your hearts in love, so that by His Grace, ye became brethren; and ye were on the brink of the pit of Fire, and He saved you from it. Thus dothGod make His Signs clear to you: That ye may be

guided. [003:103]

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If one advances confidently in the directionof his dreams, he will meet with a successunexpected in common hours

"Shoot for the moon. Even if you missit, you will land among the stars.!"

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AUTOIMMUNE DISEASES

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Autoimmunity Autoimmunity = immune reaction against self

Self-tolerance breaks down, causing disease

Two main reasons for breakdown:

Genes HLA-DR4: risk of rheumatoid arthritis HLA-B27: risk of ankylosing spondylitis

Environmental triggers

Expose hidden self-antigens Activate APCs Mimic self antigens

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Autoimmune Diseases

Loss of the ability of the cells of the immune systemto distinguish between self and non-self

May be present in two forms: Systemic, multiorgan disease Organ-specific disease limited to a single organ

Diagnosis is made when: 1) Existence of autoantibodies can be documented

2) Evidence that immune mechanisms are causing pathologic lesions3) Direct or indirect evidence of the immune nature of the order

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Autoimmune Diseases Systemic Diseases Systemic lupus erythematosus (SLE) Rheumatic fever Rheumatoid arthritis Sjgren syndrome Reiter syndrome

Inflammatory myopathy Systemic sclerosis Polyarteritis nodosa

Organ-Specific Diseases Brain: encephalomyelitis & multiple sclerosis Thyroid: Hashimoto s & Graves disease

Blood: autoimmune hemolytic anemia Stomach: atrophic gastritis of pernicious anemia Testis: Autoimmune orchitis Kidney: Goodpasture Platelet: Autoimmune thrombocytopenia

Muscle: myasthenia gravis Type 1 diabetese mellitus Skin: pemphigus vulgaris PBC, CAH, MGN, UC etc

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Connective tissue diseases

Systemic lupus erythematosus Scleroderma

localised (CREST) Systemic (systemic sclerosis)

Myositis/Dermatomyositis Sjogren s syndrome

Mixed connective tissue disease SLE + SS + DM (RNP antibodies)

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SYSTEMIC

LUPUS ERYTHEMATOSUS(SLE)

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Systemic Lupus Erythematosis

Definition:

Commonest autoimmune, inflammatory multisystemdisease of unknown cause, associated with pathogenicautoantibodies resulting in immune complex formationand complement mediated tissue damage, with diverseclinical and laboratory manifestations and Characterizedby remissions & relapses and variable course andprognosis

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SLE-Epidemiology

Relatively common: prevalence rate = 1/2,500 persons-- 1/700 adult women

Strong female predilection (9:1 female:male ratio)

Most common in young adults and middle age(onset: usually second/third decade; can be any age)

More common, more severe in blacks(1/245 adult black females)

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Aetiology

The cause is unknown but there are several predisposing factors:

- Heredity- Genetics- Complement- Sex hormone status

Premenopausal women are most frequently affected.- Immunological factors

Loss of self -tolerance has several consequences- Environmental tiggers

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Etiologic Factors in Systemic Lupus

Genetic factors in SLE: 1. High rate of concordance in monozygotic twins (25%) v. dizygotic twins (1-3%)

2. Up to 20% of clinically normal first degree relatives have autoantibodies 3. Positive association between SLE and class II HLA genes

Environmental factors in SLE: 1. Certain drugs

e.g. procainamide:15-20% will have ANA & clinical features of SLE after 6 months

e.g. hydralazine

2. Sex hormones Estrogen aids in antibody synthesis Explains female predominance?

3. Ultraviolet rays Exacerbates the symptoms and signs Damaged DNA released for antibody attack?

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Systemic Lupus ErythematosusPathogenesis

1. Basic problem: failure to maintain self-tolerance

2. ANAs : against DNA , histones , nonhistone proteins bound to RNA (anti-RNA ),nucleolar antigens

Usually detected via indirect immunofluorescence: pattern is important Positive in all SLE patients, therefore, test is very sensitive Problem: test is not very specific (5-15% of normal persons are positive, as often

are those with other autoimmune diseases

3. Some antibodies are diagnostic for SLE: Antibodies to double-stranded DNA Antibodies to Smith (Sm ) antigen

4. Antibodies against blood cells:-- RBCs-- Lymphocytes-- Platelets

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Systemic Lupus ErythematosusPathogenesis

5. 40-50% of patients have antiphospholipid antibodies If combined with cardiolipin antigens : get a false positive syphilis test (serology) Phospholipids are required for clotting: prolonged clotting tests, e.g. PTT (partial

thromboplastin time)Therefore, sometimes called lupus anticoagulants

Clinically : thrombosis, thrombocytopenia, recurrent spontaneous abortion6. Pathogenetic model: Genetic susceptibility, along with unknown environmental

trigger(s), activates CD4+ helper T cell, which react to self-antigen peptides via IgGautoantibody production, which produces most of clinical damage

Thrombus

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Systemic Lupus ErythematosusMechanism of Tissue Injury

1. Visceral lesion: mediated by immune complexes (Type III hypersensitivity)-- e.g. DNA/anti-DNA complexes in glomeruli damage the kidney

2. Blood components: autoantibodies against RBCs, lymphocytes, platelets (Type IIhypersensitivity) enhance coagulation, breakdown cells

3. If nucleus is exposed to blood via tissue damage: ANAs attack LE bodies (hematoxylin bodies ): nuclei with homogeneous chromatin after ANA

attack Once blood cells are damaged >> exposed nuclei >> ANA attack via complement

activation >> nuclei get phagocytized by neutrophils and macrophages:(LE cell ; 70% of SLE patients have this)

A i l A ib di

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Antinuclear AntibodiesFound in many autoimmune diseasesSerologic evidence for antibodies directed at components of "self" cell nuclei.These antibodies are very useful for diagnosis & categorization of autoimmune diseases.

ANA (antinuclear antibody): In general, the higher the titer, the worse the diseaseCharacteristic fluorescent staining patterns for ANA may indicate a specific diseaseDetected by indirect immunofluorescence or immunoenzyme assays

ANAs can be divided into:

those directed against dsDNAthose directed against ssDNA

those directed against histonesthose directed against non-histonenuclear proteins :nucleic acid-protein complexes

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Immunofluorescent staining of ANAs

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Patterns of IF stainingFour patterns of staining are seen:

1. Homogenous (diffuse) dsDNA, histoneseen in SLE, drug induced SLE, RA

2. Speckledseen in MCTD, SLE, Sjogren, Systemic Sclerosis

3. Nucleolar seen in Systemic Sclerosis, Sjogren, SLE

4. Rim (peripheral)dsDNA, histonescharacteristic of SLE

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ANAs in SLE

Autoantibody anti ds DNA anti ss-DNA

anti- Histones anti- Sm ( Smith) anti- RNP anti- Ro ( SSA) anti-La ( SSB)

Prevalence 50% 60-70%

70% 30% 35% 30% 15%

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Systemic Lupus Erythematosus

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Systemic Lupus ErythematosusClinical Manifestations

Multi-system autoimmune disease with variablepresentations and behaviors.

Acute or insidious onsetFatigue, Fever, Weight lossUsually affects: skin, kidneys, serosal membranes,

joints, heart

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Acute necrotizing vasculitis Affects small arteries and arterioles Necrosis and fibrinoid deposits within vessel walls that contain

antibody, DNA, complement fragments & fibrinogen Fibrous thickening and luminal narrowing of vessels

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Skin Erythematous or maculopapular eruption over the malar eminences

and bridge of nose (butterfly pattern) Exposure to sunlight exacerbates the erythema

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Photosensitivity Butterfly facial rash Discoid rashes

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Arthritis-A rthralgia

-Symmetrical, non-erosive synovitis-Jacoub s arthropathy (reducible deformities) -Nodules possible

R d h

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Raynaud sphenomenon

Livedo reticularis

Alopeciadiffuse or patchy

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Vasculitic rashes

Oral manifestations

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Oral manifestations

5% to 25% of patients Affect the palate, buccal mucosa, and gingiva Ulceration, pain, erythema, and hyperkeratosis Xerostomia, candidiasis, periodontal disease

Pulmonary features

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Pulmonary features

pleurisy commonestconsider also PE and infection

pulmonary hypertension

pneumonitis/fibrosis or haemorrhage

H

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Heart Pericarditis and myocarditis

Valvular lesions: Libman-Sacks endocarditis Nonbacterial verrucous vegetations Contain fibrin, antibody, and inflammatory cells Occur on either surface of valve leaflets

Premature coronary artery disease

Typical neurological syndromes

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Typical neurological syndromes HeadacheCerebrovascular diseaseSeizure disorderChoreaCognitive dysfunctionPsychosisMononeuropathy (single/multiplex)Polyneuropathy

Vasculitis? Non-inflammatory intimal proliferation attributable to endothelialinjury from antiphospholipid antibodies

d f f

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Reproductive features of SLERecurrent Miscarriages

Fetal growth retardation

Neonatal lupus syndrome

Congenital heart block

Premature menopause

Antiphospholipid antibody syndrome

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Antiphospholipid antibody syndrome Recurrent venous thrombosis

deep vein thrombosis pulmonary embolus

Recurrent arterial thrombosis

myocardial infarction stroke (cerebro-vascular accident)

Recurrent miscarriages

Kidneys

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Kidneys Renal failure is the most common cause of death

Pathogenesis involves the deposition of DNA/anti-DNA complexesleading to an inflammatory response causing a proliferation of endothelial, mesangial, and/or epithelial cells

Focal proliferative glomerulonephritis Diffuse proliferative glomerulonephritis

Membranous glomerulonephritis

Systemic lupus erythematosus:classification of nephritis

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y p y p

Class-I Normal glomerulia) Nil by all techniquesb) Normal by light but deposits on EM or IF

Class-II Mesangial glomerulonephritis (20%)

Class-III Focal glomerulonephritis (25%)

Class-IV Diffuse glomerulonephritis (50%)

Class-V Diffuse membranous glomerulonephritis (15%)

Class-VI Advanced sclerosing glomerulonephritis

Clinically characterized by proteinuria, hematuria, pyuria, casts

Kidneys

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Kidneys

Focal proliferative glomerulonephritis 25% of cases Involves portions of

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y Diffuse proliferative glomerulonephritis

Most serious renal lesion in SLE

Most common renal lesion (50% of patients) Endothelial and mesangial proliferation of the entire glomerulus Wire loops - thickening of the capillary loops due to subendothelial immune

complexes Hematuria, severe proteinuria, hypertension

Kidneys

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Kidneys Membranous glomerulonephritis

15% of cases Widespread thickening of the capillary walls due to increased deposition of

basement membrane material and immune complexes Severe proteinuria

L b t f t

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Laboratory features Anaemia

haemolytic anaemia secondary to chronic disease blood loss (drugs?)

Leucopenia (drugs?)

lymphopenia neutropenia

Thrombocytopenia ESR/CRP

Urinalysis Renal function

IgG/autoantibodies (ANA) anti-dsDNA Abs (& ENA) Complement (C3,C4,C3d)

APTT Anti-cardiolipin antibodies

Auto antibodies in SLE to:

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Auto antibodies in SLE to:

dsDNA 60% patients increased risk nephritis

Cardiolipin 10-30% thrombosis, fetal loss

Ro and La 20-60% and 15-40% cutaneous & neonatal lupus

and congenital heart block Sm

10-30% ?nephritis and CNS disease

RNP 10-30%

Mixed connective tissuedisease

Histones- drug induced lupus

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Connective Tissue Diseases

Disease AutoantibodySystemic Lupus Erythematosus Anti-dsDNA, Anti-SMRheumatoid Arthritis RF, Anti-RA33Sjogrens Syndrome Anti-Ro (SS-A), Anti-La (SS-B)Systemic Sclerosis Anti-Scl-70, Anti-centromerePolymyositis/Dermatomyositis Anti-Jo-1Mixed Connective Tissue Disease Anti-U1-RNP

Wegener s Granulomatosus c-ANCA

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Systemic lupus erythematosus: 1982

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classification criteria

Malar rash

Discoid rash

Photosensitivity

Oral ulcers

Arthritis

Serositis

Renal disorder

Neurologic disorder

Hematologic disorder

Immunologic disorder

Antinuclear antibody

Systemic lupus erythematosus: 1982

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classification criteria definitions

Malar rash Fixed erythema, flat or raised, sparing the nasolabial folds

Discoid rash Raised patches, adherent keratotic scaling, follicularplugging; older lesions may cause scarring

Photosensitivity Skin rash from sunlight

Oral/nasopharyngeal Usually painless ulcers

Arthritis Nonerosive, inflammatory in two or more peripheral joints

Serositis Pleuritis or pericarditis

Systemic lupus erythematosus: 1982

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classification criteria definitions, cont d

Renal disorder Persistent proteinuria or cellular casts

Neurologic disorder Seizures or psychosis

Hematologic Hemolytic anemia, leukopenia (

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g

NSAID (care!)

Corticosteroids -topical, low dose or high dose (oral/IM/IV)

Antimalarials (e.g. hydroxychloroquine)

Immunosuppressants - cyclophosphamide, azathioprine,cyclosporin A, methotrexate

Monitoring and education ( Sunblock, infection, fertility)

Prognosis

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Prognosis Clinically unpredictable Course of SLE is extremely variable Remissions and relapses Most severe is renal disease leading to hematuria, proteinuria, renal

failure, and hypertension Most common cause of death are renal failure & intercurrent infections

followed by diffuse CNS disease 5-year survival rate = 90% 10-year survival rate = 80%

Drug-induced lupus erythematosus

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240

Procainamide, hydralazin, Isoniazid, penicillamine, etc.

Anti-histone antibodies are characteristic but non-specific-

anti-native DNA is almost never detected.

Multiorgan involvement however, renal and central nervous system affection isuncommon.

Remission of the disease after cessation of the offending drug.

Drugs causing lupus like syndrome do not seem to aggravate primary SLE

Autoantibody-disease associations: SLE andd d d l

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drug-induced lupus

Antigen SLE Drug-Induced LEdsDNA 40% No

ssDNA 70% 75%-80%

Histone 70% >95%

Sm antigen 30% No

Nuclear RNP 30% No

Ribosomal RNP 10%

SS-A/Ro 35% NoSS-B/La 15% No

Neonatal Lupus

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p1. Neonatal cutaneous lupus 2. Congenital heart block

Occurs in women with:- anti Ro\SSA - anti La\SSB- anti U1 RNP

Due to placental transmission of maternal IgG abs

The mother may be : asymptomatic, have SLE, Sjogren syn, otherrheumatic disease.

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RHEUMATOID ARTHRITIS

Rheumatoid arthritis

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Rheumatoid arthritis

Chronic inflammatory disease that primarily affects the joints but may affect other organs and tissues (skin, bloodvessels, heart, lungs)

Hallmark is a nonsuppurative proliferative synovitis thatleads to destruction of articular cartilage and bone resultingin arthritis

Women > men (5:1) Peak incidence: 2nd to 4th decades of life

Morphology

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Morphology Symmetric arthritis

Small joints of hands and feet, ankles, knees, wrists,elbows, and shoulders

Chronic synovitis

Synovial cell hyperplasia and proliferation Perivascular inflammatory cell infiltrates - CD4+ T

cells, plasma cells, macrophages Increased vascularity

Morphology

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Morphology Symmetric arthritis

Chronic synovitisNeutrophils and fibrin on the synovial surface and in the joint spaceIncreased osteoclastic activity in the underlying bone

Pannus: Proliferating synovial cells, inflammatory cells, granulation tissue, andfibrous connective tissue

Erosion of the articular cartilage and bone leads to fibrosis, calcification,

and ankylosis

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Morphology

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Rheumatoid subcutaneous nodules 25% of patients Areas of mechanical trauma: extensor surface of the

forearm, tibia, Achilles tendon Central fibrinoid necrosis surrounded by macrophages

and granulation tissue Acute necrotizing vasculitis

Small or large arteries

Etiology

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gy Genetic predisposition

Association with HLA-DR1 and HLA-DR4 Immunologically mediated joint inflammation

Interaction between CD4+ T cells, cytokines, B cells,and macrophages

Rheumatoid factor 80% of patients IgM autoantibody directed against Fc portion of IgG Present in serum and synovial fluid

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Clinical course

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Weakness, malaise, low-grade fever Aching and stiffness of joints in the morning Joints become enlarged and motion is limited Radial deviation of the wrists and ulnar deviation of the

fingers Clinical course is variable: most patients are severely

crippled at 15-20 years Amyloidosis develops in 5-10% of patients

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