cp lec 6 systemic rheumatic diseases

8/8/2019 Cp Lec 6 Systemic Rheumatic Diseases

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SYSTEMIC RHEUMATICDISEASES

SYSTEMIC RHEUMATICDISEASES

UST-FMS Dept. of Lab. Medicine


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Systemic Rheumatic DiseasesSystemic Rheumatic Diseases

1. Systemic Lupus Erythematosus

2. Sjogrens Syndrome3. Progressive Systemic Sclerosis

4. Rheumatoid Arthritis

5. Mixed Connective Tissue Disease



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GENERAL CHARACTERISTICSGENERAL CHARACTERISTICS

1. Unknown etiology

2. Multi-organ involvement

3. B cell hyperactivity4. Autoantibody formation, especially

antinuclear antibodies

5. Overlap syndromes



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(contd)(contd)

6. Genetic predisposition

7. Increased frequency in women of child-

bearing age8. Tissue injury caused by immune

mechanisms, often auto-antibodies or

immune complexes



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SYSTEMIC LUPUSERYTHEMATOSUSSYSTEMIC LUPUSERYTHEMATOSUS

A chronic multi-systemic disease of unknown

etiology

Usually involves the skin, associated withathralgia, fever, glomerulonephritis,

pericarditis, pleuritis, CNS dse, splenomegaly

& lymphadenopathies

Active nephritis most common cause ofdeath



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(contd)(contd)

Circulating autoimmune complexes of

antinuclear antibodies & their antigens are

the majorcauses

of pathologic changes: Immune complex deposition in the

glomerular capillary basement

membranes & at the dermo-epidermal

junction fixation to the site activation of complement system

inflammatory reaction & tissue injury results



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(contd)(contd)

Contributing factors: chronic viral infection,

heredity, environment, hormones

Role of drugs: procainamide & hydralazinecan induce a lupus-like syndrome

ANA & LE cells in 90% of patients



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ARA CRITERIA FOR SLEDIAGNOSIS

ARA CRITERIA FOR SLEDIAGNOSIS


Malar or discoid rash False positive test for

syphilis

Photosenstivity Anti-DNA, anti-SM

Oral or nasopharyngeal

ulcers

Urinary casts or

proteinuria

Non-erosive arthritis Pericarditis or pleuritis

Antinuclear antibody Psychosis or seizures

Hemolytic anemia, leukopenia, thrombocytopenia


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COMMON ABNORMALITIESIN SLE

COMMON ABNORMALITIESIN SLE


Antinuclear antibody 99%

Arthritis/arthralgia 92%

Fever 84%Dermatitis, photosensitivity 72%

Adenopathy 59%

Anemia 56%

Anorexia, nausea, vomiting 53%

Myalgia 48%


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COMMON ABNORMALITIESIN SLE (contd)

COMMON ABNORMALITIESIN SLE (contd)


Renal Disease 46%

Pleuritis 45%

Leukopenia 43%Pericarditis 30%

CNS symptoms 26%


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PATHOLOGICABNORMALITIES IN SLE

PATHOLOGICABNORMALITIES IN SLE


Kidney

Proliferative glomerulonephritis, wire

loop common; hematoxylin bodies rare;

occasionally membranous nephropathy

Heart Libman-Sacks (nonbacterial)

endocarditis; pericarditis

Skin Chronic dermatitis with basal cell

vacuolation & fibrinoid degenaration ofconnective tissue

CNS Cerebral vasculitis; focal gliosis


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...PATHOLOGICABNORMALITIES IN SLE...PATHOLOGICABNORMALITIES IN SLE


Lung Interstitial pneumonitis; pleuritis

Spleen Onion-skin fibrosis in perivascular

connective tissue

Lymph

nodes

Follicular hyperplasia, plasmacytosis,

focal necrosis

Peripheral blood

Anemia, leukopenia, thrombocytopenia


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ARA REVISED CRITERIA FORCLASSIFICATION OF SYSTEMICLUPUS ERYTHEMATOSUS

ARA REVISED CRITERIA FORCLASSIFICATION OF SYSTEMICLUPUS ERYTHEMATOSUS

Malar rash

Discoid rash

Photosensitivity

Oral ulcers

Arthritis

Serositis

Renal disorder



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(contd)(contd)

Neurologic disorder

Hematologic disorder

Immunologic disorderPositive LE cell preparation

Anti-DNA in abnormal titer

Anti-Sm antibody to Sm nuclear antigenFalse-positive serologic test for syphilis



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CLASSIFICATION OF LUPUSNEPHRITIS

CLASSIFICATION OF LUPUSNEPHRITIS


Nomenclature Frequency Location of deposits

Focal

Proliferative

25% Focal subendothelial

(+mesangial)

Diffuse

proliferative

45% Diffuse

subendothelial

Mesangial 20% Mesangial only

Membranous 15% Subepithelial(+mesangial)

Normal 5% ---


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ANTINUECLEAR ANTIBODYPATTERNS AND SPECIFICITIESANTINUECLEAR ANTIBODYPATTERNS AND SPECIFICITIES


PATTERN SPECIFICITY

Diffuse (homogeneous) Double-stranded DNA

Histones

Speckled Ribonucleoprotein(RNP)

Sm antigen

DNA topoisomerase I

Ro/La antigen

Nucleolar Nucleolar RNA (4-6S)

protein

RNA polyisomerase I


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ANTINUECLEAR ANTIBODYPATTERNS AND SPECIFICITIESANTINUECLEAR ANTIBODYPATTERNS AND SPECIFICITIES


PATTERN SPECIFICITY

Nucelolar Nucleolar RNA (4-6S)

protein

RNA polymerase I

Fibrillarin

PM-Sc/antigen

Peripheral Double-stranded DNA;Nuclear membrane

antigens

Centromeric Kinetrochore proteins


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SYSTEMIC LUPUSERYTHEMATOSUS

SYSTEMIC LUPUSERYTHEMATOSUS

LABORATORY FINDINGS

Immunologic Abnormalities:

Presence of ANA (98%) Presence of anti-DNA antibodies (ds or

native) highly specific for SLE; active renal

disease (90%) & active disease without

renal involvement (50%)

titers reflect disease activity



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(contd)(contd)

Antibodies against extractable nuclear

antigens

Include nuclear ribo-nucleo protein (nRNP) &nuclear non-nucleic acid glycoprotein (Smith

[Sm] antigen)

The latter appears to be highly specific for

patients with SLE; present in 25% ofpatients with SLE



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(contd)(contd)

Positive test for LE cells (70%-85%) specific

for SLE but not as sensitive as ANA

LE cells may be seen in synovial, pleural &pericardial fluid

Presence of circulating immune complexes &

decrease serum complement indicate

active disease



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(contd)(contd)

Increased K-globulin (80%) reflects

increased immunologic activity

Presence of rheumatoid factor (20% -35%)reflects increased immunoglobulins

False-positive nontreponemal test for syphilis

(15%-20%) reflects increased

immunoglobulins



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Hematologic FindingsHematologic Findings

Mild-normocytic anemia (50% -80%)

Moderate leukopeniaLymphocytopenia due to lymphocytotoxic

antibodies (the most frequent initial

laboratory finding)

Thrombocytopenia



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PLASMA PROTEINSPLASMA PROTEINS

Decreased serum albumin (50%-60%)

reflects chronic renal pathology

seen in lupus nephritis Increased sedimentation rate


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UrinalysisUrinalysis

Hematuria, cellular casts & proteinuria

reflect active lupus nephritis


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SYNOVIAL FLUIDSYNOVIAL FLUID

Low WBC count (


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SPINAL FLUIDSPINAL FLUID

Findings of aseptic meningitis


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BIOPSY OF KIDNEY & SKINBIOPSY OF KIDNEY & SKIN

Immunofluorescent studies show

deposits of immunoglobulins &

complement


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POLYMYOSITISPOLYMYOSITIS

An autoimmune disorder of

unknown etiology

Diffuse inflammation & weakness ofskeletal muscles

May occur alone or in association with

tissue disorders like SLE, Sjogrensor scleroderma


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(CONTD)(CONTD)

DERMATOMYOSITIS is seen in 40% of

cases, usually in children & adults with

occult neoplasms17% of cases are older than 40 yrs old

& have associated carcinoma


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Laboratory Findings:

Mild to moderately increased in ESR,

correlates with disease activityIncreased in CPK (MM & MB) &

aldolase reflect muscle injury &

disease activity


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LDH & AST usually elevated

Increase LDH isoenzymes LDH2 toLDH5, especially LDH5 indicate

active muscle necrosis


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Slight increased in K-globulin

Occasionally, (+) rheumatoid factorPresence of antibody against PM-1 antigen

(a non-histone acid nuclear antigen often

associated with polymyositis)

Occassionally, presence of ANA

Mild, normocytic anemia


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Muscle biopsy : inflammation & muscle

degeneration & regenerationIncreased urinary creatine-creatinine

ratio, reflects increased release &

excretion of creatine from necroticmuscle


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SCLERODERMASCLERODERMA

Literally hard skin an uncommon multi-

systemic disorder affecting

connective tissues & small bloodvessels of unknown etiology

aka - systemic sclerosis

Skin involvement: most prominent

feature, results to scarring


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SCLERODERMASCLERODERMA

Diverse features: RAYNAUDS

Phenomenon (pallor, cyanosis,

reddening, swelling of toes & fingers);impaired swallowing & GI motility, heart,

lung, kidneys, musculoskeletal &

neurologic system

40% of death: due to malignant

hypertension & renal failure


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Pathogenesis:Pathogenesis:

Immunologically mediated injury to

small blood vessels & capillaries

vascular occlusion decreased bloodflow injury to surrounding connective

tissues stimulating fibroblast

proliferation & increased collagen

deposition


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(contd)(contd)

Presence of small amounts of

cryoglobulins (50%)

Absence of antibodies to native DNA &

Sm antigen

Biopsy of skin late in the disease


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Laboratory Findings that ReflectSpecific Organ InvolvementLaboratory Findings that ReflectSpecific Organ Involvement

Kidney sclerodermal renal disease

Small intestine malabsorption

Heart pericarditis

Lung diminished gas diffusion due to

interstitial fibrosis; pneumonia

Muscle - polymyositis


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SJOGRENS SYNDROMESJOGRENS SYNDROME

Autoimmune; oral & ocular dryness

(associated with SLE, scleroderma,

polymyositis)Partial or complete destruction of the

salivary & lacrimal glands by

lymphocytes & plasma cells50% of patients have RA


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(contd)(contd)

Antigenic alteration of salivary gland

tissue sensitization, lymphocytic

infiltration, production ofautoantibodies against the salivary &

lacrimal glands damage ensue


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SJOGRENS SYNDROMESJOGRENS SYNDROME

LABORATORY FINDINGS

Immunologic Abnormalities

(+) rheumatoid factor (75%-90%)

(+) ANA (50%-80%)


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(cont,d)(cont,d)

Presence of antibody to nonhistone

antigen, SS-B (60%)

Presence of antibody to nonhistoneantigen, SS-A (70%)

Occasionally, salivary-duct antibody

Lip biopsy : lymphocytic infiltration ofthe salivary glands


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(contd)(contd)

Other Laboratory Findings

Mild normocytic anemia

Leukopenia

Increased ESR (>90%)

Markedly increased K-globulins

(50%), esp IgA


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MIXED CONNECTIVE TISSUEDISEASE

MIXED CONNECTIVE TISSUEDISEASE

Unknown etiology, characterized by

varying features of SLE,

scleroderma & polymyositisS/S: polyarthralgia or polyarthritis,

diffuse swelling of the hands,

Raynauds phenomenon, impaired

esophageal motility, myositis,

reduced pulmonary lung capacity.


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MIXED CONNECTIVE TISSUEDISEASE (contd)MIXED CONNECTIVE TISSUEDISEASE (contd)

Increased K-globulin (75%)

(+) rheumatoid factor (50%)

Increased ESR reflects activeinflammation.


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MIXED CONNECTIVE TISSUEDISEASE (contd)MIXED CONNECTIVE TISSUEDISEASE (contd)

Occ, moderate anemia

Occ, moderate leukopeniaIncreased AST, aldolase & CPK reflect

muscle involvement


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RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

PATHOGENESIS: Unknown antigenic stimulus synovial tissue in susceptible patient (+) IgGproduction reacts with unknown antigen altered &unrecognized as self formation of IgM (RF) whichbecomes the antibody against the altered IgG (+)soluble immune complexes in synovium activationof complement system chemotactic factors (+)leukocytes leukocytes ingest immune complexestriggers enzymes (e.g. colagenase) & mediators of

inflammation inflammation of synovial liningintermittent course or proliferative synovitis bone-cartilage erosion or tendon destruction permanent

joint damage


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(contd)(contd)

Extra-articular manifestations:subcutaneous rheumatoid nodules,

Feltys syndrome (splenomegaly &neutropenia) vasculitis, lung disease,

pericarditis, Sjogrens syndrome, ocular,lymphoid & neuromuscular disorders

Biopsy of gum, liver, kidney & rectalmucosa shows amyloidosis in 25% ofcases


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RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

LABORATORY FINDINGS

Synovial Fluid

Yellow to white; turbidityreflects increased WBC; fibrinclot indicates chronicity

Mucin clot may be fair or

poor; a poor clot & decreasedviscosity indicates thathyaluronic acid is decreased


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(contd)(contd)

WBC usually 5,000/ul reflects the

degree of inflammation

Differential WBC 65% neutrophilsGlucose normal or low, interference

in glucose transport


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(contd)(contd)

(+) rheumatoid factor

Decreased complement

Ragocytes neutrophils with ingestedimmune complexes


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(contd)(contd)

Peripheral Blood

WBC: normal or slightly elevated

(


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(contd)(contd)

Other Laboratory Findings

(+) rheumatoid factor (IgM)

75% of patientsPresence of ANA (10%-50%), titers

are lower than in SLE


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(contd)(contd)

Increased C-RP, fibrinogen & ESR:

reflect disease activity

Increased w1 & w2 globulins:acute phase reactants

Increased K-globulin: reflects

accelerated protein breakdown inchronic disease


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(contd)(contd)

decreased complement in the

presence of severe extra-articular

disease, such as vasculitispresence of circulating immune

complexes: frequently when there

are systemic manifestations

PREVA ENCE OFPREVA ENCE OF


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PREVALENCE OFRHEUMATOID FACTOR (%)PREVALENCE OFRHEUMATOID FACTOR (%)CONDITION FACTOR (%)

Mixed cryoglobulinemia 90-100

Sjogrens syndrome 75-90

Mixed connective tissue disease 50-60Systemic lupus erythematosus 20-30

Scleroderma 20-30

Juvenile rheumatoid arthritis 20Polymyositis 5-10

Hypersensitivity vasculitis 5-15

Tuberculosis 10-20

PREVALENCE OFPREVALENCE OF


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PREVALENCE OFRHEUMATOID FACTOR (%)PREVALENCE OFRHEUMATOID FACTOR (%)

CONDITION FACTOR (%)

Leprosy 10-60

Sarcoidosis 5-33Syphilis 10

Subacute bacterial endocarditis 25-50

Salmonellosis 15-40

PREVALENCE OFPREVALENCE OF


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PREVALENCE OFRHEUMATOID FACTOR (%)PREVALENCE OFRHEUMATOID FACTOR (%)CONDITION FACTOR (%)

Acute rheumatic fever Rare

Acute viral infections (rubella,

mumps, influenza, infectiousmononucleosis)

15-65

Parasitic infections

(schistosomiasis, malaria,

trypanosomiasis

20-90


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cp lec 6 systemic rheumatic diseases

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