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AUTOIMMUNITY. Johan van Rensburg. What goes wrong?. Tissue damage due to antibodies T cells Etiology multi-factorial environmental genetic specific HLA genotypes. Self antigens. HLA II > HLA I. Tolerance. Tolerance to self-antigens deletion of self-reactive B and T cells

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autoimmunity

AUTOIMMUNITY

Johan van Rensburg

what goes wrong
What goes wrong?
  • Tissue damage due to
    • antibodies
    • T cells
  • Etiology multi-factorial
    • environmental
    • genetic
      • specific HLA genotypes

Self antigens

HLA II > HLA I

tolerance
Tolerance
  • Tolerance to self-antigens
    • deletion of self-reactive B and T cells
      • during maturation in the bone marrow and thymus
  • Recognition of peptide/MHC complexes by peripheral T cells
    • In the absence of costimulatory signals

No activation of potentially

self-reactive T cells

Anergy

tolerance1
Tolerance
  • Regulatory(suppressor) T cells
  • Immunologically privileged sites
    • eye
    • brain

TGFB IL-10

IL-4

Clonal expansion of autoreactive cells

Do not normally encounter immunocompotent cells

Self antigen inaccessible or in to low quantities

autoimmune disease
Autoimmune disease
  • Lack of tolerance
  • Triggered by
    • Infection
    • Other environmental factors
    • Unknown

Increased/ aberrant expression of costimulatory molecules

Changing antigenicity of infected tissue (now a target)

Molecularmimicracy(eg. Rheumatic fever)

Superantigens

Stimulates families of T cells expressing a particular TCR-Vß segment

slide6

GENETIC PREDISPOSITION

MHC-class II genes

Other MHCgenes

Multiple non-MHC genes

Environmental

factors

CD4+ T cell

driving force

(autoreactive)

Autoreactive B cells

CD8+ T-cells

IgG

autoantibodies

Non T cell

effector cells

Cell-mediated

organ damage

Autoantibody mediated

organ damage

in general
In general
  • Most common of multisystem connective tissue disease
    • Geographical
    • Racial
      • Caucasians
        • 30/100 000
      • Afro-caribians
        • 200/100 000
    • Gender
      • 90% Women
    • Age
      • Peak
        • 2nd to 3rd decades
etiology and pathogenesis
Etiology and pathogenesis
  • Polyclonal B and T cell activation
    • Circulating auto-antibodies
      • Multi-organ involvement
        • Wide variety of clinical presentation
      • ~50 autoantigens identified
        • Hidden from Immune system in health
          • Intranuclear
          • Intra-cellular
    • Possible mechanisms
      • Environmental factors
        • Apoptosis
          • Autoantigens expressed on cell surface
        • Induce flares of SLE
          • Pregnancy
          • Infection
          • Sunlight
diagnosis
Diagnosis
  • Revised ACR criteria for SLE
    • 4/11 in present or past
      • 4 mucocutaneous
      • 4 Systems
      • 1 pleura/pericardial/peritoneum (PPP)
      • 2 Auto-antibody
    • Anti-dsDNA
      • 30-50% of patients
      • ANA negative unlikely for SLE
      • Unless (Ro) positive
        • Most have skin rashes
4 mucocutaneous
4 mucocutaneous
  • Malarrash
    • Erythema
      • Fixed
        • Flat
        • Raised
        • Sparing nasolabial folds
  • Discoid rash
    • Erythematous
      • Raised patches
      • Adherent
        • Keratotic scaring
        • Follicular plugging
  • Photosensitivity
    • Skin rash
      • Sun burn areas
  • Oral ulcers
    • May be painless
4 systems
4 Systems
  • Arthritis/arthralgia
    • Non-erosive
    • 2 or more peripheral joints
    • (Jaccoudarthropathy)
  • Renal
    • Proteinuria
      • Persistent
        • >0.5g/day
    • Cellular casts
      • Red cell
      • Granular
      • Tubular
  • Neurological
    • Seizures
    • Psychosis
    • Absence
      • Offending drugs
      • Metabolic derangement
  • Hematological
    • In absence of offending drugs
      • Hemolytic anemia
      • Leucopenia
        • <4000/mm3
          • 2 separate occasions
      • Lymphopenia
        • <1500/mm3
          • 2 separate occasions
      • Thrombocytopenia
        • <100 000/mm3
          • 2 Separate occasions
jaccoud arthritis
JACCOUD ARTHRITIS

Jaccoud Sigismond, French physician, 1830–1913

glomerulonephritis
GLOMERULONEPHRITIS
  • Minimal change
  • Mesangeal
  • Focal proliferative
  • Diffuse proliferative
  • Membranous glomerulonephritis
  • End Stage renal failure
    • (Typical is that the complement is diminished)
1 pleura pericardial peritoneum ppp
1 pleura/pericardial/peritoneum (PPP)
  • Serositis
    • Pleuritis
      • Pleuritic pain
      • Rub
      • Effusion
    • Pericarditis
      • ECG
      • Rub
      • Effusion
2 auto antibody
2 Auto-antibody
  • Immunology
    • Anti-DNA antibodies
    • Anti-SM antibodies
    • Antiphosfolipid antibodies
  • Antinuclear antibodies (ANA)
    • Abnormal titer
      • By immunofluorescence
clinical features more than criteria
Clinical features(more than criteria)
  • Raynaud's phenomenon
  • Musculoskeletal
  • Mucocutaneous
  • Renal
    • Management
  • Cardiopulmonary
  • Central nervous system
  • Hematological
  • Other
classiffication
Classiffication
  • Adult polymiositis
  • Adult dermatomyositis
    • Important
      • Malignancy
  • Childhood dermatomyositis
clinical picture
Clinical picture
  • Proximal muscle weakness
  • Skin manifestations
    • NOT typically sun exposed areas
      • Malar rash
      • Heliotropic rash
      • V-sign
      • Shawel sign
      • Gottron’s nodules
      • Mechanic hands
malar and heliotropic rash
MALAR AND HELIOTROPIC RASH

Upper eyelid

Involving nasolabial folds

differential diagnosis nb
Differential diagnosis (NB)
  • Inclusion body myositis
  • Other causes of proximal muscle weakness
    • See Davidson’s
clinical features
Clinical features
  • Risk markers
  • Common clinical features
  • Less common features
  • Auto antibodies
  • Associated autoimmune disorders
scleroderma systemic sclerosis
Scleroderma (systemic sclerosis)

Scleros: hard

Derma: skin

systemic sclerosis
SYSTEMIC SCLEROSIS

Multisystem disorder

Fibrosis of the skin, bloodvessels, and viseral organs

Affected organs: Lungs

Heart

Kidneys

GIT

classification
CLASSIFICATION
  • Limitedcutaneous disease
  • Diffusecutaneous disease
  • Sinescleroderma
  • Undifferentiated connective tissue disease
  • Overlapsyndromes
limited cutaneous scleroderma
Limited cutaneous scleroderma
  • Skin thickening: Distal to elbow and knee

Face and neck

  • Synonym: CREST Syndrome
diffuse cutaneous scleroderma
Diffuse cutaneous scleroderma
  • Skin thickening includes: Trunk

Face

Proximal extremities

Distal extremities

sine scleroderma
Sine scleroderma
  • Internal organ manifestations
  • Vascular abnormalities
  • Serologic abnormalities
  • Noclinical detectable skin change
undifferentiated connective tissue disease
Undifferentiated connective tissue disease
  • Raynaud’sphenomenon
  • Clinical and/or serologic features of systemic sclerosis (digital ulceration, abnormal nail fold capillary loops, s-anticentromere antibody, finger edema)
overlap syndrome
Overlap syndrome
  • Systemic sclerosis in association with other connective tissue disorders
  • Eg; SLE

Inflamatory muscle disease

RA

incidence
INCIDENCE
  • 4-12/million/year (may be more than fourfold higher)
  • All geographic areas
  • All racial groups
  • All ages (Peak onset between 30 and 50)
  • M:F - 4:1 (Childbearing age at peak risk)
  • Sporadically (weak links to exposure to environmental toxins eg. silica and silicone)
familial ssc
Familial SSc
  • Other connective tissue diseases and autoantibodies in relatives - ?hereditary
  • Increased ANA in spouses - ?environmental
  • Relationship between HLA types and specific autoantibodies:

Anticentromere antibodies: HLA-DR1, -DR4, -DR5,

-DQB1

Antitopoisomerase antibodies: HLA-DR5,-DQB1

pathogenesis
PATHOGENESIS
  • Immunologic mechanisms
  • Vascular damage
  • Activation of fibroblasts
  • Overproduction and accumulation of collagen and other extracellular matrix proteins in skin and other organs
clinical manifestations
Raynaud’s phenomenon

Skin thickening

Subcutaneous calcinosis

Telangiectasia

Arthralgias / arthritis

Myopathy

Esophageal dysmotility

Pulmonary fibrosis

Isolated pulmonary arterial hypertention

Congestive heart failure

Renal crisis

CLINICAL MANIFESTATIONS
raynaud s phenomenon
Raynaud’s phenomenon
  • Episodic vasoconstriction of small arteries and arterioles of fingers, toes, and tip of nose (brought on by cold, vibration, or emotional stress)
  • May precede skin changes by months / years (tipically within a year)
  • Frequently the first symptoms of SSc
  • 95% of SSc patients
  • History of digit pallor (most reliable symptom)
  • After two or more years: few develop SSc
skin features
Skin Features
  • Early disease: Swollen fingers and hands,

relatively spared lower

extremities

  • Indurative phase: Skin becomes firm and

thickend - eventually tightly

bound to underlying

subcutanious tissue

skin features1
Skin Features
  • From distal to proximal
  • Rapid progression over 2- to 3-years: associated with greater risk for visceral dissease
  • Diffuse cutaneous scleroderma: Changes usually peak in 3 to 5 years and then slowly improves
  • Limited cutaneous Scleroderma: More gradual progression and may continue to worsen
  • Complications: Flexion contractures

Ulcers and secondary infection

Resorption of terminal phalanges

Dark pigmentation of skin

(also hypo- pigmentation)

Dry and coarse

skin features2
Skin Features
  • Subcutaneous calcinosis:

Periarticular, digital pads, olecranon and prepatellarbursae, along extensor areas of forearms

  • Face:

Loss of wrinkles and facial expresion

Microstomia and perpendicular wrinkles to lips

Pinched or beadlike nose

telangiectasia
Telangiectasia
  • On fingers, face, lips, tongue, and buccal mucosa
  • After several years
  • Limited scleroderma (85%)
  • Diffuse scleroderma (40%)
  • Capillary beds of nail folds:

Limited form: enlargement of capillaries

with little or no capillary loss

Diffuse form:disorganization of capillary beds with

dilated capillaries interspersed with areas where

capillaries have disapeared

musculoskeletal features
Musculoskeletal Features
  • Symmetric polyarthritis(like RA)
  • Leathery crepitation over moving joints
  • Carpal tunnel syndrome
  • Muscle weakness(disuse and atrophy)
  • Myopathy(Normal muscle enzymes)
  • Myositis(proximal weakness and raised muscle enzymes)
  • Bone resorption(terminal phalanges, ribs, clavicle, angle of mandible)
git features
GIT Features
  • Dysphagia
  • GERD and peptic esophagitis
  • Barrett’s metaplasia
  • Delayed gastric emptying
  • Pseudo-obstruction of small intestine
  • Malabsorption syndrome
  • Pneumatosis intestinalis
  • Benign pneumoperitonium
  • Chronic constipation and fecal impaction
  • Intussuception
  • Diverticulae
  • Incontinance and anal prolapse
  • GIT- bleeding (because of telangiectasia)
pulmonary features
Pulmonary Features
  • Exertional dyspnea
  • Dry non-productive cough
  • Restrictive lung disease:

Pulmonary fibrosis (40%)

Restriction of skin movement

  • Aspiration pneumonia
  • Alveolar cell and bronchogenic carcinoma
  • Pulmonary arterial hypertension (mean survival then plus-minus 2 years)
cardiac features
Cardiac Features
  • Pericarditis
  • Heart failure
  • Heart block and arrhythmias
  • Angina pectoris (some have normal angiograms)
  • Cor-pulmonale
renal features
Renal Features
  • Mostly those with diffuse cutaneous scleroderma
  • Renal crisis:
    • Malignant hypertension, wich can rapidly progress to renal failure
    • Presents with encephalopathy, severe headache, retinopathy, seisures, and left ventricular failure
    • Hematuria and proteinuria followed by oliguria and renal failure
  • Indicator of impending renal failure
    • Microangiopathic anemia
    • Chronic pericardial effusion
other features
Other Features
  • Sicca-syndrome
      • Sjogren’s
      • Intra- and periglandular fibrosis
  • Hypothyroidism
      • Antithyroid antibodies
      • Fibrosis of the thyroid
  • Trigeminal neuralgia
  • Male impotence
  • Biliary cirrhosis
laboratory findings
Laboratory Findings
  • Raised ESR
  • Hypoproliferative anemia
  • Iron deficiancy anemia
  • Macrocytic anemia (B12 and folic acid deficiancy)
  • Microangiopathic hemolytic anemia
  • Hypergammaglobulinemia (mostly IgG)
  • RF positive in 25%
  • ANA positive in 95% (Hep-2)
autoantibodies in ssc
Autoantibodies in SSc
  • Antitopoisomerase 1 (Scl-70)
        • 40% in diff. cut. ssc.
  • Anticentromere
        • 60-80% in lim. cut. Ssc.
diagnosis1
Diagnosis
  • Raynuad’s with tipical skin lesions and visceral involvement
  • Linear scleroderma and morphea
  • Sine scleroderma
    • Unexplained
      • Pulmonary fibrosis
      • Pulmonary hypertension
      • Cardiomyopathies
      • Heart block
      • Dysphasia
      • Malabsorption
other causes of raynaud s
Other causes of Raynaud’s
  • Thoracic outlet syndromes
  • Shoulder-hand syndrome
  • Trauma
  • Previous cold injury
  • Vinyl chloride exposure
  • Circulating cryoglobulins or cold agglutinins
chemically induced scleroderma like disorders
Chemically induced scleroderma-like disorders
  • Toxic-oil syndrome
  • Vinyl chloride-induced disease
  • Bleomycin-induced fibrosis
  • Pentazocine-induced fibrosis
  • Epoxy- and aromatic hydrocarbons-induced fibrosis
  • Eosinophilia-myalgia syndrome
other scleroderma like disorders
Other scleroderma-like disorders
  • Sclerema adultorum of Buschke
  • Scleromyxedema
  • Scleredema
  • Chronic graft-vs.-host disease
  • Eosinophilic fasciitis
  • Digital sclerosis in diabetes
  • Primary amyloidosis and amyloidosis associated with multiple myeloma
prognosis
PROGNOSIS
  • Limited cutaneous scleroderma (anti centromere antibodies) - Good prognosis with exception of pulmonary arterial hypertension (< 10%)
  • Diffuse cutaneous disease - Worse prognosis - Viceral organ disease develop early
  • Males - Worse prognosis
  • Overall 5 year survival: 86%
  • Overall 10 year survival: 69%

(HESSELSTRAND, ET AL: MORTALITY AND CAUSES OF DEATH IN A SWEDISH SERIES OF SYSTEMIC SCLEROSIS PATIENTS. ANN RHEUM DIS 1998;57:682-686)

causes of death
CAUSES OF DEATH
  • Pulmonary complications (Most frequent) - Fibrosis - Pulmonary Hipertension - Pneumonia - Pulmonary Malignancy (Mostly adenocarcinomas)
  • Cardiovascular
  • Renal crisis (< frequent since ACE-inhibitors)

HESSELSTRAND, ET AL: MORTALITY AND CAUSES OF DEATH IN A SWEDISH SERIES OF SYSTEMIC SCLEROSIS PATIENTS. ANN RHEUM DIS 1998;57:682-686)

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treatment
Treatment
  • Cannot be cured
  • Treatment of involved organ systems
    • Relieve symptoms
    • Improves function
  • Doctor-patient relationship is important
    • Explanations and reassurances
  • Monitor
    • Blood counts
    • Urinalysis
    • Renal function
    • Pulmonary function
immunosuppressives
Immunosuppressives
  • Entelin-1 receptor antagonists
  • Azathioprine
    • With life-treatening disease
    • Studies are lacking
antiplatelet therapy
Antiplatelet Therapy
  • Aspirin
    • Block the formation of Thromboxane A2
  • Dipyridamole
    • Decreases platelet adhesion

A two year double blind study did not show any benefit

glucocorticoids
Glucocorticoids
  • Inflammatory myositis
  • Pericaditis
  • May decrease edema of edematous phase
  • Not for long term treatment of SSc
  • High dosis may precipitate renal failure
management of raynaud s
Management of Raynaud’s
  • General
      • Dress warmly
      • NO SMOKING
      • Remove causes of external stress
      • Avoid drugs like amphetamine and ergotamine
      • NO beta-blockers
  • Blockers of sympathetic vasoconstriction
      • Reserpine, methyldopa, phenoxibenzamine, prazocin
  • Calcium channel blockers
      • Adalat XL
  • Other
      • Ketanserine (serotonin antagonist)
      • Iloprost
      • Pentoxifylline
renal crisis
RENAL CRISIS
  • ACE-Inhibitors
  • Dialysis
  • Treat hypertension
    • Beware of beta-blockers