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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


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


Systemic connective tissue disease

SYSTEMIC CONNECTIVE TISSUE DISEASE



Systemic lupus erythematosis sle
Systemic Lupus Erythematosis (SLE)


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





Polymyositis and dermatomyositis
Polymyositis and Dermatomyositis


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



Gottron s nodules
Gottron’s Nodules


Differential diagnosis nb
Differential diagnosis (NB)

  • Inclusion body myositis

  • Other causes of proximal muscle weakness

    • See Davidson’s


Sjogren s disease
Sjogren's disease


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)

      (


    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



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