AUTOIMMUNITY

Publish in

Documents

35 views

Please download to get full document.

View again

of 83
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Share
Description
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
Transcript
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
  • 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 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
  • 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) 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
  • 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
  • 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
  • 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
  • MALAR RASH SUBACUTE CUTANEOUS LUPUS DISCOID LUPUS LESIONS ALOPECIA ALOPECIA MOUTH ULCERS MOUTH ULCERS EARLY VASCULITIC LESIONS 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 Sigismond, French physician, 1830–1913 GLOMERULONEPHRITIS
  • Minimal change
  • Mesangeal
  • Focal proliferative
  • Diffuse proliferative
  • Membranous glomerulonephritis
  • End Stage renal failure
  • (Typical is that the complement is diminished)
  • MESANGIAL LESIONS FOCAL PROLIFERATIVE GN (WHO CLASS III) 1 pleura/pericardial/peritoneum (PPP)
  • Serositis
  • Pleuritis
  • Pleuritic pain
  • Rub
  • Effusion
  • Pericarditis
  • ECG
  • Rub
  • Effusion
  • 2 Auto-antibody
  • Immunology
  • Anti-DNA antibodies
  • Anti-SM antibodies
  • Antiphosfolipid antibodies
  • Antinuclear antibodies (ANA)
  • Abnormal titer
  • By immunofluorescence
  • Clinical features(more than criteria)
  • Raynaud's phenomenon
  • Musculoskeletal
  • Mucocutaneous
  • Renal
  • Management
  • Cardiopulmonary
  • Central nervous system
  • Hematological
  • Other
  • Lipmann Sacks Endocarditis GANGRENE OF THE TOE OSTEONECROSIS Polymyositis and Dermatomyositis Classiffication
  • Adult polymiositis
  • Adult dermatomyositis
  • Important
  • Malignancy
  • Childhood dermatomyositis
  • 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 Upper eyelid Involving nasolabial folds V-sign Gottron’s Nodules Differential diagnosis (NB)
  • Inclusion body myositis
  • Other causes of proximal muscle weakness
  • See Davidson’s
  • Sjogren's disease Clinical features
  • Risk markers
  • Common clinical features
  • Less common features
  • Auto antibodies
  • Associated autoimmune disorders
  • Scleroderma Scleroderma (systemic sclerosis) Scleros: hard Derma: skin SYSTEMIC SCLEROSIS Multisystem disorder Fibrosis of the skin, bloodvessels, and viseral organs Affected organs: Lungs Heart Kidneys GIT CLASSIFICATION
  • Limitedcutaneous disease
  • Diffusecutaneous disease
  • Sinescleroderma
  • Undifferentiated connective tissue disease
  • Overlapsyndromes
  • Limited cutaneous scleroderma
  • Skin thickening: Distal to elbow and knee Face and neck
  • Synonym: CREST Syndrome
  • Diffuse cutaneous scleroderma
  • Skin thickening includes: Trunk Face Proximal extremities Distal extremities
  • Sine scleroderma
  • Internal organ manifestations
  • Vascular abnormalities
  • Serologic abnormalities
  • Noclinical detectable skin change
  • 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
  • Systemic sclerosis in association with other connective tissue disorders
  • Eg; SLE Inflamatory muscle disease RA
  • 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
  • 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
  • Immunologic mechanisms
  • Vascular damage
  • Activation of fibroblasts
  • Overproduction and accumulation of collagen and other extracellular matrix proteins in skin and other organs
  • 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
  • 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
  • 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 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 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
  • 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
  • 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
  • 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
  • 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
  • Pericarditis
  • Heart failure
  • Heart block and arrhythmias
  • Angina pectoris (some have normal angiograms)
  • Cor-pulmonale
  • 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
  • Sicca-syndrome
  • Sjogren’s
  • Intra- and periglandular fibrosis
  • Hypothyroidism
  • Antithyroid antibodies
  • Fibrosis of the thyroid
  • Trigeminal neuralgia
  • Male impotence
  • Biliary cirrhosis
  • 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
  • Antitopoisomerase 1 (Scl-70)
  • 40% in diff. cut. ssc.
  • Anticentromere
  • 60-80% in lim. cut. Ssc.
  • 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
  • Thoracic outlet syndromes
  • Shoulder-hand syndrome
  • Trauma
  • Previous cold injury
  • Vinyl chloride exposure
  • Circulating cryoglobulins or cold agglutinins
  • 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
  • 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
  • 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
  • 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
  • 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
  • Entelin-1 receptor antagonists
  • Azathioprine
  • With life-treatening disease
  • Studies are lacking
  • 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
  • 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
  • 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
  • ACE-Inhibitors
  • Dialysis
  • Treat hypertension
  • Beware of beta-blockers
  • END
    Related Search

    Previous Document

    Dokter kecil.docx

    Next Document

    BAB I

    We Need Your Support
    Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

    Thanks to everyone for your continued support.

    No, Thanks