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AUTOIMMUNE DISEASES
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Autoimmune Disease
Autoimmunity: acquired immunereaction, against self antigens
Autoimmune diseases: the autoimmunereaction induces lesions in tissues
Auto-antibodies (Auto-Ab): Abs againstself Ags (usually IgG or IgM)
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Autoimmune Reaction
Natural up to a point Needed to eliminate unwanted auto-Ags
(old, non -efficient, alternated), or toreduce the immune response activated inexcess (anti -idiotyp)
T ly, by linking to MHC stimulate B ly tosecrete Auto-Abs (there are auto-Ab anti-albumin etc)
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Immune Tolerance
This Immune tolerance induce eitherdeletion or inactivation of autoreactive T
ly1. Central Tolerance : immature T and B lybecame tolerant to self Ags clonallydeletion (takes place during the thymusmaturation, usually an irreversibleprocess. Its is followed by positive ornegative selection)
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Immune Tolerance
Induce deletion or inactivation ofautoreactive T ly
2. Peripheral Tolerance: takes place insecondary lymphoid organs (C lonal
Anergy) proliferative functions andsecretion one are inhibited by leak ofcostimulitory mediators/signals
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Immune Tolerance
Induce deletion or inactivation ofautoreactive ly T
3. Activation of some suppressormechanisms : Ts ly act by inhibatingcytotoxic cells; idiotype anti-idiotypenetwork or death of autoreactive cells)
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Autoimmunity Hypothesis
Theory of the hidden Ags (in NervousSystem, crystalline, thyroid, sperm cells,
bile) Theory of forbidden clone (some error
in deletion of autoreactive ly during fetal
life). Forbidden clones might appear alsoafter somatic mutation (normally they areeliminated)
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Autoimmunity Hypothesis
Theory of clonal anergy : another form
of forbidden clones. Clones whichencounter the self Ag are not eliminated,they are just temporally suppressed (theyrecover at high quantities of Ags, or longpersistent of them)
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Autoimmunity Hypothesis
Theory of immune deficiency : there isfunctional inhibition of suppressor cells(CD8+ T ly) which do not block anymore
auto-aggressive phenomenon
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Bach, J.-F. N Engl J Med 2002;347:911-920
Inverse Relation between the Incidence of PrototypicalInfectious Diseases (Panel A) and the Incidence of
Immune Disorders (Panel B) from 1950 to 2000
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IL-4 GATA-3
IL-12 T-BET
Th2
Th1
IL-4IL-5CRTH2
IFN- g
TIM-3
IgE
EosinophilImmediate-typeresponses
IgG1
Antigen-presenting cellsInflammatoryresponses
Naive
TGF-b FOXP3
Treg
CD25CTLA-4IL-10TGF-b
IgG4, IgAFibroblasts, epithelial cellsRegulatory and repairresponses
Schmidt-Weber, Blaser; Curr Opinion Immunol 2004; 16:709 716
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IL-4 IL-10 IL-12
Th2 Th1
Treg
IgEIgG4, IgA
IgG1
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Immune Recognition
High organ Specificity
Without organ Specificity (systemicreactions)
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Auto-Abs
Anti-molecule Immune Complexes (CI)deposition in vessel, glomeruls
(colagenosis; SLE) Anti-cells (Ag in membranes)
cytotoxicity (C activation) or cell-mediated
cytotoxicity (CCAD) or phagocytosis Anti-receptor (cell receptor)
stimulation of function or neutralization of
receptor (myasthenia, hypertiroiditis)
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Pathogenic Effects of Auto-Abs
Cytotoxic (dependent of C, mediated bycells)
Blocking, agglutination or masking (ofsome cell function)
Activation of phagocytosis (oposonizationand activation of macrophages)
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Autoreactive T Lymphocytes
Present in experimental encephalitis inmice
NK Cells usually suppressed (they losetheir regulatory role of down-regulation ofimmune responses)
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Predisposing Factors
Genetic Factors :
HLA-B27 with Ankylosis spondylitis
- in other diseases, the importance ofgenetic factors is lesser
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Association of the Autoimmune diseases and HLA
Autoimmune diseases Gena HLA Risc
Ankylosis spondylitis B27 87.4%Reiters Syndrome B27 37%
Goodpastures Sd. DR2 15.9%
SLE DR3 15%Diabetes mellitus DR3/DR4 25%Systemic Sclerosis DR2 5%Graves Disease DR3 3.7%Hashimotos Thyroiditis DR3 3.2%Myastenia gravis DR3 2.5%Rheumatoid Artritis DR4 4%
Psoriasis DR4 14%
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Predisposing Factors
Age : frequent in old age, but colagenosisare seen in young people (SLE, RA)
Sex : female (SLE ratio F/M = 10/1;Graves disease: 7/1; spondylitis mostly
in male)
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Predisposing Factors
Infection (antigenic mimetism) :virus (vi: Epstein-Barr, Cocksakie);
bacteria (mycoplasma, Klebsiella, Borreliaburgdorferi etc)
Drugs : procainamide, hidralazine(phenomenon lupus-like)
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Autoimmune DiseasesHashimotos Thyroiditis
Autoimmune atrophic Gastritis
Pernicious Anemia
Addisons disease
Myasthenia gravis
Goodpastures Sd.
Diabetes
Autoimmunehemolytic Anemia
Thrombocytopeniaidiopathic Purpura
Sjgrens Sd.Ulcerative Colitis
Primitive Biliary Cirrhosis
Systemic Lupuserythematous
Dermatomiositis
Sclerodermia
Rheumatoid Arthritis
With organ specificity
Systemic
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Hashimotos autoimmuneThyroiditis Mechanism: humoral and cellular thyroid Cell Auto-Ab anti-tireoglobuline; - anti-
peroxidaza from thyroid La female (F/M = 5/1) 30-60 years Diffuse infiltration with ly, eosinophils,atresia of parenchimatous cells Hypothyroidism
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Graves disease Auto-Ab anti-receptor TSH (stimulatory hormone
of thyroid) - mechanism HS type II
Hyperthyroidism
Gointre (hyperplasic, diffuse)
Extrathyroid signs (exophthalmia, peritibialmixedema)
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Myasthenia gravis Auto-Ab anti-receptor for acetylcholine Neuromuscular: post-synaptic block of
nervous influx transmition to motor plate Rare: incidence 2-6 cases in 1 million of
persons
Muscular fatigue very severe: ocular,extension up to respiratory insufficiency) Treatment: extirpation of hypertrofiated
thymus (sometimes might work)
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Myasthenia gravis:- neuron-muscular junction -
Receptorsfor Ach
Auto-Ab antireceptor for Ach
Acetylcholine (Ach)
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Other autoimmune disease - organ-spf
Pancytopenia (H, L, Tr) autoimmune
Anemia pernicious (Biermer) intrinsec factor Diabetes (insulin-dependent) (B cells from
pancreas)
Addisons Disease (receptors for ACTH andmicrosoms) Systemic Sclerosis (basic myelin protein from
brain, bown marrow)
Guillain-Barr Sd (peripheral nerves ganglioside)
Pemfigus keratinocytes
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SYSTEMIC LUPUS
ERITHEMATOUSDiana Dumitrascu
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Definition Affection with unknown etiology,
where the tissues are damaged by Auto-antibodies and ImmuneComplexes
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Ethiology
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Epidemiology
90% are Female, aged 20-30 years
More frequent in blacks, followed byHispanic populations, and Asiaticpopulations
Prevalence 15-50/100,000 (SUA)
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Pathology
Lesions induced by AutoAb, IC
1. Hyperreactivity of T, B lymphocytes2. Genetic Induce
3. Environment factors: viruses,bacteria, drugs
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PathologyGenetic Induce :
- more frequent in monozigots (25 - 58%) vs dizigots(0-6%)
- more frequent in families with one patients- more frequent in pts with defects or deletion of allele of classes
III C4AQO (40-50% pts)- more frequent in homozygote with defects of C (C1q,C2, C4) (< 5% pts)
- haplotype B8.DR3.DQw2.C4AQO predispose to SLEin population from north of Europe
Genetic Predisposition for SLE induce by drugs: dependence ofthe acetilation of the drug
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Pathology- Associated with HLA-DR2 or DR3 (gene for
autoimmunity) - Cz 1 (1q23) has gene for Fc RIIA; and 1q41-
42 has poli gena (DNA-ribosil) polymerase(PARP) and them may produce defects of theway DNA is repaired and defects of apoptosis
- AutoAb are associated with some symptoms inSLE:
AutoAb to Ro/La (SS-A/SS-B) in sub acute SLEnormal Allele of Fc RIIA or Fc RIIIA whichbound to IgG2/IgG3 are more frequent innephritis (CI are not eliminated from
circulation)
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Pathology
Immunological Factors :- IFN type I (cz 9p21): -there are 13
isoforms of IFN-1 - they activate the program of T ly for IFN -2 secretion (former)
- Toll Receptors (role in innate immune sistand allows the formation of acquiredimmunity; stimulatory and inhibitory functions)
- Dendritic plasmocitoide Cells (they secreteIFN- 1 ) receptors to identified BDCA-2 si
BDCA-4
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Discoid Lupus
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Histopathology Lesions of basal membrane (epidermis) Discontinuing of dermal-epidermal junctions Infiltration with monocytes around the vessels
Hyperkeratosis IgG and C deposits (80 -100%) may bepresents in normal tissues (50%)
Leucocytoclastic vasculitis Glomerulonephritis - IC deposits or the might be
generated in situ in mesangium or in glomerularbasal membrane (if Ig and C deposits are out ofmesangium severe prognostic)
Discoid Lupus
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Clinical forms
Systemic lupus erithematous
Discoid lupus erithematous skinlesions (skin atrophy) 20%
Subacute lupus erithematous skinlesions - vasculitis type
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Symptoms
Onset One organ (after that systemic)
Systemic (most frequent: fatigue, malaise,fever, anorexia, loss in weight)
Severity : mild severe
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Symptoms
Muscular, joint, bone:- mialgia, arthralgia (most of the pts):
intermittent arthritis, usually symmetric:small
joints: hand, foot, sometimes knee etc tenosinovitis inflammatory myopathy (or after treat: K ,
GCS, hidroxiclorochin) ischemic necrosis in the bone: pelvic joint,
knee, shoulder (post-GCS)
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Symptoms Skin and mucosa:- Rash - butterfly on the face - without scarf lesion (only in discoid lupus) - Rare: urticaria, vesicles, erithema multiform,
lichen plan, paniculitis (= profound lupus)- Vasculitis lesions (SLE systemic, discoid,
subacute): purpura, subcutaneous nodules,infarctation at nails, ulcers, vasculitic urticaria,
paniculitis, necrosis of fingers - Mucosa: Ulcer on oral, nasal mucosa
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Symptoms
Renal:-
pts - glomerulonephritis (most of thepts have Ig deposits in glomeruls)
- Focal glomerulonefritis renalsclerosis
- Without symptoms or nephrotic edema- haematuria, proteinuria, renal failure
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Symptoms
Neurological symptoms:- meningitis, spine cord, central and peripheral
nerves- Unique or multiples- Associated with another organ lesions- Mild cognitive dysfunction (most frequent),
headache (migraine or unspecific headache),muscular contraction
- Rare: psychosis, acute confusion, cerebro-vascular disease, aseptic meningitis, mielopathy,mono or polineuropathy, Guillan-Barr polineuropathy, depression, anxiety
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Symptoms
Vascular symptoms:- thrombosis in the vessel (anti fosfolipidic
antibodies: anticoagulant (LA),
anticardiolipid induce coagulation withoutvasculitis)- Vasculitis- Cerebral embolus (Libman-Sacks
endocarditis)- Vascular and cerebral lesions - IC and
hyperlipidemia (induced by GCSs) inchronic disease
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Symptoms
Hematological:
- Anemia chronic disease in most of the pts- hemolytic anemia rare, withCoombs Test +
- Low Leucocytes (and lymphocytes)- Low platelets (sometimes with purpura)- Seldom Abs anti - factors for coagulation
(VIII, IX) hemorrhage
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Symptoms
Heart and lungs:
- Pericarditis- Myocarditis dysrhithmias- Endocarditis (Libman-Sacks)
- Pleuritis - Lung involvement: most frequent
infections, lupic Pneumonitis, lung fibrosis,PHT (rare)
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Symptoms
Gastrointestinal:- Nausea, diarrhea, abdominal pain- Peritonitis- Vasculitis- Pseudo-obstruction of the bowel- Lesion like scleroderma (motility
disorder)- Acute pancreatitis (disease, therapy withcorticosteroid, azathioprine)
- High level of enzymes (ASAT, ALAT)(without significant hepatic lesions)
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Symptoms
Eyes:- Retinian vasculitis blindness
- Conjunctivitis
- Episcleritis
- Optic nerve lesion
- Sicca sd.
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Acut Lupus
Discoid lupusLupus Paniculitis
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Investigations
C low (= activity of disease) CH50 total hemolytic function of C C3, C4 low CH50 very low + C3 normal = innate deficiency ofC (associated frequent with SLE - ANA neg) Anemia (normochrom, sometimes hemolytic),
low leucocytes, low lymphocytes, low plattelets
ESR is correlated with activity of disease(sometimes) Proteinuria, hematuria, creatinin may be
(periodic renal control to all pts)
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Auto-AbsIncidence Ag Clinical significance
Antinuclear 98% nucleus diagnostic Anti-ADN 70% ADN
(ds)Spf, renal les.,activity index
Anti-Sm 30% Prot.Cuplatedto nucl.
ARN
spf
Anti-RNP 30% Prot.Bond toU1ARN
In Overlap sd. with SLE,polimyositis,scleroderma, mixt conj.tis. diseaseMay protect for Renal
les.
Auto Abs
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Auto-AbsIncidence Ag Clinical
significance
Anti-Ro(SS-A)
30% Prot. Bondto y 1-y 5
ARN
Sj gren Sd., subacutlupus, deficiency ofC, lupus with ANA -neg, renal Les.
Anti-La(SS-B)
10% Fosfopro-tein
Always Associatedwith Anti-Ro,Sj gren Sd.
Rarely in nephritis
Anti-histon
70% Histon SLE induce by drugs
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Auto-AbsIncidence Ag Clinical
Significance Anti-Phospholipids
50% Phospholipids
3 type: lupus- Anticoagulant (LA) Anticardiolipin (aCL)False + syphilis(BFP)
Anti-
erythrocyte
60% Erythrocyt
e
Hemolisis (nu to all)
Anti-platelets
30% Pl Surfaceandcytoplasm
Low Pl (15%)
Anti- 70% Ly. Surface Low Leukocyte, T ly
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Auto-Abs
Incidence Ag Clinicalsignificance
Anti-neuronali 60%Suprafataneurons si aly
Lez. diffuse of CNSat high values
Anti-
ribosomal P
20% RibosomalProt. P
CNS les., psychosis,depression
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Diagnostic
Diagnostic Criteria ARA (1997):4 criteria (dg. + 98% spf and 97% sensib.)1. Rash one face2. Discoid Rash3. Photo sensibility4. Oral Ulcers5. Arthritis6. Serositis7. Renal lesion8. Neurological involvement9. Hematological Abnormalities10. Immunologic Abnormalities11. Antinuclear Antibodies
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Differential Diagnostic
Rheumatoid Arthritis Other autoimmune diseases Dermatitis Neurological Diseases: systemic sclerosis Psychiatric Diseases Hematological Diseases: idiopathic
purpura with low platelets
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Progression of the disease
Remission rarely
25% have a mild form of SLE - no lethal risk
With activity and remission periods
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Treatment No curative treatment Mild Form : better without glucocorticosteroids (GCS)
NSAD - COX-2 inhibitors Antimalarics : hidroxiclorochin (400 mg/day) UV protection oigments Topic or intralesional : GCS, quinacrin,
retinoids, dapson for drug induce withdraw the drug (rarely
short term GCS)
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Treatment Severe Form (renal, nervous system
etc) : Gluco-Corticosteroids :
- 1-2 mg/kg/day (in 2-3 dose, at8-12 hours; pulse therapy withmetilprednisolon 1000 mg/day iv, 2-5 days)
- after that in the morning, in alternativedays with GCS with short action:prednisone, prednisolon, metilprednisolonwith maintenance doses: lowest dosewithout symptoms
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Treatment
Severe Form (renal, cardiac etc) :To Reduce side effects of GCS:
vaccine supplement: Vit D , Calcium ,
Calcitonin ,
Biphosphonats association with other therapy
Treatment
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Treatment
Severe Form (renal, etc) : Cytotoxic Agent (immunosuppressive) : Azathioprin 2-3 mg/kg/day p.o., Clorambucil , Ciclofosfamid 10 -15mg/kg/day iv for 4 weeks and 1,5-2,5 mg/kg/day p.o.,Methotrexat 5-20 mg/day, once/week, p.o. or s.c.,Mofetil Micofenolate [CellCept R , cp 500mg] - 1-2,5g/day, p.o.) reduce the GCS dose: two even 3 drugs (ciclofosfamid +
azathioprina) in renal lesions (GCS + ciclofosfamida iv most efficient, but
very toxic) try to reduce doses when the disease is controlled, (even
withdraw them)
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Treatment
Severe Form (renal etc) : Anticoagulants (warfarina)
Ig iv renal transplant - allograph (high riskof
rejection) plasmaferesis (associated with
cytotoxicity)
cyclosporine
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New Treatments
Mild Forms: dihidroepiandrosteron Rituxan (Mo Ab anti B Ly - anti CD20)
Blocking the activity of B ly with anti-Blys (member of TNF superfamilymolecules)
induce tolerance to ADN MoAb anti - TNF - disappointment
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Prognostic Prognostic is good in drug induced lupus (those drugsmay be administered in pts with SLE) Remission (frequent, but short period) la 20% Survival at 2 years: 90-95%
at 5 years: 71-80%at 10 years: 63-75%
Prognostic is sever for renal involve. (mortality 50% at10 years), CNS les.
Prognostic is severe when C is very low, or platelets arelow Death: either from active disease, either infections in
first prima 10 years, or thrombembolism in next 10-20years
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Sjgren Sd.
Female (F/M = 9/1)
Young age
HLA-B8, HLA-DR3 modified Ags (viral retrovirusuri?)
lymphoid infiltration
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Sjgren Sd.
oral involvement (xerostomia)
ocular involvement (kerato-conjunctivitis) exocrine glandular involvement extra glandular symptoms
Many Auto-Abs: RF, anti-nuclear Abs, etc
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Therapy
NSAID GCS
Immunomodulation (cytostatic:methotrexat, ciclofosfamid, azathioprin)
Immunomodulation (cyclosporine,tacrolimus)
Mo Ab (anti-CD3, -CD2, -CD4, CD7, -CD8,CD25, -CD20; anti-TNF, anti-IL-6, anti-IL-8)
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RHEUMATOID ARTHRITIS
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RHEUMATOID ARTHRITIS
1859 Sir Alfred Garrod - Rheumatoid Arthritis 1893 W.A. Lane surgical therapy 1897 - acetil salicic Acid 1929 Gold Salts 1939 - Sir McFarlane Burnet - Autoimmune Theory 1948 - Philip Hench & E. C. Kendall - antiinflamatory
effect of steroid hormons 1955 prednison was use for the first time 90 immunomodulatory effects of Mo Ab anti TNF
(Infliximab - Remicade R )
RHEUMATOID ARTHRITIS
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RHEUMATOID ARTHRITIS
4500 b.h. indian scheleton in Tenesseee 123 a.h. - Carata Samhita: tumefaction,pain of joints, initial at hand and legs, andafter, extension in hole body, losingappetite, occasionaly fever
1591 - Guillaume de Baillou first bookabou arthritis : - RA + fibromialgy
1763 first treatments with willowextracts
J b J d (1593 1678) Th A ti t
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Jacob Jordaens (1593-1678) The ArtistFamily
Prado, Madrid
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David Teniers, young (1610-1690)
The Temptation of Saint Anthony
Antwerpen
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Test
Which are arguments for SLE:1. 25 years old Man
2. Polyserositis3. High circulate immune complexes4. High IgE5. Radiology signs at sacroiliac joints
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Test
Which are arguments for SLE:1. 25 years old Man
2. Polyserositis3. High circulate immune complexes4. High IgE5. Radiology signs at sacroiliac joints