AUTOIMMUNE AUTOIMMUNE DISEASESDISEASES

Autoimmune DiseaseAutoimmune Disease

• Autoimmunity:Autoimmunity: acquired immune acquired immune reaction, against self antigensreaction, against self antigens

• Autoimmune diseases:Autoimmune diseases: the the autoimmune reaction induces lesions autoimmune reaction induces lesions in tissuesin tissues

• Auto-antibodies Auto-antibodies (Auto-Ab): Abs (Auto-Ab): Abs against self Ags (usually IgG or IgM)against self Ags (usually IgG or IgM)

Autoimmune ReactionAutoimmune Reaction

• Natural – up to a pointNatural – up to a point

• Needed to eliminate unwanted auto-Needed to eliminate unwanted auto-Ags (“old”, “non-efficient”, Ags (“old”, “non-efficient”, “alternated”), or to reduce the “alternated”), or to reduce the immune response activated in immune response activated in excess (“anti-idiotyp”)excess (“anti-idiotyp”)

• T ly, by linking to MHC T ly, by linking to MHC stimulate B stimulate B ly to secrete Auto-Abs (there are ly to secrete Auto-Abs (there are auto-Ab anti-albumin etc)auto-Ab anti-albumin etc)

Immune ToleranceImmune Tolerance

• This Immune tolerance induce either This Immune tolerance induce either deletion or inactivation of deletion or inactivation of autoreactive T lyautoreactive T ly

1.1. Central Tolerance :Central Tolerance : immature T immature T and B ly became tolerant to self Ags and B ly became tolerant to self Ags – – clonally deletion clonally deletion (takes place (takes place during the thymus maturation, during the thymus maturation, usually an irreversible process. Its is usually an irreversible process. Its is followed by positive or negative followed by positive or negative selection)selection)

Immune ToleranceImmune Tolerance

• Induce deletion or inactivation of Induce deletion or inactivation of autoreactive T lyautoreactive T ly

2. Peripheral Tolerance: 2. Peripheral Tolerance: takes placetakes place in secondary lymphoid organs in secondary lymphoid organs (C(Clonallonal Anergy) Anergy) – proliferative – proliferative functions and secretion one are functions and secretion one are inhibited by leak of costimulitory inhibited by leak of costimulitory mediators/signalsmediators/signals

Immune ToleranceImmune Tolerance

• Induce deletion or inactivation of Induce deletion or inactivation of autoreactive ly Tautoreactive ly T

3. Activation of some suppressor 3. Activation of some suppressor mechanisms : mechanisms : Ts ly act by Ts ly act by inhibating cytotoxic cells; idiotype – inhibating cytotoxic cells; idiotype – anti-idiotype network or death of anti-idiotype network or death of autoreactive cells)autoreactive cells)

Autoimmunity HypothesisAutoimmunity Hypothesis

• Theory of the hidden Ags Theory of the hidden Ags (in (in Nervous System, crystalline, thyroid, Nervous System, crystalline, thyroid, sperm cells, bile)sperm cells, bile)

• Theory of forbidden cloneTheory of forbidden clone (some (some error in deletion of autoreactive ly error in deletion of autoreactive ly during fetal life). Forbidden clones during fetal life). Forbidden clones might appear also after somatic might appear also after somatic mutation (normally they are eliminated)mutation (normally they are eliminated)

Autoimmunity HypothesisAutoimmunity Hypothesis

• Theory of clonal anergyTheory of clonal anergy: another : another

form of forbidden clones. Clones which form of forbidden clones. Clones which

encounter the self Ag are not encounter the self Ag are not

eliminated, they are just temporally eliminated, they are just temporally

suppressed (they recover at high suppressed (they recover at high

quantities of Ags, or long persistent of quantities of Ags, or long persistent of

them)them)

Autoimmunity HypothesisAutoimmunity Hypothesis

• Theory of immune deficiencyTheory of immune deficiency: :

there is functional inhibition of there is functional inhibition of

suppressor cells (CD8+ T ly) which suppressor cells (CD8+ T ly) which

do not block anymore auto-do not block anymore auto-

aggressive phenomenonaggressive phenomenon

Bach, J.-F. N Engl J Med 2002;347:911-920

Inverse Relation between the Incidence of Prototypical Infectious Diseases (Panel A) and the Incidence of Immune Disorders (Panel B)

from 1950 to 2000

IL-4 GATA-3

IL-12 T-BET

Th2

Th1

IL-4IL-5CRTH2

IFN-TIM-3

IgEEosinophilImmediate-typeresponses

IgG1Antigen-presenting cellsInflammatoryresponses

Naive

TGF- FOXP3

Tre

g

CD25CTLA-4IL-10TGF-

IgG4, IgAFibroblasts, epithelial cellsRegulatory and repairresponses

Schmidt-Weber, Blaser; Curr Opinion Immunol 2004; 16:709–716

IL-4 IL-10 IL-12

Th2 Th1

Tre

g

IgEIgG4, IgA

IgG1

Immune RecognitionImmune Recognition

• High organ SpecificityHigh organ Specificity

• Without organ Specificity (systemic Without organ Specificity (systemic reactions)reactions)

Auto-AbsAuto-Abs

• Anti-molecule Anti-molecule Immune Complexes (CI)Immune Complexes (CI)

deposition in vessel, glomeruls deposition in vessel, glomeruls (colagenosis; SLE)(colagenosis; SLE)

• Anti-cellsAnti-cells (Ag in membranes) (Ag in membranes) cytotoxicitycytotoxicity (C’ activation) or (C’ activation) or cell-cell-mediated cytotoxicity mediated cytotoxicity (CCAD) or (CCAD) or phagocytosisphagocytosis

• Anti-receptor (cell receptor)Anti-receptor (cell receptor) stimulation of function or neutralization of stimulation of function or neutralization of receptor (myasthenia, hypertiroiditis)receptor (myasthenia, hypertiroiditis)

Pathogenic Effects of Auto-Pathogenic Effects of Auto-AbsAbs

• Cytotoxic Cytotoxic (dependent of C’, mediated (dependent of C’, mediated by cells)by cells)

• Blocking, agglutination or maskingBlocking, agglutination or masking (of some cell function)(of some cell function)

• Activation of phagocytosisActivation of phagocytosis (oposonization and activation of (oposonization and activation of macrophages)macrophages)

Autoreactive T LymphocytesAutoreactive T Lymphocytes

• Present in experimental encephalitis Present in experimental encephalitis in micein mice

• NK Cells – usually suppressed (they NK Cells – usually suppressed (they lose their regulatory role of down-lose their regulatory role of down-regulation of immune responses)regulation of immune responses)

Predisposing FactorsPredisposing Factors

• Genetic FactorsGenetic Factors: :

HLA-B27 with Ankylosis spondylitisHLA-B27 with Ankylosis spondylitis

- in other diseases, the importance of - in other diseases, the importance of genetic factors is lessergenetic factors is lesser

Association of the Autoimmune diseases Association of the Autoimmune diseases and HLAand HLAAutoimmune diseasesAutoimmune diseases Gena HLAGena HLA RiscRisc

Ankylosis spondylitisAnkylosis spondylitis B27B27 87.4%87.4%

Reiter’s SyndromeReiter’s Syndrome B27B27 37%37%

Goodpasture’s Sd. Goodpasture’s Sd. DR2DR2 15.9%15.9%

SLESLE DR3DR3 15%15%

Diabetes mellitusDiabetes mellitus DR3/DR4DR3/DR4 25%25%

Systemic SclerosisSystemic Sclerosis DR2DR2 5%5%

Grave’s DiseaseGrave’s Disease DR3DR3 3.7%3.7%

Hashimoto’s ThyroiditisHashimoto’s Thyroiditis DR3DR3 3.2%3.2%

Myastenia gravisMyastenia gravis DR3DR3 2.5%2.5%

Rheumatoid ArtritisRheumatoid Artritis DR4DR4 4%4%

Psoriasis Psoriasis DR4DR4 14%14%

Predisposing FactorsPredisposing Factors

• AgeAge: frequent in old age, but : frequent in old age, but colagenosis are seen in young people colagenosis are seen in young people (SLE, RA)(SLE, RA)

• SexSex: female (SLE – ratio F/M = 10/1; : female (SLE – ratio F/M = 10/1; Grave’s disease: 7/1; spondylitisGrave’s disease: 7/1; spondylitis – – mostly in male)mostly in male)

Predisposing FactorsPredisposing Factors

• Infection (“antigenic mimetism”)Infection (“antigenic mimetism”) : virus (vi: Epstein-Barr, Cocksakie); : virus (vi: Epstein-Barr, Cocksakie); bacteria (mycoplasma, Klebsiella, bacteria (mycoplasma, Klebsiella, Borrelia burgdorferi etc)Borrelia burgdorferi etc)

• DrugsDrugs: procainamide, hidralazine : procainamide, hidralazine (phenomenon lupus-like) (phenomenon lupus-like)

Autoimmune DiseasesAutoimmune DiseasesHashimoto’s ThyroiditisHashimoto’s Thyroiditis

Autoimmune atrophic Autoimmune atrophic GastritisGastritis

Pernicious Anemia Pernicious Anemia

Addison’s diseaseAddison’s disease

Myasthenia Myasthenia gravisgravis

Goodpasture’s Goodpasture’s Sd. Sd.

DiabetesDiabetesAutoimmune Autoimmune hemolytic Anemiahemolytic Anemia

Thrombocytopenia Thrombocytopenia idiopathic Purpuraidiopathic Purpura

Sjőgren’s Sd. Sjőgren’s Sd.

Ulcerative ColitisUlcerative Colitis

Primitive Biliary Cirrhosis Primitive Biliary Cirrhosis

Systemic Lupus Systemic Lupus erythematouserythematous

DermatomiositisDermatomiositis

SclerodermiaSclerodermia

Rheumatoid ArthritisRheumatoid Arthritis

With organ specificity

SystemicSystemic

Hashimoto’s autoimmune Hashimoto’s autoimmune ThyroiditisThyroiditis• Mechanism: humoral and cellularMechanism: humoral and cellular• thyroid Cellthyroid Cell• Auto-Ab anti-tireoglobuline; - anti-Auto-Ab anti-tireoglobuline; - anti-

peroxidaza from thyroidperoxidaza from thyroid• La female (F/M = 5/1)La female (F/M = 5/1)• 30-60 years30-60 years• Diffuse infiltration with ly, eosinophils, Diffuse infiltration with ly, eosinophils,

atresia of parenchimatous cells atresia of parenchimatous cells • HypothyroidismHypothyroidism

Grave’s diseaseGrave’s disease• Auto-Ab anti-receptor TSH (stimulatory Auto-Ab anti-receptor TSH (stimulatory

hormone of thyroid) - mechanism HS hormone of thyroid) - mechanism HS type IItype II

• HyperthyroidismHyperthyroidism

• Gointre (hyperplasic, diffuse)Gointre (hyperplasic, diffuse)

• Extrathyroid signs (exophthalmia, Extrathyroid signs (exophthalmia, peritibial mixedema)peritibial mixedema)

Myasthenia gravisMyasthenia gravis• Auto-Ab anti-receptor for acetylcholine Auto-Ab anti-receptor for acetylcholine

• Neuromuscular: post-synaptic block of Neuromuscular: post-synaptic block of nervous influx transmition to motor plate nervous influx transmition to motor plate

• Rare: incidence 2-6 cases in 1 million of Rare: incidence 2-6 cases in 1 million of personspersons

• Muscular fatigue – very severe: ocular, Muscular fatigue – very severe: ocular, extension up to respiratory insufficiency)extension up to respiratory insufficiency)

• Treatment: extirpation of hypertrofiated Treatment: extirpation of hypertrofiated thymus (sometimes might work)thymus (sometimes might work)

Myasthenia gravis: Myasthenia gravis: - neuron-muscular junction - - neuron-muscular junction -

Receptors for Ach

Auto-Ab anti receptor for Ach

Acetylcholine (Ach)

Other autoimmune disease - Other autoimmune disease - organ-spforgan-spf

• PancytopeniaPancytopenia (H, L, Tr) (H, L, Tr) autoimmuneautoimmune• Anemia pernicious (Biermer)Anemia pernicious (Biermer) – intrinsec – intrinsec

factorfactor• Diabetes (insulin-dependent)Diabetes (insulin-dependent) (B cells (B cells

from pancreas)from pancreas)• Addison’s Disease Addison’s Disease (receptors for ACTH and (receptors for ACTH and

microsoms)microsoms)• Systemic SclerosisSystemic Sclerosis (basic myelin protein (basic myelin protein

from brain, bown marrow)from brain, bown marrow)• Guillain-Barré Sd Guillain-Barré Sd (peripheral nerves – (peripheral nerves –

ganglioside)ganglioside)• Pemfigus Pemfigus – keratinocytes – keratinocytes

SYSTEMIC LUPUS SYSTEMIC LUPUS ERITHEMATOUSERITHEMATOUS

Diana DumitrascuDiana Dumitrascu

DefinitionDefinition

• Affection with unknown etiology, Affection with unknown etiology,

where the tissues are damaged where the tissues are damaged by by

Auto-antibodies and Immune Auto-antibodies and Immune

ComplexesComplexes

EthiologyEthiology

EpidemiologyEpidemiology

• 90% are Female, aged 20-30 years90% are Female, aged 20-30 years

• More frequent in blacks, followed by More frequent in blacks, followed by Hispanic populations, and Asiatic Hispanic populations, and Asiatic populationspopulations

• Prevalence 15-50/100,000 (SUA)Prevalence 15-50/100,000 (SUA)

PathologyPathology

• Lesions induced by AutoAb, ICLesions induced by AutoAb, IC

1.1. Hyperreactivity of T, B lymphocytesHyperreactivity of T, B lymphocytes

2.2. Genetic InduceGenetic Induce

3.3. Environment factors: viruses, Environment factors: viruses,

bacteria, drugsbacteria, drugs

PathologyPathology GGeneticenetic Induce Induce : :

- more frequent in monozigots (25 - 58%) vs dizigots- more frequent in monozigots (25 - 58%) vs dizigots (0-6%)(0-6%) - more frequent in families with one patients - more frequent in families with one patients - more frequent in pts with defects or deletion of allele - more frequent in pts with defects or deletion of allele

of classesof classes III C4AQO (40-50% pts)III C4AQO (40-50% pts) - more frequent in homozygote with defects of C’ (C1q, - more frequent in homozygote with defects of C’ (C1q, C2, C4) (< 5% pts)C2, C4) (< 5% pts) - haplotype B8.DR3.DQw2.C4AQO predispose to SLE- haplotype B8.DR3.DQw2.C4AQO predispose to SLE in population from north of Europein population from north of Europe

• Genetic Predisposition for SLE induce by drugs: Genetic Predisposition for SLE induce by drugs: dependence of the acetilation of the drugdependence of the acetilation of the drug

PathologyPathology- Associated with HLA-DR2 or –DR3 (“gene Associated with HLA-DR2 or –DR3 (“gene

for autoimmunity”)for autoimmunity”)- Cz 1 (1q23) has gene for FcCz 1 (1q23) has gene for FcγγRIIA; and RIIA; and

1q41-42 has poli gena (DNA-ribosil) 1q41-42 has poli gena (DNA-ribosil) polymerase (PARP) and them may produce polymerase (PARP) and them may produce defects of the way DNA is repaired and defects of the way DNA is repaired and defects of apoptosisdefects of apoptosis

- AutoAb are associated with some AutoAb are associated with some symptoms in SLE: symptoms in SLE:

AutoAb to Ro/La (SS-A/SS-B) in sub acute AutoAb to Ro/La (SS-A/SS-B) in sub acute SLESLE

normal Allele of Fcnormal Allele of FcγγRIIA or FcRIIA or FcγγRIIIA which RIIIA which bound to IgG2/IgG3 are more frequent in bound to IgG2/IgG3 are more frequent in nephritis (CI are not eliminated from nephritis (CI are not eliminated from circulation)circulation)

PathologyPathology

Immunological FactorsImmunological Factors: : - IFN – type IIFN – type I (cz 9p21): -there are 13 (cz 9p21): -there are 13

isoforms of IFN-1isoforms of IFN-1 - they activate the - they activate the “program” of T ly for IFN-2 secretion “program” of T ly for IFN-2 secretion (former (former γγ))

- TollToll Receptors Receptors (role in innate immune (role in innate immune sist and allows the formation of acquired sist and allows the formation of acquired immunity; stimulatory and inhibitory immunity; stimulatory and inhibitory functions)functions)

- Dendritic plasmocitoideDendritic plasmocitoide Cells Cells (they (they secrete IFN- 1secrete IFN- 1) – receptors to identified ) – receptors to identified BDCA-2 si BDCA-4BDCA-2 si BDCA-4

PathologyPathology

Environmental FactorsEnvironmental Factors: : - UV-B and UV-A (70% pts have photosensitivity)UV-B and UV-A (70% pts have photosensitivity)- Chemical Substances (hidralazine, isoniazide, Chemical Substances (hidralazine, isoniazide,

clorpromazin, D-penicilamin, practolol, clorpromazin, D-penicilamin, practolol, metildopa, quinidin, IFN-metildopa, quinidin, IFN-, hidantoine, , hidantoine, etosuximide, contraceptive oral)etosuximide, contraceptive oral)

- Infections viruses/retroviruses Infections viruses/retroviruses - Sexual hormones (female, in child bearing Sexual hormones (female, in child bearing

period)period)

HistopathologyHistopathology• Lesions of basal membrane (epidermis)Lesions of basal membrane (epidermis)• Discontinuing of dermal-epidermal junctionsDiscontinuing of dermal-epidermal junctions• Infiltration with monocytes around the vesselsInfiltration with monocytes around the vessels• HyperkeratosisHyperkeratosis• IgG and C’ deposits (80-100%) – may be IgG and C’ deposits (80-100%) – may be

presents in normal tissues (50%)presents in normal tissues (50%)• Leucocytoclastic vasculitisLeucocytoclastic vasculitis• Glomerulonephritis - IC deposits or the might Glomerulonephritis - IC deposits or the might

be generated in situ in mesangiumbe generated in situ in mesangium or in or in glomerular basal membrane (if Ig and C’ glomerular basal membrane (if Ig and C’ deposits are out of mesangiumdeposits are out of mesangium – severe – severe prognostic)prognostic)

Discoid Lupus

Clinical formsClinical forms

• Systemic lupus erithematousSystemic lupus erithematous

• DiscoidDiscoid lupus erithematous lupus erithematous – skin – skin lesions (skin atrophy) – 20%lesions (skin atrophy) – 20%

• Subacute lupus erithematous Subacute lupus erithematous – – skin lesions - vasculitis typeskin lesions - vasculitis type

SymptomsSymptoms

OnsetOnset

• One organ (after that One organ (after that systemic) systemic)

• Systemic (most frequent: fatigue, Systemic (most frequent: fatigue, malaise, fever, anorexia, loss in weight)malaise, fever, anorexia, loss in weight)

SeveritySeverity: mild severe: mild severe

SymptomsSymptoms

• Muscular, joint, bone:Muscular, joint, bone:- mialgia, arthralgia (most of the pts): mialgia, arthralgia (most of the pts): intermittent arthritis, usually intermittent arthritis, usually

symmetric: small symmetric: small joints: hand, foot, sometimes knee joints: hand, foot, sometimes knee

etcetc tenosinovitistenosinovitis inflammatory myopathy (or after treat: inflammatory myopathy (or after treat:

K K , , GCS, hidroxiclorochin)GCS, hidroxiclorochin) ischemic necrosis in the bone: pelvic ischemic necrosis in the bone: pelvic

joint, knee, shoulder (post-GCS)joint, knee, shoulder (post-GCS)

SymptomsSymptoms• Skin and mucosa:Skin and mucosa:- Rash - “butterfly” on the faceRash - “butterfly” on the face- without scarf lesion (only in discoid lupus)without scarf lesion (only in discoid lupus)- Rare: urticaria, vesicles, erithema Rare: urticaria, vesicles, erithema

multiform, lichen plan, paniculitis (= multiform, lichen plan, paniculitis (= profound lupus)profound lupus)

- Vasculitis lesions (SLE systemic, discoid, Vasculitis lesions (SLE systemic, discoid, subacute): purpura, subcutaneous nodules, subacute): purpura, subcutaneous nodules, infarctation at nails, ulcers, vasculitic infarctation at nails, ulcers, vasculitic urticaria, paniculitis, necrosis of fingersurticaria, paniculitis, necrosis of fingers

- Mucosa: Ulcer on oral, nasal mucosaMucosa: Ulcer on oral, nasal mucosa

SymptomsSymptoms

•Renal:Renal:- ½ pts - glomerulonephritis (most of ½ pts - glomerulonephritis (most of

the pts have Ig deposits in glomeruls)the pts have Ig deposits in glomeruls)

- Focal glomerulonefritis renal Focal glomerulonefritis renal sclerosissclerosis

- Without symptoms or nephrotic Without symptoms or nephrotic edemaedema

- haematuria, proteinuria, renal failurehaematuria, proteinuria, renal failure

SymptomsSymptoms

• Neurological symptoms:Neurological symptoms:- meningitis, spine cord, central and meningitis, spine cord, central and

peripheral nervesperipheral nerves- Unique or multiplesUnique or multiples- Associated with another organ lesionsAssociated with another organ lesions- Mild cognitive dysfunction (most frequent), Mild cognitive dysfunction (most frequent),

headache (migraine or unspecific headache (migraine or unspecific headache), muscular contractionheadache), muscular contraction

- Rare: psychosis, acute confusion, cerebro-Rare: psychosis, acute confusion, cerebro-vascular disease, aseptic meningitis, vascular disease, aseptic meningitis, mielopathy, mono or polineuropathy, mielopathy, mono or polineuropathy, Guillan-BarrGuillan-Barréé polineuropathy, depression, polineuropathy, depression, anxietyanxiety

SymptomsSymptoms

•Vascular symptoms:Vascular symptoms:- thrombosis in the vessel (anti thrombosis in the vessel (anti

fosfolipidic antibodies: anticoagulant fosfolipidic antibodies: anticoagulant (LA), anticardiolipid induce coagulation (LA), anticardiolipid induce coagulation without vasculitis)without vasculitis)

- VasculitisVasculitis- Cerebral embolus (Libman-Sacks Cerebral embolus (Libman-Sacks

endocarditis)endocarditis)- Vascular and cerebral lesions - IC and Vascular and cerebral lesions - IC and

hyperlipidemia (induced by GCSs) – in hyperlipidemia (induced by GCSs) – in chronic diseasechronic disease

SymptomsSymptoms

•Hematological:Hematological:

- Anemia – chronic disease in most of the Anemia – chronic disease in most of the ptspts

- hemolytic anemia – rare, with- hemolytic anemia – rare, with Coombs Test +Coombs Test +- Low Leucocytes (and lymphocytes)Low Leucocytes (and lymphocytes)- Low platelets (sometimes with purpura)Low platelets (sometimes with purpura)- Seldom – Abs anti - factors for coagulationSeldom – Abs anti - factors for coagulation (VIII, IX) hemorrhage(VIII, IX) hemorrhage

SymptomsSymptoms

•Heart and lungs:Heart and lungs:

- PericarditisPericarditis

- Myocarditis dysrhithmiasMyocarditis dysrhithmias

- Endocarditis (Libman-Sacks)Endocarditis (Libman-Sacks)

- Pleuritis –Pleuritis –

- Lung involvement: most frequent Lung involvement: most frequent infections, lupic Pneumonitis, lung infections, lupic Pneumonitis, lung fibrosis, PHT (rare) fibrosis, PHT (rare)

SymptomsSymptoms•Gastrointestinal:Gastrointestinal:

- Nausea, diarrhea, abdominal painNausea, diarrhea, abdominal pain- PeritonitisPeritonitis- VasculitisVasculitis- Pseudo-obstruction of the bowelPseudo-obstruction of the bowel- Lesion like sclerodermaLesion like scleroderma (motility disorder) (motility disorder)- Acute pancreatitis (disease, therapy with Acute pancreatitis (disease, therapy with

corticosteroid, azathioprine)corticosteroid, azathioprine)- High level of enzymes (ASAT, ALAT) (without High level of enzymes (ASAT, ALAT) (without

significant hepatic lesions)significant hepatic lesions)

SymptomsSymptoms•Eyes:Eyes:

- Retinian vasculitis blindnessRetinian vasculitis blindness

- ConjunctivitisConjunctivitis

- EpiscleritisEpiscleritis

- Optic nerve lesionOptic nerve lesion

- Sicca sd.Sicca sd.

Acut Lupus

Discoid lupusLupus Paniculitis

InvestigationInvestigation

• Antinuclear antibodies (ANA)Antinuclear antibodies (ANA):: human human substrate (WIL-2 or Hep-2) - + on > 95% substrate (WIL-2 or Hep-2) - + on > 95% (there are false + in normal subjects, (there are false + in normal subjects, other immune disease, viral infections, other immune disease, viral infections, chronic infections, drugs). Negative ANA chronic infections, drugs). Negative ANA does not exclude, but is less probabledoes not exclude, but is less probable

• Ab anti –ADN double strain (Ab anti –Ab anti –ADN double strain (Ab anti –dsDNA) and anti Sm - +, but not specific.dsDNA) and anti Sm - +, but not specific.

InvestigationsInvestigations

• C’ low (= activity of disease)C’ low (= activity of disease)• CHCH5050 – total hemolytic function of C’ – total hemolytic function of C’• C3, C4 – lowC3, C4 – low• CHCH50 50 veryvery low + C3 normal = innate deficiency low + C3 normal = innate deficiency

of C’ (associated frequent with SLE - ANA neg)of C’ (associated frequent with SLE - ANA neg)• Anemia (normochrom, sometimes hemolytic), Anemia (normochrom, sometimes hemolytic),

low leucocytes, low lymphocytes, low low leucocytes, low lymphocytes, low platteletsplattelets

• ESR – is correlated with activity of disease ESR – is correlated with activity of disease (sometimes)(sometimes)

• Proteinuria, hematuria, creatinin may be Proteinuria, hematuria, creatinin may be (periodic renal control to all pts)(periodic renal control to all pts)

Auto-AbsAuto-AbsIncidencIncidencee

AgAg Clinical Clinical significancesignificance

AntinucleaAntinuclearr

98%98% nucleunucleuss

diagnosticdiagnostic

Anti-ADNAnti-ADN 70%70% ADN ADN (ds)(ds)

Spf, renal les., Spf, renal les., activity indexactivity index

Anti-SmAnti-Sm 30%30% Prot. Prot. CuplateCuplated to d to nucl. nucl. ARNARN

spfspf

Anti-RNPAnti-RNP 30%30% Prot. Prot. Bond to Bond to U1ARNU1ARN

In Overlap sd. with In Overlap sd. with SLE, polimyositis, SLE, polimyositis, scleroderma, mixt scleroderma, mixt conj. tis. diseaseconj. tis. disease

May protect for Renal May protect for Renal les. les.

Auto-AbsAuto-AbsIncidenceIncidence AgAg Clinical Clinical

significancesignificance

Anti-Ro Anti-Ro (SS-A)(SS-A)

30%30% Prot. Prot. Bond to Bond to yy11--yy55 ARN ARN

SjSjöögren Sd., gren Sd., subacut lupus, subacut lupus, deficiency of C’, deficiency of C’, lupus with ANA- lupus with ANA- neg, renal Les. neg, renal Les.

Anti-La Anti-La

(SS-B)(SS-B)10%10% Fosfopro-Fosfopro-

teinteinAlways Associated Always Associated with Anti-Ro,with Anti-Ro,

SjSjöögren Sd. gren Sd.

Rarely in nephritisRarely in nephritis

Anti-Anti-histonhiston

70%70% HistonHiston SLE induce by SLE induce by drugsdrugs

Auto-AbsAuto-AbsIncidenceIncidence AgAg Clinical Clinical

SignificanceSignificance

Anti-Anti-PhospholiPhospholipidspids

50%50% PhospholipPhospholipidsids

3 type: lupus-3 type: lupus-Anticoagulant (LA)Anticoagulant (LA)

Anticardiolipin Anticardiolipin (aCL)(aCL)

False + syphilis False + syphilis (BFP)(BFP)

Anti-Anti-erythrocyterythrocytee

60%60% ErythrocyErythrocytete

Hemolisis (nu to Hemolisis (nu to all)all)

Anti-Anti-plateletsplatelets

30%30% Pl Surface Pl Surface and and cytoplasmcytoplasm

Low Pl (15%)Low Pl (15%)

Anti-Anti-lymphocytlymphocytee

70%70% Ly. SurfaceLy. Surface Low Leukocyte, T Low Leukocyte, T ly abnormalityly abnormality

Auto-AbsAuto-Abs

IncidencIncidencee

AgAg Clinical Clinical significancesignificance

Anti-Anti-neuronalineuronali

60%60% Suprafata Suprafata neurons si neurons si a lya ly

Lez. diffuse of Lez. diffuse of CNS at high CNS at high valuesvalues

Anti-Anti-ribosomal Pribosomal P

20%20% Ribosomal Ribosomal Prot. PProt. P

CNS les., CNS les., psychosis, psychosis, depressiondepression

DiagnosticDiagnostic• DiagnosticDiagnostic Criteria Criteria ARAARA (1997): (1997): 4 criteria (dg. + 98% spf and 97% sensib.) 4 criteria (dg. + 98% spf and 97% sensib.) 1.1. Rash one faceRash one face2.2. Discoid RashDiscoid Rash3.3. Photo sensibilityPhoto sensibility4.4. Oral UlcersOral Ulcers5.5. ArthritisArthritis6.6. SerositisSerositis7.7. Renal lesionRenal lesion8.8. Neurological involvementNeurological involvement9.9. Hematological AbnormalitiesHematological Abnormalities10.10. Immunologic AbnormalitiesImmunologic Abnormalities11.11. Antinuclear AntibodiesAntinuclear Antibodies

Differential DiagnosticDifferential Diagnostic

• Rheumatoid ArthritisRheumatoid Arthritis

• Other autoimmune diseasesOther autoimmune diseases

• DermatitisDermatitis

• Neurological Diseases: systemic Neurological Diseases: systemic sclerosis sclerosis

• Psychiatric DiseasesPsychiatric Diseases

• Hematological Diseases: idiopathic Hematological Diseases: idiopathic purpura with low plateletspurpura with low platelets

Progression of the Progression of the diseasedisease

• Remission – rarelyRemission – rarely

• 25% have a mild form of SLE - no 25% have a mild form of SLE - no lethal risklethal risk

• With activity and remission periodsWith activity and remission periods

TreatmentTreatment• No curative treatment No curative treatment • Mild FormMild Form: : • • better without glucocorticosteroids (GCS)better without glucocorticosteroids (GCS) • • NSADNSAD - - • • COX-2 inhibitorsCOX-2 inhibitors • • AntimalaricsAntimalarics: hidroxiclorochin (400 : hidroxiclorochin (400

mg/day)mg/day) • • UV protectionUV protection oigmentsoigments • • Topic or intralesionalTopic or intralesional: GCS, quinacrin, : GCS, quinacrin,

retinoids, dapsonretinoids, dapson • • for drug induce – withdraw the drug for drug induce – withdraw the drug

(rarely short term GCS)(rarely short term GCS)

TreatmentTreatment• Severe Form (renal, nervous system etc)Severe Form (renal, nervous system etc)::

• • Gluco-CorticosteroidsGluco-Corticosteroids: :

- 1-2 mg/kg/day (in 2-3 dose, at - 1-2 mg/kg/day (in 2-3 dose, at

8-12 hours; pulse therapy with 8-12 hours; pulse therapy with metilprednisolon 1000 mg/day iv, 2-5 days)metilprednisolon 1000 mg/day iv, 2-5 days)

- after that in the morning, in alternative - after that in the morning, in alternative days with GCS with short action: prednisone, days with GCS with short action: prednisone, prednisolon, metilprednisolon with prednisolon, metilprednisolon with maintenance doses: lowest dose without maintenance doses: lowest dose without symptomssymptoms

TreatmentTreatment

• Severe Form (renal, cardiac etc)Severe Form (renal, cardiac etc): : To Reduce side effects of GCS:To Reduce side effects of GCS: • • vaccinevaccine • • supplement: supplement: Vit DVit D, , CalciumCalcium, ,

CalcitoninCalcitonin, , BiphosphonatsBiphosphonats • • association with other therapyassociation with other therapy

TreatmentTreatment

•Severe FormSevere Form (renal, etc) (renal, etc)::

• • CyCytotoxic Agent (immunosuppressive)totoxic Agent (immunosuppressive): : AzathioprinAzathioprin 2-3 mg/kg/day p.o., 2-3 mg/kg/day p.o., ClorambucilClorambucil, , CiclofosfamidCiclofosfamid 10 -15 mg/kg/day iv for 4 weeks and 10 -15 mg/kg/day iv for 4 weeks and 1,5-2,5 mg/kg/day p.o., 1,5-2,5 mg/kg/day p.o., MethotrexatMethotrexat 5-20 mg/day, 5-20 mg/day, once/week, p.o. or s.c., once/week, p.o. or s.c., Mofetil MicofenolateMofetil Micofenolate – –[[CellCeptCellCeptRR, cp 500mg] - 1-2,5 g/day, p.o.), cp 500mg] - 1-2,5 g/day, p.o.)

• • reduce the GCS dose: two even 3 drugs reduce the GCS dose: two even 3 drugs (ciclofosfamid + azathioprina)(ciclofosfamid + azathioprina)

• • in renal lesions (GCS + ciclofosfamida iv – most in renal lesions (GCS + ciclofosfamida iv – most efficient, but very toxic)efficient, but very toxic)

• • try to reduce doses when the disease is controlled, try to reduce doses when the disease is controlled, (even withdraw them)(even withdraw them)

TreatmentTreatment

• Severe Form (renal etc)Severe Form (renal etc)::

• • AnticoagulantsAnticoagulants (warfarina) (warfarina)

• • Ig ivIg iv

• • renalrenal transplant - allographtransplant - allograph (high risk of (high risk of

rejection)rejection)

• • plasmaferesis plasmaferesis (associated with (associated with

cytotoxicity)cytotoxicity)

• • cyclosporinecyclosporine

New TreatmentsNew Treatments

• Mild Forms: Mild Forms: dihidroepiandrosterondihidroepiandrosteron

• RituxanRituxan (Mo Ab anti B Ly - anti CD20) (Mo Ab anti B Ly - anti CD20)

• Blocking the activity of B ly with Blocking the activity of B ly with anti-Blysanti-Blys (member of TNF (member of TNF superfamily molecules)superfamily molecules)

• induce tolerance to ADNinduce tolerance to ADN

• MoAb anti - TNFMoAb anti - TNF - disappointment - disappointment

PrognosticPrognostic• Prognostic is good in drug induced lupus (those Prognostic is good in drug induced lupus (those

drugs may be administered in pts with SLE)drugs may be administered in pts with SLE)• Remission (frequent, but short period) – la 20%Remission (frequent, but short period) – la 20%• Survival at 2 years: 90-95%Survival at 2 years: 90-95% at 5 years: 71-80%at 5 years: 71-80% at 10 years: 63-75%at 10 years: 63-75%• Prognostic is sever for renal involve. (mortality Prognostic is sever for renal involve. (mortality

50% at 10 years), CNS les. 50% at 10 years), CNS les. • Prognostic is severe when C’ is very low, or Prognostic is severe when C’ is very low, or

platelets are lowplatelets are low• Death: either from active disease, either Death: either from active disease, either

infections in first prima 10 years, or infections in first prima 10 years, or thrombembolism in next 10-20 yearsthrombembolism in next 10-20 years

Sjögren Sd. Sjögren Sd.

• Female (F/M = 9/1)Female (F/M = 9/1)

• Young ageYoung age

• HLA-B8, HLA-DR3HLA-B8, HLA-DR3

• modified Ags (viral – retrovirusuri?)modified Ags (viral – retrovirusuri?)

• lymphoid infiltrationlymphoid infiltration

Sjögren Sd. Sjögren Sd.

• oral involvement (xerostomia)oral involvement (xerostomia)

• ocular involvement (kerato-ocular involvement (kerato-conjunctivitis)conjunctivitis)

• exocrine glandular involvementexocrine glandular involvement

• extra glandular symptomsextra glandular symptoms

• Many Auto-Abs: RF, anti-nuclear Abs, Many Auto-Abs: RF, anti-nuclear Abs, etcetc

TherapyTherapy

• NSAIDNSAID

• GCSGCS

• Immunomodulation (cytostatic: Immunomodulation (cytostatic: methotrexat, ciclofosfamid, azathioprin)methotrexat, ciclofosfamid, azathioprin)

• Immunomodulation (cyclosporine, Immunomodulation (cyclosporine, tacrolimus)tacrolimus)

• Mo Ab (anti-CD3, -CD2, -CD4, CD7, -Mo Ab (anti-CD3, -CD2, -CD4, CD7, -CD8, CD25, -CD20; anti-TNF, anti-IL-6, CD8, CD25, -CD20; anti-TNF, anti-IL-6, anti-IL-8)anti-IL-8)

RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

• 1859 Sir Alfred Garrod - Rheumatoid Arthritis1859 Sir Alfred Garrod - Rheumatoid Arthritis• 1893 W.A. Lane – surgical therapy 1893 W.A. Lane – surgical therapy • 1897 - acetil salicic Acid1897 - acetil salicic Acid• 1929 – Gold Salts1929 – Gold Salts• 1939 - Sir McFarlane Burnet - Autoimmune 1939 - Sir McFarlane Burnet - Autoimmune

TheoryTheory• 1948 - Philip Hench & 1948 - Philip Hench & E. C. Kendall - E. C. Kendall -

antiinflamatorantiinflamatoryy e efffect fect of of steroi steroid d hormonhormonss• 1955 – prednison1955 – prednison was use for the first time was use for the first time• ‘‘90 – im90 – immmunomodulaunomodulatory effects of Motory effects of Mo Ab anti Ab anti

TNFTNF (Infliximab(Infliximab - Remicade- RemicadeRR))

RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

• 4500 b4500 b..h.h. – – indian scheleton indian scheleton in Tenesseeein Tenesseee

• 123 123 aa..hh. - Carata Samhita:. - Carata Samhita: tumefaction tumefaction, , pain of joints,pain of joints, initial at hand and legs, and initial at hand and legs, and after, extension in hole body, losing after, extension in hole body, losing appetite, occasionaly feverappetite, occasionaly fever

• 1591 - Guillaume de Baillou – 1591 - Guillaume de Baillou – first book first book abou arthritis abou arthritis : - R: - RAA + fibromialg + fibromialgyy

• 1763 – 1763 – first treatments with willow first treatments with willow extractsextracts

Jacob Jordaens (1593-1678) The Artist Jacob Jordaens (1593-1678) The Artist FamilyFamily

Prado, MadridPrado, Madrid

David Teniers, youngDavid Teniers, young (1610-1690) (1610-1690)

The Temptation of Saint AnthonyThe Temptation of Saint Anthony

AntwerpenAntwerpen

TestTest

• Which are arguments for SLE:Which are arguments for SLE:

1.1. 25 years old Man 25 years old Man

2.2. PolyserositisPolyserositis

3.3. High circulate immune complexesHigh circulate immune complexes

4.4. HighHigh IgEIgE

5.5. Radiology signs at sacroiliac jointsRadiology signs at sacroiliac joints

TestTest

• Which are arguments for SLE:Which are arguments for SLE:

1.1. 25 years old Man 25 years old Man

2.2. PolyserositisPolyserositis

3.3. High circulate immune complexes High circulate immune complexes

4.4. HighHigh IgE IgE

5.5. Radiology signs at sacroiliac jointsRadiology signs at sacroiliac joints