auto-immune diseases leonard h sigal md, facp, facr p.r.i.- cd& e- immunology bristol-myers...
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Auto-immune diseasesAuto-immune diseases
Leonard H Sigal MD, FACP, FACR
P.R.I.- CD& E- Immunology
Bristol-Myers Squibb
Princeton, NJ
Clinical Professor of Medicine and Pediatrics
UMDNJ – Robert Wood Johnson Medical School
New Brunswick, NJ
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““Too little immunity” is a Too little immunity” is a problemproblem
But, what about “too much” immunity?
Recall: Critical to a proper immune response is being able to differentiate
“self” from “non-self”- the entity from the attackers
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““Too much immunity”Too much immunity”
Allergy- one theory: may be due to improved hygiene and lack of ambient bacterial exposures early in life
Auto-immunity- breakdown in tolerance- genetic predisposition plus environmental exposure as trigger
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AUTO-IMMUNITYAUTO-IMMUNITY Breakdown in ability to differentiate “self”
from “non-self” Tolerance is the ability to not
immunologically react to self Self-recognition (non-auto-aggressive
behavior) is part of many normal immune and homeostatic mechanisms
5 to 8% of the US population has an auto-immune disorder, may be more than one
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AUTO-IMMUNITYAUTO-IMMUNITY Tolerance starts in thymus and continues
with active suppression in the periphery Developing “immunocytes” are exposed to
self-antigens and if their receptor recognizes self too well the cell is eliminated (“negative selection”); no recognition “positive selection”; mid- ground survive but anergized or controlled peripherally.
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AUTO-IMMUNITYAUTO-IMMUNITY
Organ-specific: single or a fewSystemicAuto-immunity of a single organ
often means there is another organ affected
Family history is often positive
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Self-recognition- Self-recognition- salubrious examplessalubrious examples
Idiotype network- regulation of antibody production
Antigen presentation: MHC and cell-surface antigen receptors interact
Ligand-receptor interactions Antigen-specific suppressor cells & factors
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Why auto-immunityWhy auto-immunity?? There are “auto-aggressive” immune clones in
your body right now Under normal circumstances these are kept
under control- breakdown in control leads to auto-aggressive behavior
A breakdown in tolerance can lead to auto-immunity
In both SLE and RA, auto-antibodies may be present for up to 9 years prior to disease
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What Induces Autoimmunity?What Induces Autoimmunity?
CENTRAL (prenatal) and PERIPHERAL (later) MECHANISMS
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Aire- a key to tolerance induction in the Aire- a key to tolerance induction in the thymusthymus
Aire- auto-immune regulator: protein expressed in the thymus that induces thymic medullary epithelial cells to express 200 to 1200 non-thymic proteins, seemingly to allow intra-thymic processing and presentation of these proteins to lead to tolerance
Defect of Aire expression associated with APECED: autoimmune polyendocrinopathy candidiasis ectodermal dystrophy
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FOXp3FOXp3
Mouse strain “scurfy”: develops an X-linked recessive auto-immune disorder with multiple organ-specific inflammation, hypergammaglobulinemia, wasting and a lymphoproliferative disorder- due to uncontrolled activation and proliferation of CD4+ T-cells.
Similar human disease phenotype: – X-linked autoimmunity, allergic dysregulation syndrome
(XLAAD) – Immune dysregulation, polyendocrinopathy,
endocrinopathy, X-linked syndrome (IPEX).
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T-regs: CD4+ CD25+T-regs: CD4+ CD25+
GITR, CD62L, CTLA4 or E/7 integrin might be better markers than CD25
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non T-reg T regulatorsnon T-reg T regulators
CD4+ TH1 cells (secreting gamma interferon)CD4+ TH2 cells (secrete IL-4)CD4+CD25+ TH3 cells (IL-10 and/or TGF)CD4+ TR1 cells (secrete IL-10)intraepithelial CD8+ /cells (IL-10) and
natural killer T-cells (IL-4).
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Antigen Presenting Cell
MHC class I MHC class II
Adaptive/Acquired Immunity: Activation of Effector T cells
Viral antigenSelf antigen
CD4+HelperCD8+
Cytotoxic
Cytotoxic cell activityAntibodiesCytokines
Effector T cells
Foreignantigen
Processing & Loading
CD4+ Th17
Possible autoimmune activity
CD4+ CD25+Treg Foxp3
Regulatory functions
TGF + IL6
TGF
TGF IL10
IL17 IL22
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CD4 cell populations of note CD4 cell populations of note
Th1 Th2 Th17 Intracellular Extracellular pathogens Extracellular
pathogens like parasites bacteria*
IFN IL4 IL17ALT IL5 IL17FTNF IL6 IL6IL2 IL9
IL10IL13
* Bacterial species implicated include : Klebsiella pneumoniae, Bordetella pertusis, Citrobacter rodentium, and Borrelia burgdorferi
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T Cells Orchestrate the Adaptive and Innate Responses
CD4+T-helper cell
B-cell
Stem cellMacrophage
Tcell
Tcell
TcellT
cell
IL-2
IFN-, TN
F-
B-cell proliferationB-cell differentiation
cytokine productionAPC activityantibody production
IL-4, IL-10
IL-3
, IL
-7, G
M-C
SF
TNF-, IL-1, IL-6, IL-12
IFN-
IL-4
IL-5
TNF-
TGF-
OsteoclastRANK-L
Proliferate and differentiate to effectors
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2. Abnormal Immune Response
C1q,C2,C4 HLA-D2,3,8 MBL FcR 2A,3A,2BIL-10MCP-1PTPN22
RashNephritisArthritisLeukopeniaCNS dzCarditisClottingEtc
Renal FailureAtherosclerosisPulm fibrosisStrokeDamage from RxEtc
Chr. inflam
Chr. oxid.
UV lightGenderEBVOther InfeOthers
3. AutoantibodiesImmune Complexes
C3
C3a
Ag
DC
Bcell
Tcell
Suppressivenetworks
Environment
1. Genes
5.Damage4. Inflammation
Ag
DC
Bcell
Tcell
Suppressivenetworks
Courtesy Bevra Hahn, MD
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Auto-antibodies- receptor targets:Auto-antibodies- receptor targets: Receptor StimulateReceptor Stimulate BlockBlock TSH R. Graves Hashimoto’s Insulin R. Hypo- Hyperglycemia ACTH R. Addison’s Intrinsic
Factor Pernicious anemia
ACh R. Myasthenia gravis
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Auto-antibodies- other targetsAuto-antibodies- other targets::
Basement membrane Goodpasture’s syndrome Uveal tract Sympathetic ophthalmia Cardiac tissue Dressler’s syndrome Exocrine glands Sjogren’s syndrome Epidermal Bullous pemphigus
hemidesmosomes Blood cells Hemolytic anemia, AITP
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TREATMENT OF AUTO-TREATMENT OF AUTO-IMMUNITYIMMUNITY
If hormonal deficiency- REPLACEIf organ inflammation- SUPPRESS
Pulse corticosteroidsOral corticosteroidsCytotoxic agentsImmunomodulatory agentsPlasmapheresis
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TREATMENT OF AUTO-TREATMENT OF AUTO-IMMUNITYIMMUNITY
Neutralize inflammatory cytokines: Solubilized receptor TNF
Monoclonal antibody TNF, BLyS
Antibody to receptor IL-6
Receptor antagonist IL-1Suppress antigen-specific response
Co-stimulation blockade CTLA4Ig
Counterbalancing cytokines
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MP/DC
DR
TCR
Peptide
Inosinic acidInosinic acid purines
IMPDHpurines IMPDH
CD28
B CellT Cell
CD20
CD22
BCMAAPRIL
YBCR Anti-CD20
EdratideLJP394
CTLA4-Ig
Mycophenolate Mycophenolate
Anti-BLySTACI-Ig
BLyS
Anti-CD22
IFNaAnti-IFNa
Clinical Trials
Treg
X
Courtesy Bevra Hahn, MD
CD28
B7
B7
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Molecular biology has given us a Molecular biology has given us a new therapeutic worldnew therapeutic world
Replace deficiencies- IVIG, ADARepair genetic defects- ADAStem cell transplantsCytokines, receptors, antibodies- antagonist
and agonist Support patients until defect identified and
toxicity of therapy can be overcome
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Abbreviations in common useAbbreviations in common use SUFFIX DESCRIPTION -mab Monoclonal antibodies -umab Human mab -ximab Chimeric mab (mixture of mouse and human
structures) -zumab Humanized mab (very short murine sequences
remain, solely in the antigen-binding regions) -cept Receptor-antibody fusion protein, often Fc
component of an IgG -kinra Interleukin receptor antagonist (-kin is suffix for
interleukin; -ra for receptor antagonist)-nakinra IL1 receptor antagonist
-tinib Inhibitor of a tyrosine kinase
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SYSTEMIC INFLAMMATORY SYSTEMIC INFLAMMATORY SYNDROMESSYNDROMES
Systemic lupus erythematosus (SLE) Rheumatoid arthritis (RA) Juvenile rheumatoid arthritis (JRA)- aka
Juvenile idiopathic arthritis (JIA) Juvenile dermatomyositis Kawasaki disease Seronegative spondylarthropathies (SNSA)
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SYSTEMIC LUPUS SYSTEMIC LUPUS ERYTHEMATOSUSERYTHEMATOSUS
Multi-system inflammatory disease Episodic features in kidneys, brain, skin,
joints, serosa Broad range of severity Steady improvement in outcomes with the
evolution of better treatment Poor outcome: CNS or renal disease; lower
socio-economic status; “externalizedlocus of control”
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SYSTEMIC LUPUS SYSTEMIC LUPUS ERYTHEMATOSUS-CriteriaERYTHEMATOSUS-Criteria
Constitutional Skin: malar rash,
discoid lesions, photosensitivity
Oral/nasal muco-cutaneous lesions
Joints and Muscle Nephritis
Brain: seizures, psychosis Pleurisy/pericarditis Cytopenias Positive ANA Immunoserologies:
dsDNA, Sm, anti-cardiolipin
Need “4 of the 11” criteria
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SYSTEMIC LUPUS SYSTEMIC LUPUS ERYTHEMATOSUSERYTHEMATOSUS
Most common cause of death used to be: active disease
Now, it is consequences of STEROIDS: early: infection late: accelerated atherosclerosis
Consequences of cyclophosphamide: malignancy
Consequences of dialysis, hypertension, etc.end-organ damage
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Crow MK, A&R, 2003
IFN
IL-10
TGFTGF
TsTs
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Miyara et al, J Immunology, 2005
Treg (Foxp3 CD4+ T) are Depleted in Patients with Active SLE
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The Path to AutoAntibodies
Tissue
C’
Th BAPC/pDC Y
Treg TsuppPhago
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TGFTGF in Normals in Normals
NK
IL-2
NK
CD8
BTGF
T
AB
Treg CD4
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Patients with SLE Make Patients with SLE Make Abnormally Low Levels of Abnormally Low Levels of
TGFTGF
0
50
100
150
200
250
300
350
400
PBL NK T
Normal
SLETGFpg/ml
Human cells stimulated with anti-CD2
Ohtsuka et al, JI 1998
* *
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SYSTEMIC LUPUS SYSTEMIC LUPUS ERYTHEMATOSUSERYTHEMATOSUS
Therapy tailored to the organ system(s) affected, severity/type of damage
NSAIDsHydroxychloroquineCorticosteroidsCyclophosphamideAzathioprineBiologics in trials- BLyS, CTLA4Ig
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Rheumatoid arthritisRheumatoid arthritis
1% of population; seems to be decreasing in incidence
Synovitis, primarily of small joints of hands and feet
Symmetric- could this be neural input?Rheumatoid factorAnti-CCP (cyclic citrullinated peptide) prior
to disease
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Rheumatoid arthritis- focus?Rheumatoid arthritis- focus?
T cellMacrophageSynoviocyte (fibroblastoid)B cell
GeneticsAnti-CCP2
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Rheumatoid arthritis- therapiesRheumatoid arthritis- therapiesNSAIDs, COX2sCorticosteroidsMethotrexate, leflunomideCyclosporine (T cell target)Anti-CD3; total nodal irradiationAnti-TNFsCo-stimulation modulationB cell assassination; B cell activation blockade
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JUVENILE JUVENILE IDIOPATHIC IDIOPATHIC ARTHRITIS (JIA)-ILAR 1995ARTHRITIS (JIA)-ILAR 1995
Seven categories: Systemic OligoarthritisPolyarthritis (RF-)Polyarthritis (RF+)Psoriatic arthritisEnthesitis-related arthritis- related to SNSAsOther arthritis
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JUVENILE RHEUMATOID JUVENILE RHEUMATOID ARTHRITIS (JRA)/ ARTHRITIS (JRA)/
IDIOPATHIC ARTHRITIS (JIA)IDIOPATHIC ARTHRITIS (JIA)
Unknown etiology Unknown immune focus in joints, eyes, etc. Age < 16 years at onset Genetic pre-disposition Multiple cytokines involved,
e.g. TNF, IL-1, IL-6
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Macrophage Activation Macrophage Activation Syndrome- Syndrome- complication of systemic JRAcomplication of systemic JRA
Acute onset- high fever, lymphadenopathy, acute hepatitis, profound cytopenias, DIC
Can be post-viral, NSAIDs, Methotrexate Can mimic JRA flare Hematophagocytosis by well-differentiated
macrophages in bone marrow Rx?: steroids, IVIG, cyclosporin
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Macrophage activation syndromeMacrophage activation syndrome
Myelocyte within activated macrophage, and multiple adherent red blood cell and myeloid precursors.
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Macrophage activation syndromeMacrophage activation syndrome
Neutrophilic bands and metamyelocyte within an activated
macrophage.
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JUVENILE IDIOPATHIC JUVENILE IDIOPATHIC ARTHRITIS- New management ARTHRITIS- New management Methotrexate Etanercept Infliximab Adalimumab Leflunomide Abatacept (CTLA4-Ig) Anakinra not very effective Anti-IL-6 effective; not yet approved
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DERMATOMYOSITISDERMATOMYOSITIS
Multi-system inflammatory diseaseAdults and childrenAcute and chronic inflammation of
striated muscle and skin
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SERONEGATIVE SERONEGATIVE SPONDYLOARTHROPATHIESSPONDYLOARTHROPATHIES Ankylosing spondylitis Psoriatic arthritis Psoriatic spondyloarthropathy Inflammatory joint disease associated with
inflammatory bowel disease Reactive arthritis
(no longer called Reiter syndrome)
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SERONEGATIVE SERONEGATIVE SPONDYLOARTHROPATHIESSPONDYLOARTHROPATHIESNo serum rheumatoid factor Inflammation of spine and sacroiliac
jointsPrimary focus of inflammation is the
enthesisHLA-B27: independent linkage with
aortic disease (and anterior uveitis)
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SNSA- therapySNSA- therapy
NSAIDs, COX2SulfasalazineTNF blockade
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SYSTEMIC INFLAMMATORY SYSTEMIC INFLAMMATORY SYNDROMES-VasculitisSYNDROMES-Vasculitis
Classified by size of vessel affectedLarge: Takayasu Medium: PAN; Churg-Strauss Medium: Wegener; Goodpasture Small: Henoch-Schonlein Purpura
Pathogenesis is unclear: immune complex; auto-antibody; cellular reactivity
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COMBINATIONS OF FEATURES COMBINATIONS OF FEATURES GREATLY ENHANCE GREATLY ENHANCE
PROBABILITY OF PROBABILITY OF VASCULITISVASCULITISFeverGlomerulonephritisPalpable purpuraPeripheral neuropathyEstablished auto-immune diseaseIschemia, e.g. gut, heart, brain
especially in young patients
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DIAGNOSING DIAGNOSING VASCULITIDESVASCULITIDES
Based on collection of current findings Consider historical features May be overlap in syndromes Always try to substantiate diagnosis by
biopsy of affected tissue(s)
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RESULTS OF VASCULAR RESULTS OF VASCULAR INFLAMMATIONINFLAMMATION
STENOSIS & OCCLUSION ISCHEMIA / INFARCTIONDILATATION & RUPTURETURBULENT FLOW / BLEED
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VASCULITIDES OF OF OLDER OLDER PEOPLEPEOPLE
Giant cell arteritis Polyarteritis nodosa (PAN) Wegener granulomatosis Cryoglobulinemia Leukocytoclastic vasculitis
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SIGNS AND SYMPTOMS OF GCASIGNS AND SYMPTOMS OF GCA> 50 years of age 100%ESR: >100 60%Headache 70%Tenderness of arteries 50%Jaw claudication 50%Bruits 40%Visual symptoms: 10-15%
Diplopia Vision loss Ultimate blindness
Weight Loss 40%Fever 20%
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POLYMYALGIA RHEUMATICAPOLYMYALGIA RHEUMATICAShoulder and hip girdle painPerceived weakness, but normal strengthMorning stiffness, but not obvious synovitisOver age 50 Dramatic and rapid response to steroidsOverlap with GCA; up to 40% of PMR have GCA
(may be delayed) and up to 65% of GCA have PMRRecent studies suggest the shoulder and hip pain is
due to a mild synovitis of those joints
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GIANT CELL ARTERITISGIANT CELL ARTERITIS
Disrupted internal elastic lamella
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Not merely “temporal Not merely “temporal arteritis”arteritis”
ANEURYSMS
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Classical Polyarteritis Nodosa :Classical Polyarteritis Nodosa :Medium-sized vesselMedium-sized vessel involvement.
Absence of vasculitis of arterioles, venules andcapillaries. Renal diseaseRenal disease may occur, but notnot
glomerulonephritis.glomerulonephritis.
Microscopic Polyangiitis:Microscopic Polyangiitis: Involvement of "microscopic" vessels "microscopic" vessels (arterioles, venules, and capillaries), with or without medium-size with or without medium-size vessel vessel involvement.
Glomerulonephritis is commonGlomerulonephritis is common and pulmonary capillaritis may occur.
Few or no "immune deposits," no granulomasFew or no "immune deposits," no granulomas - distinct from HSP, cryoglobulinemic vasculitis, lupus, serum
sickness.
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Polyarteritis NodosaPolyarteritis NodosaSkin: Small (purpura) and medium (gangrene) vessels,
subcutaneous nodules, livedo reticularis, ischemic atrophy
Renal: Rapid renal failure as a consequence of multiple infarcts
Gastrointestinal: abdominal pain, bleeding, bowel perforation, and malabsorption.
Cardiac and pulmonary: Cardiomegaly, pericarditis, coronary artery involvement leading to ischemia and infarction,
Reproductive: Orchitis in males.
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WEGENER'S GRANULOMATOSISWEGENER'S GRANULOMATOSIS
• Idiopathic systemic inflammatory disease
with an unusual propensity to affect the
respiratory tract and kidneys.respiratory tract and kidneys.
• Small and medium-sized vessels.vessels.
• Tissue damage often associated with necrosis necrosis and and granuloma formation.granuloma formation.
• Active disease is often associated with
antibody formation to proteinase 3 (Pr3)antibody formation to proteinase 3 (Pr3).
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Wegener GranulomatosisWegener Granulomatosis
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Wegener GranulomatosisWegener Granulomatosis
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ANCA:ANCA: anti-neutrophil cytoplasmic anti-neutrophil cytoplasmic
antibodiesantibodies
Myeloperoxidase, Lactoferrin, Proteinase-3
elastase, cathepsin C
WG
MPA
CG
UC
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CryoglobulinemiaCryoglobulinemiaImmunoglobulin and other molecules associate in
blood; immune complexes then settle on blood vessel wall and cause inflammation.
Linked to underlying abnormality of plasma cells- making antibody that self-associates, causing complexes
Can be associated malignancy or underlying inflammatory disease, e.g. Sjogren syndrome
– BUT, “idiopathic” is common and no clear explanation until… a few years ago discovery of association with Hepatitis C infection
– Now known that essentially all of these “idiopathic” cases are due to Hepatitis C infection
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CryoglobulinemiaCryoglobulinemia
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BEHÇET SYNDROMEBEHÇET SYNDROMEAdamantiades-BehcetAdamantiades-Behcet
May have been described first by Hippocrates in the 5th century BC, in his 3rd Epidemion.
First modern formal description published in 1922 by Hulusi Behçet, Turkish dermatologist.
Sometimes called "Adamantiades’ syndrome" or "Adamantiades-Behçet syndrome".
Males:females = 1:1; more female in US, Japan, Korea, “the West”
Increasing prevalence with increased awareness– Turkey 300/100,000; US/EU 10-17/100,000
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BEHÇET SYNDROMEBEHÇET SYNDROME
HLA-B51The Silk Road
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BEHÇET SYNDROMEBEHÇET SYNDROME
Mucosal lesions- very painful aphthous ulcers Cutaneous lesions- erythema nodosum, acneiform,
folliculitis Ocular- panuveitis, anterior uveitis, retinal vasculitis Arthritis/arthralgia CNS and PNS disease- meningomyelitis, brainstem,
organic confusional syndromes, changes of personality, psychosis
GI inflammation- intestinal ulcerations Deep vein thrombosis/superficial thrombophlebitis Other organs: lungs, kidneys, epididimytis
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BEHÇET SYNDROMEBEHÇET SYNDROME
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BEHÇET SYNDROMEBEHÇET SYNDROME
Hypopyon
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BEHÇET SYNDROMEBEHÇET SYNDROME
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BEHÇET SYNDROMEBEHÇET SYNDROME
Pathergy sign
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VASCULITIDES OF OF YOUNGER PEOPLEYOUNGER PEOPLE
Takayasu aortitis Henoch-Schonlein purpura (HSP) Leukocytoclastic vasculitis (LCV) Kawasaki syndrome Serum sickness-immune complex-mediated Goodpasture syndrome
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TAKAYASU ARTERITISTAKAYASU ARTERITISYoung womenDisease of aorta and its first branchesLoss of pulse (“Pulseless disease”), stroke,
hypertensionCan affect pulmonary circulation, as wellProgression in up to half of patients even though
thought to be in remission; may occur silently
• Even when thought to be quiescent ~40% of patients
still have active inflammation at surgery
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Takayasu arteritisTakayasu arteritis
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HENOCH-SCHONLEIN HENOCH-SCHONLEIN PURPURAPURPURA
Palpable purpura
Glomerulonephritis
Arthritis
Abdominal pain
Malesfemales; mean age 5 yrs.
Preceding URI in 2/3 (1-3 weeks).
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HENOCH-SCHONLEIN HENOCH-SCHONLEIN PURPURAPURPURA
Small vessels, esp. Post-capillary venules.
All lesions about same stage in evolution.
Bx with i.F. TYPICALLY IgA deposits in skin and kidney
Usually single episodes < 4 weeks duration.
40% recurrence rate after period of wellness.
May be permanent renal damage
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Henoch-Schonlein purpuraHenoch-Schonlein purpura
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KAWASAKI DISEASE- CriteriaKAWASAKI DISEASE- Criteria
Fever 100% 5 days or more, remittent
Conjunctivitis 85 Bilateral
Lymphadenopathy 70 Cervical >1.5 cm
Lips/oral mucosa 90 Strawberry tongue
Dry, red vertical fissures Red oropharynx
Extremities 70 Erythema of palms/soles Convalescent fingertip
desquamation
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KAWASAKI DISEASE-KAWASAKI DISEASE-other featuresother features
Cardiac- most serious complicationPericarditis, arrhythmias,
infarction Myocarditis- Heart failure, aneurysms
CNS- irritability is almost universalconsider aseptic meningitis,
focal lesions, seizures- CNS vasculitis
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Goodpasture SyndromeGoodpasture Syndrome
Typically young men presenting with pulmonary-renal syndrome: hemoptysis AND renal failure
Caused by auto-antibodies that uniquely bind to basement membranes of lung and kidney, causing alveolitis and glomerulonephritis
Serum from patients can cause a similar syndrome to develop in serum-recipient monkeys
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Goodpasture SyndromeGoodpasture Syndrome
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Goodpasture SyndromeGoodpasture Syndrome
anti-GBM antibodies directed against noncollagenous (NC1) globular domain of the 3 chain of type IV GBM collagen
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VASCULITIS- TreatmentVASCULITIS- Treatment
Which organ system? How severe? Rate of damage? Potential reversibility?
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VASCULITIS- TreatmentVASCULITIS- Treatment
Corticosteroids Daily or Pulse Cytotoxic agents, e.g. Methotrexate
Azathioprine Cyclophosphamide
Immunomodulatories Mycophenolate mofetil
Cyclosporine
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ImmunomodulationImmunomodulationGeneral PrinciplesGeneral Principles
If we accept the premise that many systemic inflammatory diseases are auto-
immune, manipulation of the immune response may help control the disease
Identification of which immune mechanism is causative/contributory is crucial
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Immunomodulation-Immunomodulation- Immediate control of diseaseImmediate control of disease
Pulse IV corticosteroids can be very useful in getting some diseases under control immediately
Plasmapheresis has limited usefulness auto-antibody- (Goodpasture) or immune-complex-mediated (systemic JRA?) diseases
IVIG- ITP, dermatomyositis
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Immunomodulation: PresentImmunomodulation: Present
IVIG: Regulatory idiotypes vs. Saturating Fc receptors? vs. Induction of IL-10
Steroids: Lympholysis Cytotoxics: Kill inflammatory cells Pheresis: Removal of effector cells
and “evil humors”
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MOLECULAR BIOLOGIC MOLECULAR BIOLOGIC AGENTSAGENTS
Interfere with TNFSoluble receptor- Etanercept
Interfere with TNFMonoclonal antibody- Infliximab
Adalimumab Interfere with IL-1
Receptor antagonist- Anakinra Interfere with T cell costimulation Abatacept
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Immunomodulation: FutureImmunomodulation: Future
Interfere with antigen-specific responses- costimulation blockade*
Regulatory “anti-inflammatory” cytokineMonoclonal antibody and soluble
receptors for effector moleculesReceptor antagonists
*- Abatacept- BMS -please recall my conflict of interest
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Immunomodulation: FutureImmunomodulation: Future
Enzyme blockade- e.g. TACE, ICE*Kinase blockade, e.g. p38 MAP kinase-
intracellular messengers to nucleus Induce tolerance- oral tolerance is the
Holy Grail
*TNF or IL-1 activating-converting enzyme- frees TNF or IL-1 from membrane-bound form- makes it a circulating pro-inflammatory cytokine
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Molecular biology has given us a Molecular biology has given us a new therapeutic worldnew therapeutic world
Repair immunodeficiencies- IVIG, ADARepair genetic defects- on hold for nowStem cell transplantsCytokines, receptors, antibodies- antagonist
and agonist Support patients until defect identified and
toxicity of therapy can be overcome
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Confused?Confused?
[email protected] JCR: Journal of Clinical Rheumatology
– Basic Science for the Clinician
Immunology Today Nature Immunology Reviews Science- introductory pieces Annual Review of Immunology Current Opinions in Immunology
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Auto-immune diseasesAuto-immune diseases
Leonard H Sigal MD, FACP, FACR
P.R.I.- CD& E- Immunology
Bristol-Myers Squibb
Princeton, NJ
Clinical Professor of Medicine and Pediatrics
UMDNJ – Robert Wood Johnson Medical School
New Brunswick, NJ