Rheumatic,Connective tissue disorders
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Transcript of Rheumatic,Connective tissue disorders
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Rheumatic &Connective Tissue Disorders
Involve Multiple organs (joint, skin, renal)
Bone and cartilage (synovial
membrane) Myelin basic protein of CNS
(multiple sclerosis)
Other associated disorders egSjogrens syndrome, polymyositis,vasculitis and scleroderma
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AETIOLOGYGenetic and environmental
components
Functional polymorphism of
genes active in apoptosis Antigen recognition
Adhesion and cytokineproduction and role in immunedsyregulation
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Aetiology cont Abnormalities in B and T
lymphocytes and myeloid cellsderived from haematopoietic stemcells and stromal cells.
Environmental triggers eg smokingand infections
Changes in levels of hormones(estrogens during and afterpregnancy= female preponderance todisorders)
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Systemic lupus erythematosus (SLE)
Invol ve j oints, sk in, ki dney,brai n l ung, heart and GIT Character ized by B ce ll
pol ycl onal acti vatio n,hypocomplementaemia;defective cellular mechanisms
Nucleosome, primary
immunogen in autoimmunity
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SLE presentations Involvement of the skin or joints and
complaints of photosensitive rash
often alopecia.
Systemic effects eg fatigue,musculoskeletal symptoms,
dermatological manifestations,
anaemia, and glomerulopathy,
cardiac and neuropsychiatriccomplications.
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Immunopathogenesis Strong HLA association (HLA-DR2
and DR3;HLA-A1 and B8)
Abnormal co-stimulatory signals toautoimmune B cells leading to
Anti-DNA, a nti-Sm and anti-nuclear r ibonucleoproteinantib odies 1C deposit ion in GB M (1 0% SL E
patie nts d eve lop end - stagerenal disease,ESRD). IgG anti- dsDNA antib odies.
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SLE skin disordersIC deposition and associated injury Deposition of Igs and complement
component (fibrinoid) below the basementmembrane of skin
Skin butterfly rash from sunlight on malar
face areas and the discoid rash (discoid)dipigmented, hair loss, scaly and shinydermal-epidermal junctions.
Profound hypocomplementaemia egreduced C4, C3 and C1q with marked
decreased CD8 suppressor activity and IL-2 production.
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SLE complications Opportunistic infections Psychiatric dysfunction common
manifestation
Women of child bearing have
gastrointestinal manifestations. Mixed connective tissues diseases
(MCTD) have features of lupus,polymyositis and scleroderma
Antibodies against blood cells causehaemolytis anaemia, neutropeniaand thrombocytopenia (Type II)
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SLE Diagnostic markers
IgG, DNA and complement foundin glomerular deposited immunecomplexes
Anti-DNA antibodies anti-Smithand anti-nuclear antibodies
Demonstration of dermatitis,photosensitivity and malar ordiscoid rash.
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LE bodies Haematoxylin stained
bodies: round, oval or
spindle in involved tissues
at the periphery of necrotic
areas.
Positive antinuclearantibodies and leucopenia.
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Rheuma toid arthritis(RA)Chronic destructive disease :causes
pain, stiffness, swelling and loss of
function in joints and inflammation
of other organs.
May lead to invasion of bone
cartilage characterized by
Presence of rheumatoid factors (RF)
associated HLA-DR4 or HLA-DR9class II MHC antigens.
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ImmunopathogenesisInvolves immune complex diseaseassociated with
RFs - IgG deposition in articularcartlilage (joint)
Aggregation/self-association Ig RF,complement activation (decreasedC3 and C4)
C5a mediated recruitment andactivation of polymorphs andcontinuous release and consumptionof IL-2.
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ExacerbationExacerbating factors in joint damage Hydrolytic enzymes
Collagenase and proteases
Prostaglandins, leukotrienes ROI, synovial macrophage derived IL-
1, IL-6, TNF- cytokines
Responsible for major membranedamage.
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Exacerbating factors contCollagenase produced by polymorphs,
synovial cells, fibroblasts andmonocyte-machrophage lineage cells
Degrades collagen
Frustrated macrophages produce
Leakages of acid hydrolases,neutrophil derived ROI, MBP, peptidesand peroxidase.
Remission function of cytokines:IL-10contributes to reduced inflammation
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RA complications 30% of RA suffer Sjogrens syndrome
(middle-aged women)
Pain, crippling deformity and loss ofindependence
Pregnancy may ameliorate RAdepending on
Hormonal balances and MHC class IIantigen expression betweenmaternal-foetal interphase
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RA diagnosisAgglutination tests used in
determination of Rheumatoid factors with cross-
reactivity in liver diseases,leishmaniasis, sarcoidoisis and
syphilis. About 60-90% of rheumatoid arthritis
patients seropositive.
Seropositivity associated with morerapid progressive, severe and activedisease with poor prognosis.
Concentrations of IgM and IgG RFs
correlate with disease activity.
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RA immunotherapy Immunosuppressive agents
(azathioprine, cyclophosphamide andmethotrexate)
Physical procedures (lymphopheresis
and total lymphoid irradiation) Corticosteroids
Cytokines and anti-TNF monoclonalantibodies.
Monoclonal antibodies against CD4,CD5, CD7, CD25 and CD45
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Syngrones syndrome
Inflammation of exocrine glands
Lacrimal and salivary glandsleading to hallmark symptoms
Xerostomia (dry mouth) andxerophthalmia (dry eyes)
Upper airway and
gastrointestinal mucous-secreting glands.
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SS symptoms
Increased plaque accumulation Thickened saliva, froth and gum
decay
Inflamed or smooth tongue
Dry or chapped lips and oral
candida infection.
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Secondary SSDemonstrates
IgM and IgG hypergammagloblnmia
Anti-salivary duct RFs
Positive anti-nuclear antibody (ANF)specific for Ro (SS-A) and La (SS-B)
antigens
Strong HLA DR3 and HLA B8
association
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Immunopathogenesis, SS
Involves genetic and T cell mediatedresponses. T cells infiltrate and destroy the
glands.
Epithelial cells in glands show anabnormal expression of HLA-DRmolecules.
All female Sjogrens patients have
antibodies against cytoplasmicantigens (anti-R0 /S-A and anti-La /SS-B)
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SS immunopathogenesis cont
Partial or complete destruction ofsalivary and lacrimal glands occurs
mediated by T and B lymphocyte
associated functions.
Patients show ocular and oralsymptoms linked with RA, SLE and
polymyositis.
Complications include infections,cancer and lymphomas.
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SS diagnosis
Antinuclear antibodies found(70% patients),
Anti-SS-A and SS-B antibodies
(40-70% patients) and Rheumatoid factors (60-70%
patients).
Schirmers test (eyes ability towet testing paper) useful.
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SS management strategies
Replacing external moisture, Stimulating endogenous
secretion and relieving systemic
manifestations with artificialtears and eye lubricant
ointments
Cyclosporin eye drops (Restacis)and hydroxychloroquine
(plaquenil) reduces inflammation
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Systemic sclerosisScleroderma connective-tissue
disease due to
Overproduction of collagen causing
Progressive symmetrical thickening,
Tightening and indurations of tissuein the skin and internal organs
Frequently involving gastrointestinaltract, respiratory, renal,cardiovascular and genitourinarytracts.
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Aetiology
Involves Endothelial cell injury
Fibroblast activation and
immunological derrangement.
Environmental factors eg silica
exposure, solvents (epoxy resins,
benzene and trichloroethylene), and
CMV and herpex viruses.
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Major characteristics
Speckled or nucleolar ANF Hypergammaglobulinaemia
Acute inflammatory lymphocytic
infiltration to diffuse fibrosis. Excessive production and
deposition of types I and IIIcollagen molecules found in theconnective tissue.
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Immunopathogenesis
Associated with T lymphocytes, phagocytes and mast
cells
Anti-nuclear antibodies, with
speckled pattern (95% patients) Topoisomerase (Scl-70) in 20-30%patients
Anti-centromere antibodies (60-90%patients)
Anti-topoisomerase (Scl-86) markerof severe diffuse disease in the lung.
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Pol ymyosi ti s(dermatomyosi tisIdiopathic inflammatory myopathytriggered possibly by
Viral infections
Injury or microvascular insult leads
to release of muscle autoantigenswhich activate T lymphocytes.
Damages to skeletal muscles aretriggered by toxoplasmosis,parvoviruses, immunizations, stress
and C2-deficiency
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Diagnostic criteria
Dependent on
Antisynthetase antibodies
Antinuclear antibodies
Antibodies to signal recognition
particles.