Rheumatic,Connective tissue disorders

8/14/2019 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.

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Rheumatic,Connective tissue disorders