Connective tissue disorders
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Connective Tissue Disorders. Terminology. Collagen vascular diseases Auto immune diseases Rheumatology = study & treatment of diseases of immune system Examples: SLE JRA Dermatomyositis Vasculitides Ankylosing spondylitis. Immunological tolerance.

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  • Collagen vascular diseases

  • Auto immune diseases

  • Rheumatology = study & treatment of diseases of immune system

  • Examples:

    • SLE

    • JRA

    • Dermatomyositis

    • Vasculitides

    • Ankylosing spondylitis

Immunological tolerance
Immunological tolerance

  • Individual is incapable of developing an immune response against a specific antigen

  • Self tolerance = lack of immune responsiveness to one’s own tissue antigens

  • Necessary for our tissues to survive and live harmoniously with the body’s own lymphocytes

Mechanisms of tolerant state
Mechanisms of tolerant state

  • Central tolerance

    • Deletion of self-reactive T & B lymphocytes during maturation in central lymphoid organs (thymus & bone marrow)

    • T cells and B cells bearing receptors for autoantigens not present in thymus/bone marrow escape into the periphery

Peripheral tolerance
Peripheral tolerance

  • Self-reactive T cells that escape negative selection in thymus can potentially wreak havoc

  • Mechanisms in peripheral tissue to silence autoreactive T cells

    • Anergy = prolonged / irreversible inactivation of lymphocytes

    • Activation induced cell death ( Fas-Fas ligand system)

    • Peripheral suppression by T cells (regulatory T cells modulate function of other T cells)

Mechanisms of autoimmune disease
Mechanisms of autoimmune disease


    • failure of activation-induced cell death

    • breakdown of T cell anergy

    • bypass of B cell requirement for T cell Help

    • failure of T cell mediated suppression

    • molecular mimicry (infectious agents share epitopes with self antigen)

    • Polyclonal lymphocyte activation

    • Release of sequestered antigens (spermatozoa)

Infection in autoimmunity
Infection in autoimmunity

  • Microbes may trigger autoimmunity as follows :

    • Share cross-reacting epitopes with self–antigens

    • Microbial antigens & autoantigens may become associated →immunogenic units →bypass T cell tolerance

    • Infections→ tissue necrosis & inflammation → upregulation of co-stimulatory molecules on resting APCs→ breakdown of T cell anergy

Genetic factors
Genetic factors

  • Predisposition to autoimmune diseases

    • Familial clustering

    • Linkage of autoimmune disease to HLA II antigens

    • Induction of autoimmune disease in transgenic rats

Connective tissue disorders

Revised Diagnostic Criteria

  • Malar rash

  • Discoid rash

  • Photosensitivity

  • Oral ulcers

  • Arthritis

  • Serositis

  • Renal disorder

Connective tissue disorders

  • Haematologic disorder

  • Neurologic disoder

  • Immunologic disoder

  • Antinuclear antibody

    Diagnose if 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation

Model for pathogenesis of sle
Model for pathogenesis of SLE

Adapted from Pathologic basis of disease 7th edition

Clinical manifestations sle
Clinical manifestations SLE

  • Feature prevalence in pts %

    • Haematologic 100

    • Arthritis 90

    • Skin 85

    • Fever 83

    • Fatigue 81

    • Weight loss 63

    • Renal 50

    • CNS 50

Clinical sle
Clinical SLE

  • Feature prevalence in pts %

    • Pleuritis 46

    • Myalgia 33

    • Pericarditis 25

    • GIT 21

    • Raynaud’s phenomenon 20

    • Ocular 15

    • Peripheral neuropathy 14

Adapted from pathologic basis of disease 7th edition

Skin manifestations of sle
Skin Manifestations of SLE

Increased nailbed capillaries

Lupus nephritis
Lupus Nephritis

  • WHO has described 5 classes of renal disease in SLE

Lupus nephritis1
Lupus nephritis

  • WHO class I lupus nephritis

  • Minimal changes: <5% of biopsies

  • Light microscopy is normal

  • Immunoperoxidase staining will show extensive C1q (associated with IgG and C3) throughout mesangial areas.

Lupus nephritis2
Lupus nephritis

  • WHO class II lupus nephritis

  • Mesangial disease

  • 10–25% of renal biopsies.

  • Mesangial expansion but little increase in tuft cellularity and the peripheral capillary walls are normal.

Who ii severe
WHO II severe

  • Extensive mesangial IgG deposits demonsstrated with immunoperoxidase staining

  • Aggregates just begin to invade peripheral capillary walls.

  • This represents the most severe changes in this class.

Who iii

  • WHO class III lupus nephritis

  • Focal proliferative changes are seen on biopsy

  • Accounts for 20–35% of renal biopsies

Who iv

  • WHO class IV lupus nephritis

  • Diffuse proliferative changes

  • Accounts for 35–60% of biopsies

  • The tuft is increased in size by both a diffuse increase in matrix and an excess of cells

  • Capillary walls are irregularly thickened when stained with hematoxylin/eosin

Who v

  • WHO class V membranous

  • Accounts for 10–15% of biopsies

  • The predominant aggregates are along the outside of the capillary wall

  • Focal and diffuse proliferative lesions are absent

Vascular damage in nephritis
Vascular damage in nephritis

  • 'Thrombus' may occlude a glomerular capillary loop in more severe disease

  • Such a 'thrombus' contains platelets and cross–linked fibrin as well as immunoglobulins and thus has some characteristics of a TRUE thrombus

Management goals
Management goals

  • Early diagnosis

  • Appropriate therapy

  • Preserving kidney function

  • Preventing undue side effects

  • Thus early biopsy

    • Diagnosis

    • Prognosis

    • Guide therapy

Treatment recommendations
Treatment recommendations

  • Class I & II no specific therapy

  • Class III

    • mild → glucocorticoids

    • Moderate → glucocorticoids + MMF(mycophenolate mofetil)

    • Severe as for class IV

      Class IV induction (6 months) IV CYC or MMF

      maintenance: MMF or AZA or quarterly IV CYC

      Class V Glucocorticoid+/- (ciclosporin,AZA,MMF,CYC )


Current recommendations
Current recommendations

  • Immune therapy for Lupus

    • Anticytokines – TNF + IFN gamma pathway inhibition

    • Targeting B cells (CD20 –Rituximab)

    • Inhibiting co-stimulation- (anti-CD40L antibodies to prevent 2nd signal for T cell activation)

      Better safety profile than traditional immunosuppressive agents


  • Genetically engineered

  • Chimeric murine/human monoclonal antibody

  • Binds to cell surface marker CD20 which is mainly expressed on B cells

  • Used in > half a million patients since 1996

  • Used successfully in patients with therapy resistant SLE

Vasculitis treatment
Vasculitis treatment

  • Current therapy induces remission effectively


  • Significant & serious side effects

  • ? Long term maintenance regimens

  • ? Therapy resistant patients


Connective tissue disorders

  • New approaches using standard therapeutic agents

  • New immunosuppressive agents

  • IVIG and Plasma exchange

New look at old drugs
New look at old drugs

  • No evidence yet- still undergoing trials

  • Steroids ↑dose + cyclophosphamide-induction

  • Steroids ↓dose + Azathioprine – maintenance

  • Oral vs IV cyclophosphamide

  • PE+ oral CYC+ prednisolone instead of methyl prednisolone → benefit for 12months

  • MMF

Mycofenolatemofetil mmf

  • Potency to induce complete remission

  • Superior to pulsed IV CYC for induction of lupus nephritis

  • Fewer side effects

  • Alternative choice for maintenance therapy of severe LN

New immunomodulatory strategies biologic agents
New immunomodulatory strategies& biologic agents

  • Blockade of circulating mediators & surface receptors

  • Lymphocyte depletion &immunoablation

    • TNF-alpha blockade using infliximab & etanercept

      → improved control of refractory vasculitis

      →allowed lower steroid dosing in induction therapy

      →benefit as induction therapy in refractory WG

Immunoablation autologus stem cell transplant
Immunoablation &autologus stem cell transplant

  • Life saving

  • Costly

  • Benefit in severe auto immune disease


  • Early diagnosis

  • Early biopsy in renal disease

  • May still utilize tried & tested agents initially BUT in regimens that minimise adverse effects

  • Newer immunosuppressive & immunomodulatory strategies are becoming more popular


  • Kumar .Abbas. Fausto. Robbins and Cotran Pathologic basis of disease 7th edition

  • Richard johnson. John Feehally. CLINICAL NEPHROLOGY 2nd edition

  • Michael J. Dillon Vasculitis treatment-new therapeutic approaches. Review. Eur J Peditr (2006)

  • Sandra Navarra. Immune therapy of lupus: what is on the horizon? Nephrol Dial Transplant (2006)

  • Annette Friederike Jansson. Uwe Wintergerst et al.Rituximab-induced long-term remission in two children with SLE. Short report . Eur J Pediatr (2007)

  • Geoffrey R. Bihl, Micchelle Petri & Derick M. Fine. Kidney biopsy in lupus nephritis : look before you leap. Nephrol Dial Transplant (2006)