Outline

Definition Systemic lupus erythematosus Rheumatoid arthritis Sjogrens syndrome Progressive systemic sclerosis Polymyositis-Dermatomyositis Behcets disease Spondyloarthropathies

Rheumatic Diseases

Systemic Lupus Erythematosus (SLE)

SLE is a disease where a persons immune system attacks & injures the bodys own organs & tissues Almost every system of the body can be affected

General Features
Autoantibodies to multiple nuclear antigens, including double stranded DNA Numerous other antibodies Depression of serum complement during activity Immunoglobulins and complement deposit in the kidney and dermal-epidermal junction Genetic risk factors : Deficiency of early components of the classical complement cascade

General Features
Chronic systemic inflammatory disease Course of alternating exacerbations & remissions Involvement of multiple organ systems Cause is unknown Affects female predominantly

Genetics
Both genetic and environmental factors contribute HLA-DR2 & DR3 confer increased risk of SLE HLA-class II alleles are associated with antibodies to particular autoantigens Strongest link with HLA-DQ alleles and anti Ro Most common susceptibility gene is the null allele at the C4A locus located in class III region Prevalence of SLE is high in individuals with deficiencies of ( C4, C1q, C1r or C2 )

Apoptosis as a Source of Self Antigens

Immune responses to self antigens are fundamental to lupus pathogenesis Dead & dying cells are a major source of self antigens targeted in lupus Impaired clearance of apoptotic cells is considered important in pathogenesis

Impaired Elimination of Autoreactive Cells

Apoptosis of immune cells participating in autoimmune responses (T, B, DCs) is a major mechanism for the induction of self tolerance Gene mutations leading to defects in immune cell apoptosis have been linked to increased risk of lupus Development of autoreactive immune memory cells & the induction of lupus target organ injury lead to sustained & self-amplifying cycle of lupus-like autoimmunity

Autoantibody-mediated Pathogenesis of SLE

The Clearance of Apoptotic Cells

See next figure A-In the normal immune response, apoptotic cells are opsonized by complement components or pentraxins, and cleared by macrophages or dendritic cells Macrophages and DCs are induced to secrete immunosuppressive cytokines, such as TGF- and IL10 These cytokines act upon macrophages to induce an immunosupressant phenotye (type II), and upon T cells to downregulate TH1 cells and activate TREG cells
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The Clearance of Apoptotic Cells

B- When the clearance of apoptotic cells is impaired (because of a deficiency of complement or pentraxins, or inactivation by specific autoantibodies), the apoptotic cells undergo necrosis, triggering the release of proinflammatory cytokines such as IL-12 and TNF, and inducing the maturation of dendritic cells Mature dendritic cells can present apoptotic selfantigens leading to T-cell priming, with loss of selftolerance and induction of autoimmunity
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The Clearance of Apoptotic Cells

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Etiology of SLE

Initiation of Autoimmunity

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T and B Cell Abnormalities

Unchecked B lymphocyte activation and antibody production, probably due to uncontrolled T cell hyper-responsiveness Both Th1 and Th2 responses are elevated These T and B lymphocyte abnormalities have been attributed, at least partly, to defective production and function of TGF-

Immunopathology
DNA-anti DNA antibodies are important in lupus glomerulonephritis Autoantibodies to organ specific, cell surface antigens such as platelets leads to thrombocytopenia

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Immunopathology
Impaired clearance of immune complexes Impaired clearance of apoptotic bodies UV light which exacerbates disease activity in the majority of SLE can induce apoptosis of keratinocytes Tolerance to many self components fails in SLE, the precise mechanism is unknown

Pathogenesis of SLE

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The Adjuvant & Bystander Effect

Active infection or products of infection can provide the adjuvant response that is responsible for pathogenic autoimmunity

Bystander Effect of EBV

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Toll-like Receptor (TLR) Activation

Nucleic acid components associated with dead cell debris activate the adjuvant effect through TLR activation RNA activation of TLR7 on B cells & plasmacytoid DCs

Induction & Amplification of Lupus Autoimmunity

Although normal T cells exposed to self-antigen in the periphery become tolerized, lupus-prone T cells are sensitive to lower thresholds of activation by agonist or weak-agonist peptides Once activated, T cells can provide primary stimulation to genetically hyper-responsive B cells These autoantigen-stimulated B cells undergo somatic hypermutation and affinity maturation

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Induction & Amplification of Lupus Autoimmunity

On the synthesis of pathogenic autoantibodies, tissue damage results in the release of self-antigen Self antigens are also taken up and presented by specific antigen-presenting B cells in a second round of T-cell activation therefore leading to a positivefeedback cycle

Induction & Amplification of Lupus Autoimmunity

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Immunopathgenesis

Complement System
Deficiencies of the complement system may result in the aberrant clearance of apoptotic bodies and are implicated in the pathogenesis of lupus

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Immunopathology
Autoantibodies against: ds-DNA - ss-DNA Histones - Ro ( SS-A) RNPs CMI contributes to certain manifestations Autoantibodies play the key role in pathogenesis Immune complexes activate complement & engage FcR on macrophages & inflammatory cells

Clinical Features
Constitutional symptoms: fever, weight loss, malaise, lethargy Joints & muscles: polyarthritis, myalgias Skin: rash in exposed areas, few classic butterfly rash Nonscarring skin lesion termed subacute cutaneous lupus erythematosus occurs in patients with anti- Ro Vasculitic lesions

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Systemic Manifestations of SLE

Clinical Features
Polyserositis: pleurisy, pericarditis Kidneys; 75% of cases have nephritis at autopsy, mesangial GN ( IC deposition) Lungs: pleurisy, vasculitis Nervous: psychosis Eyes, GIT, cardiac Vascular: small & medium vessel vasculitis, hypercoagulability leads to arterial & venous occlusion in patients with antiphospholipid abs

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Clinical Features
Sjogrens syndrome in 30% of patients Drug-induced lupus-like syndrome; In susceptible individuals Hydralazine, procainamie Arthralgia, arthritis, rash, fever, pleurisy Anti histone & anti ss-DNA

Laboratory Findings
Anemia, neutropenia, thrombocytopenia Hematuria, proteinuria, red cell casts Increased ESR in active disease Immunologic diagnosis Autoantibodies: -Antinuclear antibodies; antibodies from all classes may form ANA

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Antinuclear Antibodies
ANA testing involves the use of IIF to detect antibodies that bind to various nuclear antigens Most laboratories employ a HEp-2 cell line (a line of human epithelial cells) as the substrate for this test The sensitivity of ANA tests can differ when other animal-based substrates are used ANAs are reported as titers, and higher values are more likely to represent true-positive results

Antinuclear Antibodies
Although titers of 1:20 or 1:40 are commonly reported as positive, patients with rheumatologic syndromes rarely have such low titers ANA tests are frequently positive in patients with connective tissue diseases In SLE and drug-induced lupus, the sensitivity of ANA testing approaches 100 percent; the specificity for SLE is approximately 90 percent

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Antinuclear Antibodies
Anti -native DNA (n-DNA) Anti-histone Anti ENA: Anti Sm (Smith): specific for SLE, present in 30% of cases Anti RNP (ribonucleoprotein): present in MCTD ,SLE Anti Ro (SS-A):present in SS, SLE Anti-La (SS-B): present in SS,SLE Anti-Scl-70 : present in sclerodermA Anti-Jo-1 : present in polymyositis Anti-centromere : present in CREST
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Interpretation of ANA by IF
A homogenous pattern may obscure a speckled or nucleolar pattern Antibodies are present at different titers, so dilution may change the pattern Stability of antigens is different, anti Ro can not be detected by tissue sections or human epithelial cells

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ANA Patterns
When an ANA test is positive, the nuclear staining pattern is frequently reported This pattern reflects the intracellular target of ANA The most commonly described nuclear staining patterns are : Homogeneous and rim: (both specific for SLE) Speckled: (associated with Sjgren's syndrome and mixed connective tissue disease) Nucleolar: (associated with diffuse scleroderma) Anti-centromere: (highly specific for CREST syndrome
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Indirect Immunofluorescence ANA Patterns

Is of limited value in discriminating SLE from other collagen diseases, but may suggest subsequent tests 1- Homogenous pattern: Associated with antibodies to DNA-histone High titers are more strongly associated with SLE than with other diseases Found in drug-induced lupus Found in many CT diseases

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ANA Patterns
2-Rim (peripheral pattern) : Is associated with anti-ds-DNA and has the highest specificity for SLE 3-Speckeled pattern: Detects numerous antigens (e.g., Sm, RNP, SS-A, SS-B) 4- Nucleolar pattern: Characteristic of scleroderma, rarely in other autoimmune disorders
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Hep-2 Cells Positive Rim Pattern

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Hep-2 Cells Positive Nucleolar Pattern

ANA-Homogenous Pattern on Hep-2 Cells

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ANA-Speckled Pattern on Hep-2 Cells

Other Causes of Positive ANA

Other rheumatic diseases Use of certain drugs ( hydralazine, isoniazid, chlorpromazine) Patients with various chronic infections

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Other Causes of Positive ANA

ANA tests can positive in many conditions, including: Subacute bacterial endocarditis Human immunodeficiency virus infection Liver disease Malignancy Type 1 diabetes Pulmonary fibrosis Multiple sclerosis Positive tests also occur in pregnant women and the elderly
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Interpretation of ANA Results

Positive ANA without other manifestations is not diagnostic High titers are most often associated with SLE May become negative during remission Titers correlate poorly with remission/relapse Persistently negative ANA occur in about 5% of SLE patients Negative ANA in patient with active multisystem disease is strong (but not absolute) evidence against SLE
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ANA-Negative SLE
Despite high sensitivity, a negative ANA test does not rule out SLE Rarely, patients with isolated anti-Ro (anti-SS-A) antibodies or antisingle-stranded DNA (anti-ssDNA) have a negative ANA test Also, patients with the systemic lupus erythematosuslike antiphospholipid syndrome may be ANA negative

Anti-extractable Nuclear Antigens (ENA)

Anti-RNP Found in 25-30% of SLE 10% of RA 22% of Scleroderma 100% of MCTD Anti-Sm: Speckeled pattern Found in 25-30% of SLE patients Most specific diagnostic test for SLE; occurs almost exclusively in SLE Serum levels are not related to disease activity

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Anti-Ro and Anti-La

Anti-Ro (SS-A) and anti-La (anti-SS-B) are commonly identified in patients with Sjgren's syndrome, and their presence is associated with extraglandular manifestations of the disease Anti-Ro activity is also found in approximately 40 percent of patients with SLE and is associated with photosensitive skin rash, pulmonary disease and lymphopenia, neonatal lupus

Anti-Ro and Anti-La

Anti-La activity is detected in 10 to 15 percent of patients with SLE and is associated with late-onset disease, secondary Sjgren's syndrome and neonatal lupus syndrome Anti-Ro and anti-La testing may help to confirm the diagnosis of Sjgren's syndrome These tests may also be useful in patients with a positive ANA test and suspected SLE

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Significance of Anti-RNP and Anti-Sm

Anti-RNP are detectable in 25-47% of SLE patients High titers of anti-RNP antibodies are diagnostic of mixed connective tissue disorder (MCTD) The measurement of anti-Sm and anti-RNP antibodies is more important in the diagnosis of SLE than in the follow-up of patients However, anti-RNP antibodies are more prevalent in patients with Raynaud's phenomenon and are associated with milder renal involvement On the contrary, anti-Sm antibodies are associated with the severity and the activity of renal involvement

Anti-double-stranded DNA
High titers of anti-dsDNA antibodies are highly specific for SLE However, only about 60 percent of patients with the disease have high anti-dsDNA titers Absence of anti-dsDNA should not be used to exclude the diagnosis of SLE Low titers of anti-dsDNA can be present in normal persons and in patients with Sjgren's syndrome, rheumatoid arthritis and other disorders The presence of anti-dsDNA tends to correlate with lupus nephritis, and the anti-dsDNA level often correlates with disease activity inSLE
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Crithidia Luciliae Positive Anti-native DNA

Anti Centromere
Present in 22 to 36 percent of patients with scleroderma Their presence is correlated with Raynaud's phenomenon, CREST syndrome and limited skin involvement Present in some patients with primary biliary cirrhosis Testing may be helpful when scleroderma is suspected

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ANTI-TOPOISOMERASE I
Anti-topoisomerase I ( anti-Scl-70) is highly specific and is found in 22 to 40 percent of patients with scleroderma Its presence is correlated with diffuse cutaneous disease, pulmonary fibrosis, cardiac involvement and longer disease duration Testing for anti-topoisomerase I may be useful in patients with suspected scleroderma

Hep-2 Cells Positive Anti-scleroderma-70

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Anti-Jo1
Anti-Jo1 (histidyl-tRNA synthetase) antibody is found in 30 percent of patients with polymyositis or dermatomyositis It is associated with pulmonary fibrosis and Raynaud's phenomenon

Hep-2 Cells Positive Anti-JO1

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Anti-native DNA
Anti-double stranded DNA Found in 40-80% of SLE patients (50% of negative patients have anti-Ro (ss-A) High specificity High titers are characteristic of SLE and rarely in other diseases (e.g.,chronic active hepatitis) Low titers are found in other rheumatic diseases Absence throughout clinical course is associated with improved prognosis Severe clinical disease frequently correlates with a high initial titer which declines with clinical improvement May be present for prolonged periods without clinical activity

Anti-single-stranded DNA
Found in all other rheumatic diseases Found in many chronic inflammatory conditions Not specific for SLE

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Other Autoantibodies
Antierythrocyte antibodies IgG antibodies, detected by direct Coombs test cause hemolytic anemia (warm antibodies) Antiphospholipids antibodies Occur in 10-15 % of patients Associated with false positive test for syphilis Can possess anticoagulant activity in vitro (Lupus anticoagulant) Prolongation of PTT Thrombotic states
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Other Autoantibodies
Circulating anticoagulants Anti-factor VIII Potent anticoagulant May be associated with bleeding Antiplatelet antibodies In 75-80 % f patients Thrombocytopenia

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Other Autoantibodies
Rheumatoid factor Present in 30% of cases Anticytoplasmic antibodies: Antimitochondrial, antiribosomal, antilysosomal: not organ or species specific False positive test for syphilis: occurs in less than 20% of cases

Complement and Immune Complexes

Decreased C3 and C4 in active lupus due to consumption by ICs. Helpful in following response to therapy ICs of n-DNA with anti n-DNA cause lupus nephritis & correlate with activity Cryoglobulins containing IgM, IgG aggregates and complement are present ( correlates with disease activity Circulating immune complexes are present in active disease
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Tissue Immunofluorescence
Kidneys: Granular deposition of Immunoglobulins & complement along glomerular basement membrane & in mesangium in lupus nephritis Skin: Almost 90% of patients with SLE have Igs (IgG or IgM) &complement deposition in derma-epidermal junction of sun-exposed skin Discoid lupus: deposition of Ig & Complement in involved skin

Discoid Lupus
Benign subtype of lupus May be precipitated by trauma, stress, sunburn Most patients only develop skin manifestations 10% of patients will go on to SLE Discoid skin lesions may occur in patients with SLE

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Diagnosis of Discoid Lupus

Skin biopsy Negative ANA

Treatment of SLE
Spontaneous remission do occur Spectrum of management: No treatment Minimal disease: nonsteroidal antiinflammatory drugs ( NSAIDs), antimalarial treatment Intensive disease: corticosteroids, cytotoxic drugs Immunosuppressive drugs

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Neonatal Lupus
Passively transferred autoimmune disease, transplacental passage of anti-Ro and/or anti-La Babies born to mothers with SLE or Sjogrens syndrome Serious complication is complete heart block More in patients with high titer anti-Ro and/or antiLa Combination of both anti-Ro and anti-La increases the likelihood of Cutaneous manifestations

Rheumatoid Arthritis
An autoimmune disease that is caused by chronic inflammation of the joints or the synovial membrane causing swelling, pain & at times deformity due to irreversible destruction of the cartilage

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Rheumatoid Arthritis
Presence of RF ( autoantibodies against Fc portion of IgG) in serum & synovial fluid Infiltration of lymphocytes & activated macrophages into synovium Local production of TNF alpha & other proinflammatory cytokines in inflamed synovium

Rheumatoid Factor

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Rheumatoid Arthritis
Chronic recurrent symptomatic inflammatory disease primarily involving the joints More in females Begins in small joints of hands and feet Deformities are common Extramedullary manifestations: Vasculitis, atrophy of skin & muscles Subcutaneous nodules, serositis, pneumonitis Enlargement of LNs & spleen

Etiology of RA
Genetic factors Environmental factors Hormonal factors

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Immunopathology
Genetically susceptible individual Environmental event, such as infection Inheritance of certain HLA-DRB alleles T cells are prominent in inflammatory infiltrate in rheumatoid synovium Tendency to a bias toward Th1 cytokine Macrophage-derived cytokines (TNF alpha & IL1 ) are responsible for degradation of cartilage

Pathogenesis of RA

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The Cytokine Network in RA

Immunopathology
The synovial infiltrate contains activated B cells ,ICs of IgG & RF fix complement & amplify inflammatory response PMNs predominate in synovial fluid & contribute to inflammation RFs may play a role in extraarticular manifestations Patients with vasculitis have high titers of monomeric & pentameric IgM, IgA ,& IgG RFs

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Activation of Synovial T Cells

Role of Infection in Autoimmunity

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Role of Complement in Joints

Role of Cytokines
Monocytes are attracted to the RA joint, where they differentiate into macrophages and become activated and secrete TNF and IL-1 TNF increases the expression of adhesion molecules on endothelial cells, which recruit more cells to the joint Chemokines, such MCP1 and IL-8, are also secreted by macrophages and attract more cells into the joint

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Role of Cytokines
IL-1 and TNF induce synovial fibroblasts to express cytokines (such as IL-6), chemokines (such as IL-8), growth factors (such as GM-CSF) and matrix metalloproteinases (MMPs), which contribute to cartilage and bone destruction TNF contributes to osteoclast activation and differentiation IL-1 mediates cartilage degradation directly by inducing the expression of MMPs by chondrocytes

Role of TNF in RA

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Role of Macrophages

Clinical Features
Onset mainly with joint manifestations Articular manifestations: Stiffness, joint pain, deformities Extraarticular manifestations: 20-25 % of cases SC nodules, pleurisy, pericarditis, vasculitis Sjogrens syndrome in 30% of cases Myositis Feltys syndrome; RA, splenomegaly, neutropenia

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Typical Deformities in RA

Laboratory Diagnosis
Normochromic normocytic anemia, thrombocytosis in activity Increased ESR, correlates with activity Synovial fluid is inflammatory than SLE RF in 80%, not specific for RA RF is positive in: SLE, SS ,PM Chronic infections ( hepatitis C ,SBE) Malignancy old age
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Laboratory Diagnosis
Many patients have ANA Serum complement usually normal, may be low in active vasculitis Cryoglobulinemia in rheumatoid vasculitis Anti-citrullinated-cyclic peptide (anti-CCP)

Anti-CCP
Low sensitivity, so not used as a screening test High specificity especially when present in high concentration( 98 % specificity) Helpful for choice of the best therapeutic strategy in patients with recent onset arthritis Could be detected in almost 70% of patients of recent onset RA Anti-CCP positive patients develop more severe radiological damage than patients who are anti-CCP negative
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Treatment
Physical therapy Drugs: Methotrexate, sulfasalazine, antimalarial, azathioprine, cyclosporin Anti TNF NSAIDs, corticosteroids Prognosis: Spontaneous remission rarely occurs The presence of rheumatoid nodules & high titers RF are unfavorable prognostic factors

Juvenile RA
Hidden RF Positive ANA in some patients Onset : less than 16 years May present as Stills disease, seronegative pauci-or polyarthritis, or seropositive polyarthritis identical to adult RA Upper respiratory tract infection and trauma may be precipitating factors

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Immunopathology
Both humoral and cellular defects occur Diffuse hypergammaglobulinemia 10% have positive IgM RF Theories of hidden RF : IgM RF binds IgG so can not be detected Abnormal IgM binds IgM RF Cold reactive pentameric IgM RFs (cryoglobulins) are associated with severe disease

Immunopathology
Increased serum complement Decreased synovial complement Association with certain HLA tissue types

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Clinical Features
Onset: in 20 % present < 4 years High fever , rash, polyserositis, hepatosplenomegaly,& lymphadenopathy (Sills disease) 40% present with pauciarticular arthritis 25% onset is late with RF positive Limitation of movements Systemic : cardiac, lung *Rarely Stills disease occurs in adults

Complications
Impairment of growth Vasculitis, encephalitis

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Laboratory Findings
Leukocytosis, some with leucopenia NN anemia, increased ESR & CRP Very high serum ferritin in Stills disease Positive RFs & ANA in older children with polyarticular disease ANA almost never occurs in Stills disease Hypergammaglobulinemia Increased neutrophils in synovial fluid

Treatment
Physical treatment Drugs: aspirin, NSAIDs, antimalarial, salfasalizine Corticosteroids in Stills disease Prognosis 70% spontaneous remission Stills disease tends to have several recurrences per year

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Sjogrens Syndrome (SS)

Chronic inflammatory disease of unknown cause Decreased salivary and lacrimal secretions leading to keratoconjunctivitis sica and xerostomia Infiltration of salivary and lacrimal glands by CD4 T & B cells Autoantibodies to Ro (SS-A) and La ( SS-B) Genetic predisposition linked to HLA region

Sjogrens Syndrome (SS)

Dryness of mucous membranes and skin Primary SS in 50% of cases 50% associated with RA, or other CT disorders 90% are females Middle age, may occur in children Carry risk for development of B-cell lymphoma

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Sjogrens Syndrome

Immunopathology
CMI plays a role, CD4 T cells predominate , (activated Th1) Epithelial cells in salivary glands express HLA-class II & B7, suggesting presentation of antigens to CD4 T cells B cells & plasma cells are present leading to hypergammaglobulinemia, Positive RF & anti Ro & anti La In primary SS : both anti Ro & anti La Anti-Ro & anti La are not specific for SS

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Immunopathology
Virus infection leads to IFN alpha production by plasmacytoid DC (pDC) Apoptosis of epithelial cells Exposure of SSA/SSB & RNP in apoptotic blebs B cells produce antibodies Immune complexes bind to Fc gamma IIa on pDC Secretion of IFN alpha Activation of T & B cells

Sjogrens Syndrome

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Anti-Ro
Present in 50% of patients with SLE Transplasental transfer of anti Ro and anti-La plays a direct role in pathogenesis of neonatal SLE

Clinical Features
Oral: dryness of mouth Ocular: burning, itching Dryness of mucous membranes, active synovitis ( in RA) Two thirds of primary SS have Raynauds phenomenon 10% have extraarticular manifestations: Kidneys, lung, LNs, muscles Few patients develop lymphomas

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Laboratory Diagnosis
Anemia, leukopenia, elevated ESR No immunologic test is diagnostic Increased gamma globulins Occasionally M band in serum protein electrophoresis RF in 90% ANA homogenous in 70% Anti La is specific for primary SS ONLY Anti Ro may be found in SS alone or with SLE Patients with SLE & RA have neither antiRo nor antiLa

Treatment
Oral hygiene, artificial tears, moisturing cream for skin Systemic: NSAIDs Corticosteroids or immunosuppression for severe cases Complications: Splenomegaly, vasculitis, 5% autoimmune thyroiditis, PBC, CAH, GN, PM, lymphomas

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Systemic Sclerosis (Scleroderma)

Disease of unknown cause characterized by abnormally increased collagen deposition in the skin Slowly progressive course or rapidly progressive if involving internal organs Third or fourth decade, children are occasionally affected More in women Patients with extensive visceral involvement often have widespread skin involvement

Systemic Sclerosis (SSc)

Autoimmune rheumatic CT disease Inflammation, fibrosis & hardening of the skin & internal tissues Stiffness, discomfort & often disfigurement In many patients the internal organs (heart, lung, blood vessels, kidneys) are involved leading to scarring & loss of function

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Etiology of SSc
Both genetic & environmental factors contribute Genetic variant of connective tissue growth factor (CTGF) CTGF is present in high levels in SSc

Initiation & Progression

4 components are involved in the initiation & progression of SSc: 1-Vascular dysfunction 2- Autoimmune process 3-Extravascular inflammation mediated by leucocytes 4- Uncontrolled CT fibrosis

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Scleroderma

Immunological Findings
Frequent ANA with speckled or nucleolar pattern Anticentromere antibodies particularly in limited scleroderma Antibodies against topoisomerase-1 (Scl-70) particularly in generalized disease

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Classification of Scleroderma

Skin Lesion in SSc

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Overlap of Collagen Diseases

CREST ( Limited Scleroderma)

Calcinosis Raynauds phenomenon Esophageal dysmotility Sclerodactly Telangiectasia

Morphea is a scleroderma-like cutaneous lesion without visceral involvement

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CREST

Immunopathology
Association of scleroderma with several autoimmune diseases: PBC, SS, thyroiditis Existence of overlap syndromes( features of scleroderma and SLE) Clinical similarity between scleroderma and GVHD The presence of antibodies to nuclear components All of the previous provide evidence of immune mechanisms in pathogenesis of scleroderma

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Immunopathology
CMI, antibodies, and circulating immune complexes have potential to injure vascular endothelium Cytokines produced by T cells & macrophages can activate fibroblasts to produce collagen and other matrix components

Clinical Features
Onset: Raynauds phenomenon in 90 % of cases, may precede other manifestations for many years Begins with skin changes In one third of patients polyarthralgias and polyarthritis are the first manifestation Rarely initial visceral involvement without skin changes

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Skin Abnormalities
3 stages Edematous phase ; hands, forearms, arms Sclerotic phase: skin is tight ,smooth Atrophic stage

Other Manifestations
Joints & muscles: arthralgias, stiffness Lungs: interstitial fibrosis Cardiac: Myocardial fibrosis Kidneys: Uncommon, scleroderma kidney GIT : common, dysphagia in 80% Sjogrens syndrome: 5-7 %

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Laboratory Diagnosis
NN anemia, microangiopathic anemia, elevated ESR Increased gamma globulins: frequent ANA in 90 %: speckled or nucleolar Anticentromere in CREST Anti Scl-70 in diffuse disease

Hep-2 Cells Anticentromere Antibodies by IIF

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Treatment
No treatment Corticosteroids for myositis Cyclophosphamide for lung disease Complications Spontaneous remission occurs Progression from dermal to visceral involvement

Mixed Connective Tissue Disease (MCTD)

Syndrome with features of : Scleroderma, RA, SLE, & PM Clinical features Arthritis, Raynauds phenomenon Scleroderma of fingers Muscle weakness & tenderness Intestinal lung disease Skin rash resembling DM or SLE Renal disease is unusual

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Mixed Connective Tissue Disease (MCTD)

About 10% of SLE patients fulfill criteria of MCTD ANA profile: High titer of anti-RNP in more than 95 % of patients without anti-Sm and other antibodies is characteristic of MCTD

Idiopathic Inflammatory Myopathy Polymyocytis (PM)

Non genetic inflammatory myopathy May be idiopathic or due to infection May be associated with skin disease (dermatomyositis), collagen or malignant disease Syndrome may include pulmonary fibrosis , Raynauds syndrome

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Immunopathology
An unknown trigger (for example viral infection or ultraviolet radiation) in the respiratory tract or through the skin leads to the cleavage of histidyltRNA synthetase by granzyme B through antiviral CD8+ T lymphocytes in the lungs Upon activation, the immature DC matures into APC and undergoes changes that enable it to activate pathogen-specific lymphocytes in the lymph node

Immunopathology
T lymphocytes become activated and B lymphocytes, with active help from CD4+ T lymphocytes, proliferate and differentiate into plasma cells Activated DCs, T lymphocytes, and B lymphocytes could release cytokines into the bloodstream

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Immunopathology
T lymphocytes have been shown to bind in close contact with muscle cells and to release perforin, granzyme A, and granulysin, which may cause necrosis of muscle tissue or cells

CD8 Infiltration of Muscle

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Immunological Findings
Autoantibodies to : Aminoacyl-tRNA synthetases, Signal recognition particle, and Nuclear antigens Increased expression of class I and II molecules on myocytes CD8 T cell infiltration of muscle in PM Perivascular infiltrates of B cells & CD4 T cells in muscle in DM Deposition of Ig & MAC in microvasculature in DM
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Diagnosis
Serum CK is the most useful enzyme, increased in 70% of patients ( level becomes normal with steroid therapy) Serum aldolase is increased in 70 % of cases Serum LD is increased in 25 % of cases Serum AST is increased in 25 % of cases Increased ANA titer in 20 % of cases RF may be present in 50 % of cases Muscle biopsy findings are definitive

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Dermatomyositis

General Features
Acute and chronic inflammatory disease of muscle and skin at any age More in women Classified into 6 categories 1-Idiopathic PM 2- Idiopathic DM 3- PM-DM associated with cancer 4- Childhood PM-DM 5- PM-DM associated with other rheumatic diseases( SS, PSS,DM) 6- Inclusion body myositis
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Immunopathology
Associated with class II HLA alleles (HLA-DQ) Muscle damage in PM & inclusion body myositis (CMI) Evidence for perforin-mediated cytotoxicity by CD8 T cells Muscle fibers in myositis express increased levels of HLA-class I Humoral immunity has role in DM MAC deposits in DM leads to tissue damage Biopsy of involved muscles is diagnostic in 50-80%
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Clinical Features
Muscle : weakness of involved muscle Skin: characteristic rash in 40% ( thickening, eruption) Cancer : concomitant malignant tumor Miscellaneous: mild arthritis, SS in 5-7 % In children: vasculitis leads to GI ulceration

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Laboratory Diagnosis
Increased ESR, mild anemia, 50% increased alpha2 & gamma globulins Myoglobinemia, myoglobinuria Increased CK, GOT, aldolase Anti Jo-1( PM-1) in PM , Anti Mi-2 in DM Antibodies to cytoplasmic antigen signal recognition particle (SRP) in acute PM Antibodies to PM-Scl (a nucleolar ag ) in patients with PM & scleroderma Anti RNP in myositis with MCTD

Behcets Disease
Chronic inflammatory disease affecting adults Aphthous stomatitis, iritis, genital ulcers Skin vasculitis, pulmonary artery aneurysm Arthritis, thrombophlebitis Pathergy ( a pastular lesion appearing after needle puncture of the skin) is highly suggestive

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Behcets Disease
Genetic & environmental factors HLA association A virus may play a role Antibodies against various human mucosal antigens Immunofluorescence shows vascular deposition of Igs & circulating anticytoplasmic antibodies Amyloidosis may develop in some patients Treatment: corticosteroids, chlorambucil

Spondyloarthropathies
Ankylosing spondylitis Reiters syndrome Psoriatic arthritis Relapsing polychondritis

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General Features
Absence of RF Absence of ANA A predilection for axial skeletal involvement particularly sacroiliac joints Asymptomatic pattern of peripheral joint involvement ( tenosynovitis producing dactylitis) Association of HLA B27

Ankylosis Spondylitis
Chronic progressive inflammatory disorder involving sacroiliac joints & large peripheral joints 90% in males in second or third decade Low back pain & stiffness Ankylosing in sacroiliac joints & spine Peripheral arthritis if present involves shoulder or hips 25% have iritis & iridocyclitis

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Ankylosing Spondylitis
Genetic disease, environmental factors may be involved HLA B27 may present an arthritogenic peptide, or act as autoantigen Increased ESR & anemia in active disease Patients with inflammatory bowel disease can develop sacroiliitis & spondylitis Treatment: antiinflammatory, physical therapy

Reiters Syndrome
A triad of : arthritis, urethritis, & conjunctivitis Asymmetric arthritis, oligoarticular Fever & malaise in acute arthritis Urethritis is frequently asymmptomatic Mucocutaneous manifestations: painless oral ulcerations, thickening of palms and soles Complications: spondylitis ,carditis

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Reiters Syndrome
Mild leukocytosis, sterile synovial fluid Increased synovial fluid PMN Many follow bacterial infection( shigella, salmonella) Arthritis follows after 1-3 weeks of infection Autoimmune process triggered by infection Treatment: NSAIDs, immunosuppressive Recurrences are common

Psoriatic Arthritis
Chronic recurrent, asymmetric, erosive polyarthritis that occurs in 25% of psoriasis Arthritis is preceded by skin disease Severe erosion may lead to deformity of hands and feet Vertebral involvement can result in ankylosing of the spine Characteristic radiological changes HLA-B27 in 45% of cases

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Laboratory Findings
Increased ESR, mild anemia Hyperuricemia in severe skin disease Negative RF Normal immunoglobulins Synovial fluid ( increased PMN)

Relapsing Polychondritis
Rare disease Recurrent episodes of inflammatory necrosis involving cartilaginous tissues of ears, nose, upper respiratory tract, & peripheral joints May occur alone or with RA, SLE, systemic vasculitis, or malignancy Deformities in ear, nose & collapse of trachea

151

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Relapsing Polychondritis
Infiltration of lesions with lymphocytes, plasma cells & PMN Immune complexes: at fibrocartilagenous junction Antibodies to human collagen type II ( seen in other rheumatic diseases) CD4 in inflammatory infiltrates Laboratory abnormalities: Increased ESR Increased Igs, False positive VDRL

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