Andre bindevevssykdommer

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Andre bindevevssykdommer

• Abid Hussain Llohn
• Immunologisk og transfusjonsmedisinsk avd
• Akershus universitetssykehus

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Andre bindevevssykdommer

• Systemisk sklerose
• Polymyositt dermatomyositt
• Sjögrens syndrom
• Blandet bindevevssykdom (MCTD)

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Systemic Sclerosis

• Systemic disease
• History
• Hippocrates
• Carlo Curzio (1752)
• Fantonetti (1836)
• Prevalence 7/100.000
• 3-4 times higher risk for women
• Peak onset at age 30-50 years

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Systemic Sclerosis

• Clinical
• Vascular system
• Raynauds phenomenon
• 70 of patient initially present the symptoms
• 95 of all patients
• Skin
• Diffuse pruritis, induration, tightness,
  pigmentary changes
• Microstomia
• Telangiectasias
• Calcinosis
• CREST(Calcinosis, Raynauds phenomenon, Esophagus
  dysmotility, Sclerodactyli, Telangectasia)

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Clinical (2)

• Gastroesophageal reflux, Barrett metaplasia, anal
  sphincter incompetence
• Interstitial fibrosis, pulmonary hypertension
• Arthralgia, muscle weakness, acrosteolysis
• Facial pain and hand paresthesias due to sensory
  peripheral neuropathy
• Sicca syndrome in 5-7 of patients
• Renal crises
• Erectile dysfunction, dyspareunia

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Hypopigmentation. In black skin hypopigmentation
and vitiligo can occur in scleroderma
Acrosclerosis and terminal digit resorption
2
1
The hands show an alteration in pigment and loss
of shape on the terminal aspects of the fingers
flexion contractures of the fingers
Microstomia
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3
4
7
Raynauds fenomen
Telangiectasia.
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6
Nail-fold capillaroscopy Tortuous, dilated
capillary loops are seen at the base of the nail
in this patient.
Calcinosis
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8
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Systemic Sclerosis

• Classification
• Limited cutaneneous scleroderma (lcSSc)
• Raynauds phenomenon for years
• Skin changes limited to hands, face, feet,
  and forearms (acral distribution)
• Anti centromere antibodies (70)
• CREST
• Pulmonary hypertension (10-15)
• Diffuse cutaneous scleroderma (dcSSc)
• Raynauds phenomenon followed, within one
  year, by rapid skin changes (acral truncal)
• Tendon friction rub
• Anti Scl-70 (30), Anti-RNA polymerase III
  (12-15)
• Renal crisis, interstitial fibrosis in lungs
• Scleroderma sine scleroderma
• Environmentally induced scleroderma
• Overlap syndrome
• Pre-scleroderma

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Major Immunologic features

• Antinuclear antibodies (ANA)
• Sensitivity 85 Specificity 54
• Anti centromere antibodies (ACA)
• Sensitivity 24-33 Specificity90- 99,9
• Anti topoisomerase 1 (Scl-70) antibodies
• Sensitivity 20-43 Specificity 90-100

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Etiology/Pathogenesis

• Complex yet incompletely understood
• Immune activation, vascular damage, and excessive
  synthesis of extracellular matrix with deposition
  of increased amounts of structurally normal
  collagen are all known to be important in the
  development of scleroderma

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Etiology/Pathogenesis

• Genetic Factors
• 20 times higher prevalence in Choctaw
  native-Americans in Oklahoma. HLA DQ7, DR2
  strongly linked with anti-Scl-70.
• HLA-DQA1 0501 allel in 42 of Caucasian men with
  dsSSc, 29 in healthy men.
• Infectious Agents
• CMV, Human Herpes virus 5
• Noninfectious Environmental
• Petroleum-based products, Silica dust? Silicone
  implant?
• Dugs Bleomycin, Pentazocine, Cocaine
• Microchimerism

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Etiology/Pathogenesis

• Role of autoantibodies
• Association with highly specific autoantibodies
• Presence at disease onset
• Correlation between aAB titers SSc activity
  severity
• SSc aAB share the feature of pathogenic
  immunoglobulins

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Autoantibodies in SSc
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Anti centromere antibody (ACA)

• Initially described in 1980
• Six centromere proteins (CENP-A-F)
• All sera containing ACA react with CENP-B (80
  kDa).
• Highly specific for SSc,
• strongly associated with
• CREST

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Anti centromere antibody
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Anti-Scl-70 antibody

• Scl-70 (70 kDa) was initially described in 1979
• Subsequent analysis (1986) revealed topoisomerase
  1
• Interconverts different topological forms of
  DNA
• Located in the nucleoplasm, nucleolus
  nucleolar organizing region (NOR)
• Variation in anti-Scl-70 levels (ELISA) with
  extent of disease involvement, even seronegative
  conversion with disease remission
• IIF pattern is homogeneous
• or fine nuclear speckled,
• condensed chromatin
• material during mitosis

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Anti-Scl-70 antibody
Method ELISA
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Autoantibodies in SSc (2)
CIE, counterimmunoelectrophoresis HA,
hemagglutination IB, immunoblotting ID,
immunoduffusion IP, immunoprecipitation IIF,
indirect immunofluorescence ELISA, enzyme-linked
immunosorbent assay
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Treatment of SSc

• Skin Thickening D-pencillamine, methtrexate,
  interferon gamma, cyclophosphamide
• Raynaud Calcium blockers (Adalat), ACE
  inhibitors
• GIT symptoms H2 blockers, proton pump inhibitors
• Pulmonary fibrosis cyclophosphamide
• Renal crisis ACE inhibitors
• Myositis steroids
• Arthralgias NSAIDs

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Polymyositis dermatomyositis

• Idiopathic inflammatory myopathy
• Incidence 0,5-1/100.000/år
• 2 times higher risk for women
• Peak onset at age 50 (45-65) years
• 5-15 years in children

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Polymyositis DermatomyositisClinical

• 1- Dermatologic features
• Heliotrope rash / Guttron Papules
• Poikiloderma, calcinosis, mechanics
  hand
• 2- Proximal muscle weakness
• Trunk, thighs, shoulders
• 3- Muscle pain on grasping or spontaneously
• 4- Non destructive arthritis or arthralgia
• 5- Increased serum CPK, Aldolase
• 6- EMG myogenic changes
• 7- Positive anti-Jo 1 antibody
• 8- Systemic inflammatory signs
• 9- Pathologic inflammatory signs
• Diagnostic Criteria PM 4 findings fra 2-9
  DM 4 findings fra 2-9 Skin changes

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Dermatomyositis. Poikilodermatous changes
Typical dermatomyositis shows the overlap
features with early scleroderma-marked shininess
and erythema on the knuckles.
Gottrons papules.
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Clinical -2

• Cardiac CHF, arrhythmia
• Lung Interstitial lung disease, pneumonia
• Gastrointestinal Dysphagia
• Joints Arthralgias, symmetric arthritis
• Antisynthetase syndrome

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Polymyositis Dermatomyositis

• Type 1 Idiopathic Polymyositis (33)
• Type 2 Idiopathic Dermatomyositis (25)
• Type 3 Neoplasia related
• Type4 Childhood Polymyositis Dermatomyositis
• Type 5 Polymyositis Dermatomyositis
• associated with others rheumatic
  diseases
• Type 6 Inclusion body myositis

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Etiology/Pathogenesis

• Genetic predisposition
• Association with DR3, DR5, DR7?
• Immunological abnormalities
• Perforin-dependent cytotoxicity of CD8 T
  cells in PM
• ? expression of HLA class I in muscle cells
• Humoral immunity play larger role in DM
• Perivascular deposition of CD4 C5b-C9
  complex
• Infectious agents
• Viruses Coxsackievirus, echovirus, HTLV-1,
  HIV
• Toxoplasma and Borrelia species
• Drugs Hydroxyurea, Pencillamines, quinidine,
• phenylbutazone
• Silicon breast implants?

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Myositis Specific antibodies

• Anti-tRNA-synthetase antibodies
• Anti-Jo-1 (anti-histidyl-)
• PL-7, PL-12, OJ, EJ
• Anti-SRP (Signal Recognition Particles)
• (classic PM)
• Anti-Mi-2 (classic DM)

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Anti-Jo-1

• Antigen histidyl-tRNA-synthetase, 50-52kD
• Present in 20-40 of PM patients
• Specificity gt95
• IgG1 isotype
• IIF pattern
• Cytoplasmic speckled
• HLA-DR3/-DRw52
• Interstitial lung disease
• Drug induced PM (D-pencillamine)
• Rare in children DM

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Anti-SRP

• Antigen 7SL-RNA complex, 54-kD
• HLA DRw52
• IIF pattern cytoplasmic speckled
• Acute severe myositis
• No overlap with other CTDs

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Myositis Specific antibodies
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Myositis-overlap Antibodies
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Treatment

• Corticosteroids
• Methotrexate, Cyclophosphamide
• IVIG
• Rituximab

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Sjögrens Syndrome

• Systemic rheumatic disorder
• Mikulicz 1892
• Sjögren 1933
• Prevalence. 1 (30-40000 nordmenn)
• Peak incidence 40-50 years, Children rare
• Female to male ratio 9 to 1

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Sjögrens SyndromeClinical

• Sicca syndrome
• Keratoconjunctivitis
• Dry eyes with, reduced tear production and
  sandy sensation under the lids red eyes
  photosensitivity
• Xerostomia
• ? saliva production ? difficulties in chewing,
  swallowing, even speech abnormality in taste
  smell dental caries

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Sjögrens Syndrome

• Primary Sjögrens Syndrome
• Keratoconjunctivitis sicca
• Secondary Sjögrens Syndrome
• Keratoconjunctivitis sicca
• Other rheumatic disease

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Organ manifestations in pSS

• Dry mucous membranes
• Joint pain
• Fibromyalgi (20)
• Interstitial nephritis
• Chronic atrophic gastritis
• Primary biliary cirrhosis
• Peripheral neuropathy

• Mild interstitial disease
• Myalgia, muscle weakness
• Autoimmune thyroiditis
• Gravide SSA/SSB risiko for CHB
• Lymphomas ?risiko
• CNS disorders

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Other clinical features in pSS

• Fatigue 88
• Dry skin 88
• Arthralgia (hands) 85
• Dryness in URT 83
• Hoarseness 68
• Dysphagia 68
• Dry cough 54

• Diarrhea 54
• Vaginitis 53
• Dyspareunia 36
• ?sense of smell 37
• Synovitis (hands) 32
• Raynaud 29
• Purpura (legs) 15

Bergen
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Classification Criteria for SSAmerican-European
revised Rules for Classification of SS

• I- Ocular symptoms of inadequate tear production
• II- Oral symptoms of decreased saliva production
• III- Ocular signs of corneal damage due to
  inadequate
• tearing
• IV- Salivary gland histopathology demonstrating
  foci
• of lymphocytes
• V- Tests indicating impaired salivary gland
  function
• VI- Presence of autoantibodies (anti-Ro/SSA,
  anti-La/SSB, or both)
• Primary SS I- The presence of any 4 of 6, as
  long as either IV or VI is positive
• II- The presence of any 3
  of the 4 objective items III-VI
• Secondary SS The presence of item I or II plus 2
  from III-IV plus another well defined CTD
• Exclusion Criteria Past head and neck radiation
  treatment hepatitis C infection AIDS,
  pre-existing lymphoma GvHD, Use of
  anticholinergic drugs (since a time shorter than
  4-fold the half life of drug)

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Etiology/Pathogenesis

• Genetics
• HLA-DR3, HLA-B8, DQ-2
• Sex hormones
• Virus infection
• Epstein Barr virus
• Retrovirus HIV, HTLV-I
• Coxsackievirus

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Etiology/Pathogenesis

• Inflammatory reactivity
• Cell mediated immune response
• CD4 T cells (activated TH-1-type) predominates
• Cytokines (IL-1, IL-2, IL-6, TNF)
• B-cell abnormalities
• Hypergammaglobulinemia, elevated RF,
  anti-Ro/SSA anti-La/SSB

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Autoantibodies in SS

• ANA 70-80
• RF 80-90
• Anti-RO/SSA 70
• Anti-La/SSB 50

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Anti-La/SSB

• 48 kD antigen termination factor for RNA
  polymerase
• IIF Fine speckled
• Clinical
• Sjögrens syndrome (40-50)
• SLE (15)
• RA (5)
• Systemic sclerosis (1)
• MCTD (lt5)

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Treatment of SS

• Artificial tears
• Cholinergic agonists (pilocarpine)
• NSAIDs
• DMARDs (disease modifying antirheumatic drugs)
  methotrexate
• Dry skin Hydrokortisone krem
• Immunosuppressive agents vasculitis, visceral
  involvement

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Mixed Connective Tissue Disease (MCTD)

• Generalized CT disorder characterized by presence
  of anti-RNP with some clinical features of SLE,
  SSc, PM
• Incidence. 1/100000
• Peak incidence 15-25 years
• Female to male ratio 10 to 1

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MCTD Clinical manifestations

• Raynauds Phenomenon swollen hands or puffy
  fingers
• Absence of severe renal and CNS disease
• More severe arthritis insidious onset of
  pulmonary hypertension
• Anti-U1 RNP autoantibodies

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Digital gangrene in MCTD
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MCTD Diagnostic Criteria

• Common symptoms
• Raynauds phenomenon, swollen hands or
  fingers
• Anti-U1-RNP (titergt160)
• Mixed clinical features
• SLE-like findings
• Polyarthritis, lymphadenopathy,
  pericarditis or pleuritis,
• leukopenia or thrombocytopenia, facial
  erythema
• Scleroderma like findings
• Sclerodactyly, pulmonary fibrosis,
  hypomotility of esophagus
• Polymyositis-like findings
• Muscle weakness, ?serum muscle enzymes,
  myogenic pattern on EMG
• Diagnosis Positive anti-U1-RNP one common
  symptom one or more findings in two or three
  diseases

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MCTD Common clinical features
Cumulatively At presentation
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Etiology/Pathogenesis

• Immune response against apoptically modified
  self-antigens
• Molecular mimicry
• B lymphocyte hyperactivity

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Autoantibodies in MCTD

• ANA
• Sensitivity gt 95 with low specificity
• Anti-U1-RNP
• Sensitivity gt 90
• IIF pattern
• Coarse speckled
• Others RF, Antiphosphlipid antibodies
• Absence of anti-Sm, anti-dsDNA, anti-Scl-70,
  anticentrmere

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Treatment/Prognosis

• Steroids, NSAIDs, COX-2 inhibitors, Proton pump
  inhibitors, antimalarial agents, Prostaglandins,
  cytotoxic agents, Calcium channel blocking agents
• Occasionally evolve into SSc, SLE other CTD
• Pulmonary hypertension is the most frequent
  disease-associated cause of death