Andre bindevevssykdommer

1
Andre bindevevssykdommer

• Abid Hussain Llohn
• abll_at_ahus.no
• Immunologisk og transfusjonsmedisinsk avdeling
• Akershus universitetssykehus HF
• 06.10.2011

2
Andre bindevevssykdommer

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

3
Systemic Sclerosis

• Systemic disease
• History
• Hippocrates
• Carlo Curzio (1752)
• Fantonetti (1836)
• Prevalence 7/100.000
• 3-5 times higher risk for women
• Peak onset at age 30-50 years

4
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)

5
Clinical (contd)

• 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

6
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
6
3
4
6
7
Telangiectasia.
Raynauds fenomen
5
6
Nail-fold capillaroscopy Tortuous, dilated
capillary loops are seen at the base of the nail
in this patient.
Calcinosis
7
8
7
8
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)
• 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

9
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

10
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

11
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

12
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
Autoantibody Method of testing Clinical association Prognosis
ACA (24-33) IIF, IB, ELISA lcSSc, CREST Pulmonary hypertension Better than anti-Scl-70 No benifit in following levels over time
Anti-Scl-70 (20-43) ID, CIE, IB, ELISA dcSSC, pulmonary fibrosis, cor pulmonale Worse prognoosis Levels fluctuate with severity of disease
Anti-RNAP (15) IP, EIA dcSSc, cor pulmonale, renal disease Increased mortality
AFA (4) IP dcSSc, pulmonary hypertension, renal disease Younger patients with internal organ involvement
Anti-RNP (8) IIF,ELISA,HA IP/CIE/ID lcSSc, cor pulmonale, sicca, myositis Benign prognosis, response to steroids
CIE counterimmunoelectrophoresis, HA
hemagglutination, IB immunoblotting, ID
immunoduffusion, IP immunoprecipitation,
IIF indirect immunofluorescence, ELISA
enzyme-linked immunosorbent assay
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Autoantibodies in SSc (cont)
Autoantibody Method of testing Clinical association Prognosis
Anti-PM-Scl (3) ID, IP lcSSc PM/SSc overlap Better response to steroids
Anti-Th/TO (2-5) IP LCssC, ? joint involvment, ? puffy fingers, GIT involvement, hypothyroidism Worse prognosis with reduced 10 years survival
Anti-Ku IB, IP, ELISA Overlap syndrome with scleroderma features
Anti-Ro ID, ELISA, IIF Seen with 1/3-1/2 of SSc patients with sicca complex
Reveille JD The clinical relevance of
autoantibodies in scleroderma. Arthritis Res Ther
2003, 580-93
15
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

16
Anti centromere antibody
SSC versus Sensitivity () Specificity()
Normal controls 33 99.9
Other CTDs 31 95-97
Primary Raynaud 24 90
Non-SSc relatives 19 99
CREST versus
Normal controls 65 99.9
Other CTDs 61 98
Primary Raynaud 60 83
SSc 61 84
Reveille JD The clinical relevance of
autoantibodies in scleroderma. Arthritis Res Ther
2003, 580-93 Method IIF
17
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

18
Anti-Scl-70 antibody
SSC versus Sensitivity () Specificity ()
Normal controls 43 100
Other CTDs 43 90
Primary Raynaud 28 98
Non-SSc relatives 35.5 100
Reveille JD The clinical relevance of
autoantibodies in scleroderma. Arthritis Res Ther
2003, 580-93 Method ELISA
19
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
• Autologous hematopoietic cell transplantation
  Blood. 2007 Aug 15110(4)1388-96.

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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

22
Dermatomyositis. Poikilodermatous changes
Gottrons papules.
Typical dermatomyositis shows the overlap
features with early scleroderma, marked shininess
and erythema on the knuckles.
22
23
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

28
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
Ab Ag Clinical association IIF pattern
Jo-1 Histidyl-tRNA synthetase PM 30 DM 13 Specgt 95 Lung fibrosis Cytoplasm speckled
PL-7 Threonyl-tRNA synthetase PM/DM 3-5, lung fibrosis Cytoplasm speckled
PL-12 Alanyl-tRNA-synthetase PM/DM 3, lung fibrosis Cytoplasm speckled
EJ Glycyl-tRNA synthetase PM 3 DM 80, Lung fibrosis Cytoplasm speckled
OJ Isoleucyl-tRNA synthetase PM/DM 3, lung fibrosis ?
SRP 54 kD protein in 7SL-RNAcomplex PM 5 spec 83 Acute onset severe Cytoplasm speckled Nucleolus
Mi-2 Nuclear protein complex DM 15 - 35 PM 5-9 Nucleoplasm Fine speckled
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Myositis-overlap Antibodies
Autoantibody Clinical association IIF pattern
PM-Scl PM 8 -12 Scleroderma 25 Nucleolus nucleus Homogen
SSA/Ro PM/DM 5 - 10 Sjögrens 90 Nucleoplasm Fine speckled
U1-nRNP PM/DM 4 - 17 SLE SSc 30 MCTD 95 Nucleoplasm Speckled
U2-nRNP PM/DM 4 - 17 SLE SSc 30 Nucleoplasm Speckled
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Treatment

• Corticosteroids
• Methotrexate, Cyclophosphamide
• IVIG
• Rituximab
• Ref.
• Dalakas MC, et al. A controlled trial of
  high-dose intravenous immune globulin infusions
  as treatment for dermatomyositis. N Engl J Med
  19933291993-2000.
• Levine, TD. Rituximab in the treatment of
  Dermatomyositis. Arthritis Rheum 200552601-607

32
Sjögrens Syndrome

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

33
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

34
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
• Fibromyalgia (20)
• Interstitial nephritis
• Chronic atrophic gastritis
• Primary biliary cirrhosis
• Peripheral neuropathy

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

36
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

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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
• Ref. Vitali, C, et al. Classification criteria
  for Sjögren's syndrome a revised version of the
  European criteria proposed by the
  American-European Consensus Group. Ann Rheum Dis
  2002 61664-558.

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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

Price EJ, et al. The etiopathogenesis of
Sjogren's syndrome. Semin Arthritis Rheum 1995
25117-33. Venables PJ et al. The response
to Epstein-Barr virus infection in Sjogren's
syndrome. J Autoimmun 19892439-48.
Triantafyllopoulou A, et al. Autoimmunity and
coxsackievirus infection in primary Sjogren's
syndrome. Ann N Y Acad Sci
20051050389-96. Vernant, JC, et al.
T-lymphocyte alveolitis, tropical spastic
paresis, and Sjogren syndrome. Lancet 1988
1177.
39
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

40
Autoantibodies in SS

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

41
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)

42
Treatment of SS

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

43
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

44
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

45
Digital gangrene in MCTD
45
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MCTD Diagnostic Criteria

• Common symptoms
• Raynauds phenomenon, swollen hands or
  fingers
• Anti-U1-RNP (titergt1600)
• 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
• Ref. Doria, A et al. J Rheumatol 199219259

47
MCTD Common clinical features
Cumulatively At presentation
Raynauds phenomenon 96 74
Arthralgia/arthritis 96 68
Esophageal hypomotility 66 9
Pulmonary dysfunction 66 rare
Swollen hands 66 45
Myositis 51 2
Rash 53 13
Leukopenia 53 9
Sclerodactyly 49 11
Pleuritis/pericarditis 43 19
Pulmonary hypertension 23 rare
48
Etiology/Pathogenesis

• Immune response against apoptically modified
  self-antigens
• Molecular mimicry
• B lymphocyte hyperactivity
• Ref. Greidinger EL, et al. A major B cell
  epitope present on the apoptotic but not the
  intact form of the U1-70-kDa
  ribonucleoprotein autoantigen. J Immunol 2004
  172 709-16.
• Davies, JM. Introduction Epitope mimicry as
  a component cause of autoimmune disease. Cell Mol
  Life Sci 2000 57523.

49
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

50
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