Anti Scl-70 - Oslo universitetssykehus

Andre bindevevssykdommer
Abid Hussain Llohn
abll@ahus.no
Immunologisk og transfusjonsmedisinsk avdeling
Akershus universitetssykehus HF
06.10.2011
1
Andre bindevevssykdommer
•
•
•
•
Systemisk sklerose
Polymyositt – dermatomyositt
Sjögrens syndrom
Blandet bindevevssykdom (MCTD)
2
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
3
Systemic Sclerosis
• Clinical
• Vascular system
• Raynaud’s phenomenon
70% of patient initially present the symptoms
95% of all patients
• Skin
•
•
•
•
•
Diffuse pruritis, induration, tightness, pigmentary changes
Microstomia
Telangiectasias
Calcinosis
CREST(Calcinosis, Raynaud’s phenomenon, Esophagus
4
dysmotility, Sclerodactyli, Telangectasia)
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
5
Hypopigmentation. In black skin
hypopigmentation and vitiligo can occur
in scleroderma
1
The hands show an alteration in pigment and
loss of shape on the terminal aspects of the
fingers + flexion contractures of the fingers
Acrosclerosis and terminal
digit resorption
2
Microstomia
6
3
4
6
6
5 Raynaud’s fenomen
Calcinosis
7
Telangiectasia.
6
Nailā€fold capillaroscopy: Tortuous, dilated
capillary loops are seen at the base of the nail in
7
this patient.
8
7
Systemic Sclerosis
• Classification
• Limited cutaneneous scleroderma (lcSSc)
Raynaud’s 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)
•
•
•
•
Raynaud’s 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
8
Major Immunologic features
• Antinuclear antibodies (ANA)
Sensitivity: 85% Specificity: 54%
• Anti centromere antibodies (ACA)
Sensitivity: 24-33% Specificity:90- 99,9%
• Anti topoisomerase 1 (Scl-70) antibodies
Sensitivity: 20-43% Specificity: 90-100%
9
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
10
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
11
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
12
Autoantibodies in SSc
Autoantibody
Method of
testing
Clinical
association
Prognosis
ACA
(24-33%)
IIF, IB, ELISA
lcSSc, CREST
Better than anti-Scl-70
Pulmonary hypertension 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
13
Autoantibodies in SSc (cont)
Autoantibody
Method of Clinical association
testing
Prognosis
Anti-PM-Scl
(3%)
Anti-Th/TO
(2-5%)
ID, IP
lcSSc
PM/SSc overlap
Better response to
steroids
IP
LCssC, ↓ joint involvment, ↑ Worse prognosis with
puffy fingers, GIT
reduced 10 years
involvement, hypothyroidism 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, 5:80-93
14
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
15
Anti centromere antibody
SSC versus:
Normal controls
Other CTDs
Primary Raynaud
Non-SSc relatives
Sensitivity (%)
33
31
24
19
Specificity(%)
99.9
95-97
90
99
65
61
60
61
99.9
98
83
84
CREST versus:
Normal controls
Other CTDs
Primary Raynaud
SSc
Reveille JD: The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003, 5:80-93
Method: IIF
16
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
17
Anti-Scl-70 antibody
SSC versus:
Sensitivity
(%)
43
Specificity
(%)
100
Other CTDs
43
90
Primary Raynaud
28
98
Non-SSc relatives
35.5
100
Normal controls
Reveille JD: The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003, 5:80-93
Method: ELISA
18
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 15;110(4):1388-96.
19
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
20
Polymyositis – Dermatomyositis
Clinical
•
1- Dermatologic features
Heliotrope rash / Guttron Papules
Poikiloderma, calcinosis, mechanic’s 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
21
Dermatomyositis. Poikilodermatous changes
Gottron’s papules.
Typical dermatomyositis shows the overlap features
with early scleroderma, marked shininess and erythema
on the knuckles.
22
22
Clinical -2
•
•
•
•
•
Cardiac: CHF, arrhythmia
Lung: Interstitial lung disease, pneumonia
Gastrointestinal: Dysphagia
Joints: Arthralgias, symmetric arthritis
Antisynthetase syndrome
23
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
24
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?
25
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)
26
Anti-Jo-1
•
•
•
•
•
Antigen: histidyl-tRNA-synthetase, 50-52kD
Present in 20-40% of PM patients
Specificity >95%
IgG1 isotype
IIF pattern:
Cytoplasmic speckled
•
•
•
•
HLA-DR3/-DRw52
Interstitial lung disease
Drug induced PM (D-pencillamine)
Rare in children & DM
27
Anti-SRP
•
•
•
•
•
Antigen: 7SL-RNA complex, 54-kD
HLA DRw52
IIF pattern: cytoplasmic speckled
Acute severe myositis
No overlap with other CTDs
28
Myositis Specific antibodies
Ab
Ag
Clinical association
IIF pattern
Jo-1
Histidyl-tRNA synthetase
PM 30%; DM 13% Spec> 95% Cytoplasm: speckled
Lung fibrosis
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 7SLRNAcomplex
PM 5%; spec 83%
Acute onset; severe
Cytoplasm: speckled
Nucleolus
Mi-2
Nuclear protein complex
DM 15% - 35%; PM 5%-9%
Nucleoplasm
Fine speckled
?
29
Myositis-overlap Antibodies
Autoantibody
Clinical association
IIF pattern
PM-Scl
PM 8% -12%
Scleroderma 25%
PM/DM 5% - 10%
Sjögren’s 90%
PM/DM 4% - 17%
SLE & SSc 30%
MCTD 95%
PM/DM 4% - 17%
SLE & SSc 30%
Nucleolus & nucleus
Homogen
SSA/Ro
U1-nRNP
U2-nRNP
Nucleoplasm
Fine speckled
Nucleoplasm
Speckled
Nucleoplasm
Speckled
30
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 1993;329:1993-2000.
•
Levine, TD. Rituximab in the treatment of Dermatomyositis. Arthritis Rheum 2005;52:601-607
31
Sjögren’s 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
32
Sjögren’s Syndrome
Clinical
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
33
Sjögren’s Syndrome
• Primary Sjögren’s Syndrome
Keratoconjunctivitis sicca
• Secondary Sjögren’s Syndrome
Keratoconjunctivitis sicca
+
Other rheumatic disease
34
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
35
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%
36
Classification Criteria for SS
American-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; 61:664-558.
37
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; 25:117-33.
** Venables PJ; et al. The response to Epstein-Barr virus infection in Sjogren's syndrome. J Autoimmun 1989;2:439-48.
** Triantafyllopoulou A, et al. Autoimmunity and coxsackievirus infection in primary Sjogren's syndrome. Ann N Y Acad Sci
2005;1050:389-96.
** Vernant, JC, et al. T-lymphocyte alveolitis, tropical spastic paresis, and Sjogren syndrome. Lancet 1988; 1:177.
38
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, antiRo/SSA & anti-La/SSB
39
Autoantibodies in SS
• ANA 70-80%
• RF 80-90%
• Anti-RO/SSA 70%
• Anti-La/SSB 50%
40
Anti-La/SSB
• 48 kD antigen: termination factor for RNA polymerase
• IIF: Fine speckled
• Clinical:
•
•
•
•
•
Sjögren’s syndrome (40-50%)
SLE (15%)
RA (5%)
Systemic sclerosis (1%)
MCTD (<5%)
41
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
42
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
43
MCTD – Clinical manifestations
• Raynaud’s 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
44
Digital gangrene in MCTD
45
45
MCTD – Diagnostic Criteria
• Common symptoms
Raynaud’s phenomenon, swollen hands or fingers
• Anti-U1-RNP (titer>1600)
• 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 1992;19:259
46
MCTD – Common clinical
features
Cumulatively At presentation
Raynaud’s phenomenon
Arthralgia/arthritis
Esophageal hypomotility
Pulmonary dysfunction
Swollen hands
Myositis
Rash
Leukopenia
Sclerodactyly
Pleuritis/pericarditis
Pulmonary hypertension
96%
96%
66%
66%
66%
51%
53%
53%
49%
43%
23%
74%
68%
9%
rare
45%
2%
13%
9%
11%
19%
rare
47
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; 57:523.
48
Autoantibodies in MCTD
• ANA
Sensitivity: > 95% with low specificity
• Anti-U1-RNP
Sensitivity: > 90%
IIF pattern:
Coarse speckled
• Others: RF, Antiphosphlipid antibodies
• Absence of anti-Sm, anti-dsDNA, anti-Scl-70,
anticentrmere
49
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
50