Andre bindevevssykdommer
Abid Hussain Llohn
abll@ahus.no
Immunologisk og transfusjonsmedisinsk avdeling
Akershus universitetssykehus HF
06.10.2011
1
Andre bindevevssykdommer
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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
• 3-5 times higher risk for women
• Peak onset at age 30-50 years
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Systemic Sclerosis
• Clinical
• Vascular system
• Raynaud’s phenomenon
70% of patient initially present the symptoms
95% of all patients
• Skin
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Diffuse pruritis, induration, tightness, pigmentary changes
Microstomia
Telangiectasias
Calcinosis
CREST(Calcinosis, Raynaud’s phenomenon, Esophagus
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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
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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
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3
4
6
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5 Raynaud’s fenomen
Calcinosis
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Telangiectasia.
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Nail‐fold capillaroscopy: Tortuous, dilated
capillary loops are seen at the base of the nail in
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this patient.
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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)
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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
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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%
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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
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
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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
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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
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
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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
SSC versus:
Sensitivity
(%)
43
Specificity
(%)
100
Other CTDs
43
90
Primary Raynaud
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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
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Treatment of SSc
• Skin Thickening: D-pencillamine, methtrexate, interferon gamma,
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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.
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Polymyositis – dermatomyositis
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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 – Dermatomyositis
Clinical
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1- Dermatologic features
Heliotrope rash / Guttron Papules
Poikiloderma, calcinosis, mechanic’s hand
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2- Proximal muscle weakness
Trunk, thighs, shoulders
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3- Muscle
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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
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Diagnostic Criteria:
PM: ≥ 4 findings fra 2-9; DM: ≥ 4 findings fra 2-9 +Skin changes
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Dermatomyositis. Poikilodermatous changes
Gottron’s papules.
Typical dermatomyositis shows the overlap features
with early scleroderma, marked shininess and erythema
on the knuckles.
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Clinical -2
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Cardiac: CHF, arrhythmia
Lung: Interstitial lung disease, pneumonia
Gastrointestinal: Dysphagia
Joints: Arthralgias, symmetric arthritis
Antisynthetase syndrome
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Polymyositis – Dermatomyositis
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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
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Antigen: histidyl-tRNA-synthetase, 50-52kD
Present in 20-40% of PM patients
Specificity >95%
IgG1 isotype
IIF pattern:
Cytoplasmic speckled
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HLA-DR3/-DRw52
Interstitial lung disease
Drug induced PM (D-pencillamine)
Rare in children & DM
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Anti-SRP
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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% 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
?
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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
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Treatment
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Corticosteroids
Methotrexate, Cyclophosphamide
IVIG
Rituximab
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Ref.
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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.
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Levine, TD. Rituximab in the treatment of Dermatomyositis. Arthritis Rheum 2005;52:601-607
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Sjögren’s Syndrome
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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
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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
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Sjögren’s Syndrome
• Primary Sjögren’s Syndrome
Keratoconjunctivitis sicca
• Secondary Sjögren’s Syndrome
Keratoconjunctivitis sicca
+
Other rheumatic disease
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Organ manifestations in pSS
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Dry mucous membranes
Joint pain
Fibromyalgia (20%)
Interstitial nephritis
Chronic atrophic
gastritis
• Primary biliary cirrhosis
• Peripheral neuropathy
• Mild interstitial disease
• Myalgia, muscle
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weakness
Autoimmune thyroiditis
Pregnants + SSA/SSB
risk for CHB
Lymphomas ↑ risk
CNS disorders
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Other clinical features in pSS
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Fatigue
88%
Dry skin
88%
Arthralgia (hands) 85%
Dryness in URT 83%
Hoarseness
68%
Dysphagia
68%
Dry cough
54%
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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 SS
American-European revised Rules for Classification of SS
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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)
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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
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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.
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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; 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.
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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, antiRo/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:
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Sjögren’s syndrome (40-50%)
SLE (15%)
RA (5%)
Systemic sclerosis (1%)
MCTD (<5%)
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Treatment of SS
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Artificial tears
Dry skin: Hydrokortisone krem
Cholinergic agonists (pilocarpine)
NSAIDs
DMARDs: (disease modifying antirheumatic drugs) methotrexate,
antimalarial drugs
• 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
• 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
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Digital gangrene in MCTD
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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
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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
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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.
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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
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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
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