UNDIFFERENTIATED CONNECTIVE TISSUE
DISEASE (UCTD)
The clinical onset of Connective Tissue Diseases (CTDs)
may undifferentiated.
Signs and symptoms suggestive of a CTD, but not
fulfilling the criteria for any defined CTDs.
EVOLUTION OF THE WELL ESTABLISHED CTD
Genetic factors
Immunoserological
+Enviromental
abnormalities
factors
(hormones, drugs)
Clinical symptoms
+
Serological
abnormalities
UCTD
Established CTD
SLE
MCTD
Sjögren sy
PM/DM
SSc
RA
FEATURES OF UCTD
History: Systemic symptoms
fatique
fever
weight loss
Clinical symptoms
Joints- Polyarthritis in the small joints
Vascular- Raynaud’s phenomenon, color changes in the skin of the
digits, history of arterial or venous thrombosis, or vasculitis
Muscle- muscle weekness, muscle pain, or history of myositis
Eyes- Dry eyes, conjunctivitis, or ocular inflammation
Salivary glands- Dry mouth or salivary gland enlargement
Pleuritis/ pericarditis
FEATURES OF UCTD
Clinical symptoms
Skin- Malar rash, skin ulcers, purpura, alopecia, skin
tightening urticaria, or pigmentation, erythema nodosum,
discoid rash
Nervous system- History of seizures, neuropathy, or altered
mental status
GIAnorexia, dysphagia, dyspepsia,
Heart- Angina, dyspnoe, atypical chest pain
Lung- Cough, wheezing, or pleuritic chest pain
Fever
Non-specific immunoserological
abnormalities
RF positivity
High serum levels of IC-s
Hypocomplementemia
Elevated level of gamma globulin
(Signs of inflammation, or other diseases)
Lab Studies
Routine screening:
ESR
urinanalysis
chemistry panel (CK)
Immunoserological abnormalities:
Antibodies to nuclear os cytoplasmatic antigens Anti- ANA
anti-ENA
anti-DNA
anti-Sm
anti-RNP
anti-SSA
anti-SSB
anti-centromer
anti-Jo1
anti-cardiolipin
Diagnosis of UCTD: 2 clinical symptoms + 1 presence of
autoantibody
Physical finding can be limited or may involve
many organs
Skin- teleangiectaia, purpura, digitals ulcers or scars, sclerodactyly,
heliotrope eyelids,
Eye- conjunctivitis, episcleral disease, uveitis, iritis, KCS
Salivary glands- Xerostomia or salivary gland enlargement
Reticuloendothelial- Lymohadenopathy or splenomegaly
Lungs- Rales, pleural effusion, or pleural rub
Heart- enlarged heart, murpur, pericardial rub, arrhytmia
Vascular- acrocyanosis, absent pulses, arterial and/or venous thrombosis
Muscles- Muscle tenderness, muscle atrophy, or proximal muscle weakness
Joints- Joint tenderness, swelling, effusion, synovitis, or deformity
GI- Hepatomegaly, esophageal dysmotiliy
Nervous system- Cranial nerve palsy, peripheral motor neuropathy, sensory
neuropathy, psychosis, or personal change
Raynaud’s phenomenon
Primary or
Secondary
Capillary microscope
-vascular abnormalities may be the first
sign of the CTD
Polyarthritis: Diff dg.
Bacterial infection
Reactive arhritis
(Bang, Widal, Yersinia, Clamydia)
Inflammated arthrosis
Hypergammaglobulinaemia (purpura, allergic reaction)
-Lymphoma
-CTD (connective tissue disease)
Recurrent serositis
Origin -virus or others?
Immunological investigation
Serositis (ANA positivity, a DNA)
SLE
Outcome of UCTD
Well-established CTD
(SLE, MCTD, Sj, SSc)
50%
Remain undefined over time
30%
Symptoms discontinued
20%
Antibodies and clinical symptoms in UCTD
a-nativ DNS
a-hiszton
a-Sm
Kidney GN
Skin
Kidney- mucous ulcer
a-U1RNP
Raynaud, esophageal
hypomotility
MCTD
a-SSA
a-SSB
Sicca coplex, skin
skin
Sjögren sy
a-foszfolipid
Recurrent thrombosis
APL
a-Mi2
Heliotrop rash
PM/DM
a-Jo1
Pulmonary fibrosis
Anti- szintetáz
szindróma-PM
a-Scl70
a-centromer
Skin, Raynaud
skin
Diffúz scleroderma
Limitált scleroderma
a-citrullinált
peptid
arthritis
RA
SLE
Evolution of undifferentiated diseases to defined
CTD
Fever, serositis or photosensitivity + anti-DNA or anti-Sm
homogeneous ANA
SLE
Polyarthritis, Raynaud + anti RNP
granular ANA
MCTD
Raynaud, sclerodactyly + anti centromer
anti-SCL-70
nucleolar ANA
SSc
KCS, Xerostomia + anti-SSA, anti-SSB
Sjögren sy
Polyarthritis + RF or anti CCP
RA
Evolution of undifferentiated diseases to defined
CTD
Recurrent thrombosis + anti-phospholipid ab
APS anti-phospholipid sy
recurrent abortion
Myositis + elevated CK
Myositis specific and associated AB
PM/DM
Myositis+ Raynaud + pulmonary fibrosis
anti-Jo1
Anti-synthetase sy
Outcome to CDS-s
•
•
•
•
•
Recurrent symptoms
New symptoms
Positive familiar anamnesis
Positive immunological tests
Good reactivity to CS treatment
Therapy
Only a small % of UCTD are treated
NSAID
40 %
low dose corticosteroids (8-12 mg/day)
30-50%
antimalarial drugs
10-30 %
Sometimes cytotoxic drugs
(erythema nodosum, serositis)
3-4 %
MIXED CONNECTIVE TISSUE DISEASE (MCTD)
MIXED CONNECTIVE TISSUE DISEASE
(MCTD)
Well-established chronic inflammatory
connective tissue disease.
Female/ Male: 9:1
Characteristic signs
Specific autoantibodies (anti-U1RNP)
Genetic factors
HLA-DR2/DR4
HLA-DR1- erosive arthritis
HLA-DR3 pulmonary fibrosis
CLASSIFICATION AND DIAGNOSTIC CRITERIA FOR
MIXED CONNECTIVE TISSUE DISEASE
Criteria
1. Serological
Presence of the anti-U1RNP antibodies*
2. Clinical (at least three**)
Edema of the hands
Synovitis
Myositis (laboratory or biopsy proven)
Raynaud’s phenomenon (2 or 3 color phase)
Acrosclerosis (with or without proximal scleroderma)
*Anti-U1RNP was detected by ELISA and immunoblotting
**The association of edema of the hands, Raynaud’s phenomenon and
acrosclerosis requires of at least one of the other two criteria
Alarcon-Segovia D. and Villarreal M. (1987)
U1-RNP
U1-RNP autoantitest kimutatás
ranularis típus
SA
Hoffman et al. Clin Immunology 2008
PATHOGENESIS
U1-70 kD peptides, modified self antigens and molecular
mimicry
Apoptotic and oxidative modification of U1-70 kD may play a
role in autoimmunity
Apoptotic modification- associated with skin disease
Oxidative modification- Raynaud's phenomenon
New findings about autoantibodies in MCTD
Anti-hnNRNP-A2 subset specific for MCTD
SYMPTOMS
-May present as fever of unknown
origin
-Polyarthritis- 85 %
60 % frank arthritis, 50 % with
erosion and deformation
-Swollen hands and fingers
-Proximal inflammatory myopathy –
CK, Aldolase is muscle-specific and
may also be checked
biopsy or EMG
Raynaud's phenomenon
SYMPTOMS
Esophageal hypomotility- x- ray, radionuclide method
reflux, vomiting, esophageal hypomotility
Pulmonary disease
Interstitial lung disease (ILB)- 40 %
Pulmonary hypertension 25-50%
ILB - Diffuse alveolar inflammation and interstitial disease
Fever, cough, dyspnoe, tachycardia
decreased ventilation capacity
Dg: Chest x ray- small opacity, bibasilar fibrosis
High resolution CT
Open lung biopsy
Prokoagulant activity
Thromboxán
?
a-U1RNP, ANA, a-PL
Proinflammatory
cytokines
VASCULAR
REMODELLING
PAI 1
Endothelial cell dysfunction
Relaxing factors
Endothelin
NO
Thromboxán
Prosztaciklin
VEGF
Angiopoietin
Vazoconstrictor factors
Smooths cell
activation
ET-1
TGF-béta
Media hypertrophia
Cell proliferation
Inflammation,fibrosis
angiogenezis
OTHER SYMPTOMS
Myositis- usually focal and mild
Renal involvements- 5-10 % Glomerulonephritis
Cutaneous symptoms: vasculitis rashes
teleangiectasia
alopecia
sclerodermatous skin- usually limited to fingers
Serositis- rare
Thrombosis – 25-30 % (MCTD+ APL)
MCTD may associated with Sjögren sy and thyroiditis
IMAGING STUDIES
Chest radiograph
Barium swallow to evaluate esophageal motility
Echocardiography- PAH, myocardial and valvular function
Pulmonary function tests
Scintigraphy- alveolitis, pulmonary fibrosis
MRI of the brain
Renal function- urine, UH
LABORATORY FINDINGS
1.
2.
3.
4.
5.
6.
7.
8.
anti-U1RNP in patient’ sera ( anti-SSA, anti SSB)
ANA positivity - granular pattern
Marked hypergammaglobulinaemia
Hypocomplementemia - 25%
Circulating immune complexes in the active disease
Leukopenia, thrombocytopenia
Elevated level of CK
Inflammation (lymphocytes, plasma cells) in
various tissues
TREATMENT
-
High dose CS (prednisone 1-2 mg/kg) - Pulmonary disease (ILB or PAH) or
renal disease
-Cytotoxic therapy (cyclophosphamide or azathioprine)
Cyclophosphamid: 600 mg/m2/ month 3 month- 1 yr
Therapy of the PAH
•
Pulsus steroid - 0,5-1 g/day 3 days, and 0.5-1 mg/kg/day 6-12
months
Cyclophosphamid: 600 mg/m2/ month 3 month- 1 yr
•
Nitrit oxide or prostaglandins
•
Ca chanell blockers and oxygen may be effective
•
Aerosolized prostacyclin (Iloprost) is effective in early stage
•
ET-1 R blockers
•
Anticoagulant therapy (LMWH - warfarine)
-Methotrexat myositis, arthritis – 15-25 mg/ week
TREATMENT
-Raynaud's diseaseVasodilatorsNitroglicerine
Ca chanel blockers
Alpha1-antagonists may also be effective
Cyclosporine A- severe myositis, arthritis
Dosage: 3 mg/tkg/day
-NSAID- in the inactive stage
-Antimalaric drugs
-Pentoxyfilline
-Mycophenolat mofetil-Biological therapy – anti-CD20, TNF-alpha blocker, or
TNF- R blockers
-Vascular prevention: statins, ACE inhibitors