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Mixed connective tissue disease

Jindaprasert, J.

Introduction

Introduction
1972- Dr Sharp published syndromes assosciated with autoAb to ribonucleoprotein... later U1RNP Concept: overlap syndrome or disease
systemic lupus erythematosus (SLE) Systemic sclerosis (scleroderma, Scl) polymyositis (PM)

With time, overlap features occur sequentially

Fact!!
Some autoantibodies can cause disease. Rheumatoid arthritis
Rheumatoid factor Anti cyclic citrullinated peptide

What about anti U1RNP?

Is MCTD a specific disease?


Still a debate Evidence suggests that U1RNP Ab play a pathophysiological role in the disease

Evaluation of the patient with anti-U1RNP


Presentation:
new-onset Raynauds phenomenon Polyarticular joint pain +- frank synovitis Swollen, puffy hands +- muscle weakness

Evaluation of the patient with anti-U1RNP


Serological
Level 1 - Positive ANA High-titier ANA: speckle type / anti U1RNP x anti Sm x anti Ro/La Level 2 - High titer, speckled ANA pattern Level 3 - Anti-U1 RNP antibodies Level 4 - Anti 70 kD and A' antibodies

Diagnosis
Sharp criteria Kasukawa criteria Alarcon-Segovia and Kahn criteria
THE BEST Sensitivity 63 Specificity 86

Alarcon-Segovia and Kahn criteria


Serologic criteria
Anti-RNP antibodies (hemagglutination) titer > 1:1600

Clinical criteria

Swollen hands Synovitis Myositis Raynauds phenomenon Acrosclerosis with or without proximal sclerosis

3/5 clinical + serological

Clinical Presentation
Early Clinical Findings
Malaise, easy fatiguability Arthralgias Myalgias Raynauds phenomenom Low-grade fevers

Unusual Presentations
FUO Serositis Trigeminal neuropathy Severe polymyositis Acute arthritis Aseptic meningitis Digital gangrene

any organ system can be involved features that suggest


Raynaud's phenomenon and swollen hands Absence of severe renal and CNS disease More severe arthritis and the insidious onset of pulmonary hypertension (not related to lung fibrosis) differentiate MCTD from both SLE and Scl Autoantibodies whose fine specificity is anti-U1 RNP, especially antibodies to the 68 Kd protein

Clinical features
General- women>men, 20-30 yr Sun exposure: NOT precipitating factor No drug induced MCTD Associated agents: silica, vinyl chloride

Skin
Raynaud s phenomenon Swollen digits Discoid plaques Malar rash Buccal ulceration Nasal septal perforation Sicca complex

Raynaud s phenomenon
Clinical criteria
Definite RP Repeated episodes of biphasic color changes upon exposure to cold Possible RP Uniphasic color changes plus numbness or paresthesia No RP No color changes

Primary RP
Onset 15-30 years

Current criteria :
Symmetric episodic attacks No evidence of peripheral vascular disease No tissue gangrene, digital pitting, or tissue injury Negative nailfold capillary examination Negative antinuclear antibody test and normal erythrocyte sedimentation rate (ESR)

Secondary RP
connective tissue diseases (MCTD, PM, DM, RA, vasculitis) Occlusive vascular disease (arteriosclerosis, emboli, and TAO) Drug-induced Hemorrheologic (Cold agglutinin disease, cryofibrinogenemia, cryoglobulinemia, paraproteinemia, and polycythemia) Vibration-induced (pneumatic drills and hammers) Vascular trauma Frostbite

Drug-induced RP

Arthritis
More common, more severe than LE 60% obvious arthritis Deformity: boutonniere, swan neck Film: resembles Jaccoud s arthropathy
small marginal erosion

Destructive: arthritis mutilans rare

Myositis
myopathy identical to PM Myalgia, no weakness Sometimes flare

Cardiac
Pericarditis 10-30% EKG: RVH, RAE, interventricular conduction defects PHT: cause of death asso- capillary nailfold pattern in SSc antiendothelial cell Ab, anticardiolipin

Pulmonary
75% of patients Interstitial lung dz
30-50% Reduced DLCO HRCT

Renal
Absence of severe renal disease High titer U1RNP
Protect against DPGN

Some- membranous nephropathy or nephrotic-range proteinuria Very rare- scleroderma renal crisis

Gastrointestinal
Motility disorder Malabsorption
From bacterial overgrowth

Mesenteric vasculitis Colonic perforation pancreatitis

CNS
MCTD patients do not develop severe CNS complications Trigeminal neuropathy Headaches- vascular, aseptic meningitis, tension

Hematological presentation
Anemia Leukopenia, mainly lymphocyte Hypergammaglobulinemia RF + 50-70% APS- correlate with thrombocytopenia, pulmonary hypertension NOT abortion/ thrombosis

Vasculopathy
Raynaud s : typical+early MCTD Patho: bland intimal proliferation and medial hypertrophy of vv Abnormal nailfold capillary Angiography: medium-sized

Autoantibodies
Autoimmunity to spliceosomal components Spliceosomes: complex nuclear particles involved in the processing of pre-mRNA into mature "spliced RNA major spliceosomal sub-units
small nuclear ribonucleoprotein protein particles (snRNP) heterogeneous nuclear RNP particles (hnRNP).

Small nuclear RNP particles


snRNPs: contain small RNA species, high content of uridine U-RNAs 5 different U-RNAs (U1, U2, U4, U5, and U6) Auto-antibodies to protein components of these complexes

Anti-Sm antibodies precipitate 5 proteins common to the U1, U2, U4, U5, and U6 RNAs Anti-RNP antibodies precipitate 3 proteins with molecular weights of 68,000 (70K), 33,000 (A'), and 22,000 (C) associated with U1 RNA

U1RNP

Treatment
Not much evidence Original- all manifestations response to 1 mg/kg prednisolone BUT not the case for vascular involvement Organ based

Treatment
Anti inflammatory
NSAIDS Corticosteroids

Immunomodulatory
Chloroquine HQ Azathioprine MMF cyclophosphamide

Practice points

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