Mixed Connective Tissue Disease?
Mark Wener, MD
Rheumatology Division, Medicine
Immunology Division, Lab Medicine
MCTD – Original Description
American Journal of Medicine 1972; 52: 148-159
MCTD: Sharp’s Original Description
• Clinical overlap syndrome, with features of:
– Scleroderma: Raynaud’s, sclerodactyly, GI
– Myositis: myalgias, elevated CK, abnormal muscle
biopsy
– Lupus: leukopenia, rashes (not photosensitive),
but NOT renal, NOT CNS
– Arthralgias/arthritis
– Responds to corticosteroids, good prognosis
– Demographics: women 21/men 4, age 36 (13-66)
Raynaud’s Phenomenon
Edematous
Phase of
Sclerodactyly
Sclerodactyly /
Acrosclerosis
MCTD: Sharp’s Original Description
• Clinical overlap syndrome, with features of:
– Scleroderma: Raynaud’s, sclerodactyly, GI
– Myositis: myalgias, elevated CK, abnormal muscle
biopsy
– Lupus: leukopenia, rashes (not photosensitive),
but NOT renal, NOT CNS
– Arthralgias/arthritis
– Responds to corticosteroids, good prognosis
• Lab: High-titer speckled ANA, with
– Autoantibody to extractable nuclear antigen (ENA)
which contains RNA + protein = ribonucleoprotien
(RNP antigen). NOT anti-Sm, NOT anti-DNA
• Demographics: women 21/men 4, age 36 (13-66)
ANA, Speckled Pattern
ANA Patterns
Homogeneous
Nucleolar
Speckled
Centromere
1000x
Extractable Nuclear Antigens ‘ENA’
• Nuclei (thymus)
– ‘Extract’ with saline, i.e. create pool of nuclear
antigens that are soluble in normal saline
– ENA subtypes (1972)
• Smith (Sm) antigen: identical pattern as
antibody from lupus pt Ms. Smith
–Antigen is destroyed by trypsin, i.e. has
protein, not by RNase (no RNA)
• RNP antigen: antigen destroyed by trypsin and
by RNase = ribonucleic acid-protein complex
–High levels associated with MCTD
IFA Patterns & Ags Associated
Centromere = centromere antigens.
Homogeneous: DNA, chromatin, histones, etc.
Speckled: Extractable nuclear antigens (Sm,
RNP, SS-A, SS-B), Scl-70, RNA polymerase
III, etc.
Nucleolar: scleroderma (fibrillarin, Th/To,
PM/Scl, Scl70, etc.
Cytoplasmic: ribosomal P, Jo-1
IFA Patterns & Ags Associated
Centromere = centromere antigens.
Homogeneous: DNA, chromatin, histones, etc.
Speckled: Extractable nuclear antigens (Sm,
RNP, SS-A, SS-B), Scl-70, RNA polymerase
III, etc.
Nucleolar: scleroderma (fibrillarin, Th/To,
PM/Scl, Scl70, etc.
Cytoplasmic: ribosomal P, Jo-1
MCTD Classification Criteria
• No official criteria, 5 proposed sets, with 5-15
clinical criteria.
• Alarcon-Segovia’s simplest, sensitive
• Serologic criterion: anti-RNP at high titer.
• Clinical criteria
1. Edema of the hands,
2. Synovitis
3. Myositis
4. Raynaud’s phenomenon
5. Acrosclerosis
Serologic criterion plus at least three of five clinical
criteria, including synovitis or myositis.
MCTD: Typical Clinical Features
• Rheumatic disease ‘overlap syndrome’
• High levels of antiRNP in isolation
• Frequent clinical features:
– Raynauds (almost 100%)
– Arthritis/arthralgias
– Sclerodactyly
– Pulmonary hypertension, interstitial lung disease
– Low grade myositis
– GI: pseudo-obstruction, bacterial overgrowth
– Rash: variable. Malar, not usually photosensitive
– Cardiac, variable
MCTD: Course & Treatment
• Course variable
• Treatment requirement variable, often requires
immunosuppressives
– No randomized trials
• Pulmonary hypertension often prominent,may
require treatment
MCTD: Followup of Original Cohort
MCTD Followup of Original Cohort,
N=25
• Alive N= 14
– Disease duration 8-25 years (average 15)
– Age at onset 32 (13-45), at followup 46 (21-65)
• Dead, N= 8
– Disease duration 3-15 years (average 8)
– Age at onset 37 (12-65), at death 44 (20-69)
MCTD: Long-Term Followup of
Original Patients
Final Diagnosis
N
MCTD
3
Systemic Sclerosis (SSc)
5
SSc with mild myositis
3
SLE
0 (2 SLE overlap)
RA
1
Asymptomatic
4
Unknown
5
MCTD: Stanford Cohort Long-Term
Sharp: Long-Term Followup of
Missouri Cohort
Long-Term Followup of Missouri
Cohort of MCTD
Long-Term Followup of Missouri
Cohort of MCTD
Clinical Feature
Sclerodactyly
Diffuse
scleroderma
Pulmonary
hypertension
Renal disease
Nervous system
disease
Raynauds
Arthritis/Arthralgia
Cumulative %
49
19
23
11
17 (mild, mostly)
96
96
Genetics of MCTD
•
•
•
•
More frequently associated with HLA-DR4 (like RA)
Relative risk modest (2-3)
Not seen in all studies
Genome-wide screens not reported
MCTD vs UCTD
• UCTD = Undifferentiated connective tissue disease
– Vague criteria
– No antibody signature
• MCTD = characteristic overlap syndrome
– Anti-RNP highly linked
U1 RNA
U1 RNP
Spliceosome
Model
Scleroderma Autoantibodies
Speckled: RNP, Scl70
Nucleolar: several
Centromere
Gabrielli A et al. N Engl J
Med 2009;360:1989-2003
Autoantibodies & Scleroderma
Prognosis
Scl70
Th/To
RNA polymerase
Fibrillarin
U3-RNP
RNP (U1-RNP)
Centomere
PM-Scl
Modified from Reveille, 2003, Arthritis Res Ther 2003; 5:80-93
MCTD: A Scleroderma Subset?
•
•
•
•
•
•
Sclerodactyly > diffuse cutaneous disease
Pulmonary hypertension
Low –grade myositis
Arthralgias/Arthritis
Esophageal disease
Gut motility
• Treatment based on site and severity of organ
involvement, not based on dx of ‘MCTD’
Autoantibodies & Scleroderma Clinical
Features
Gabrielli A et al. N Engl J
Med 2009;360:1989-2003
‘MCTD?’
Methotrexate Hepatotoxicity
• Histology:
– steatosis
– stellate cell hypertrophy
– anisonucleosis (nuclei of varying sizes)
– hepatic fibrosis
• Transaminase elevation ~`10%
– Often mild and transient
– Usually resolves within one month of stopping MTX