Mixed Connective Tissue Disease? Mark Wener, MD Rheumatology Division, Medicine Immunology Division, Lab Medicine
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. Synovitis3. Myositis4. Raynaud’s phenomenon5. 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,mayrequire 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 Cumulative %
Sclerodactyly 49
Diffuse scleroderma
19
Pulmonary hypertension
23
Renal disease 11
Nervous system disease
17 (mild, mostly)
Raynauds 96
Arthritis/Arthralgia 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
SpliceosomeModel
Scleroderma AutoantibodiesSpeckled: RNP, Scl70 Nucleolar: several Centromere
Gabrielli A et al. N Engl J Med 2009;360:1989-2003
Autoantibodies & Scleroderma Prognosis
Modified from Reveille, 2003, Arthritis Res Ther 2003; 5:80-93
Scl70Th/ToRNA polymerase
CentomerePM-Scl
FibrillarinU3-RNPRNP (U1-RNP)
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’
Gabrielli A et al. N Engl J Med 2009;360:1989-2003
Autoantibodies & Scleroderma Clinical Features
‘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