1. “Mixed Connective Tissue Disease: Still Crazy After All These Years”
Christina Kahl
March 12, 2008
Rheum Dis Clin N Am 31 (2005)

2. History 1972 Sharp and colleagues
Identified patients with high levels of antibodies against a ribonucleic protein (RNP)
These patients shared several clinical features including Raynaud’s phenomenom, arthralgias, mild arthritis, puffy hands, abnormal esophageal mobility, and myositis
Additional findings – hypergammaglobulinemia (80%), anemia and leukopenia (50%); pulmonary, renal and CNS involvement was “rare”

3. History 1980 Nimelstein and colleagues
Doubts after reviewing 22/25 original patients
Many patients evolved into scleroderma
High mortality rate (8/22)
Not everyone had antibodies to RNP
Some patients had antibodies without clear clinical features of the syndrome
Then, 20 years of contradictory views regarding the existence and nature of MCTD

4. Diagnostic Criteria
Features of SLE, systemic sclerosis, RA, and polymyositis
Four different diagnostic criteria have been proposed
Sharp
Kasukawa
Alarcon-Segovia
Kahn
Highest sensitivity (62%) and specificity (86%) with Alarcon-Segovia and Kahn in 45 patients

5. Diagnostic Criteria – Sharp
Major Criteria
Myositis
Pulmonary Involvement
Raynaud phenomenom or esophageal dysmobility
Swollen hands or sclerodactyly
High anti-U1-RNP with negative anti-Sm
Definite – 4 major plus serology
Probable – 3 major or 2 major (1st 3 listed) and 2 minor; and serology
Minor Criteria
Alopecia
Leukopenia
Anemia
Pleuritis
Pericarditis
Arthritis
Trigeminal Neuralgia
Malar Rash
Thrombocytopenia
Mild Myositis
h/o swollen hands

6. Diagnostic Criteria Alarcon-Segovia
Clinical Criteria 3/5 (must have synovitis or myositis)
Edema of the hands
Synovitis
Myositis
Raynaud’s phenomenon
Acrosclerosis
Serologic: high titers of anti-U1 RNP

7. Diagnostic Criteria
“The crux of the MCTD diagnosis is the presence of high titers of antibodies to U1-RNP.”
Many patients who satisfy criteria for MCTD also satisfy ACR criteria for RA or SLE, and many had symptoms of systemic sclerosis.
“With serology superseding the clinical symptoms in the diagnosis, there is a risk of fitting the clinical symptoms to the antibody signs”

8. Clinical Presentation
Early Clinical Findings
Malaise, easy fatiguability
Arthralgias
Myalgias
Raynaud’s phenomenom
Low-grade fevers
Unusual Presentations
FUO
Serositis
Trigeminal neuropathy
Severe polymyositis
Acute arthritis
Aseptic meningitis
Digital gangrene

9. Characteristic
At Diagnosis
Cumulative at 5 years
Raynaud’s Phenomenom
89%
96%
Arthralgia/Arthritis
85%
Swollen Hands
60%
66%
Esophageal Dysmotility
47%
Pulmonary Dysfunction
43%
Serositis
34%
Hematologic
30%
53%
Erythematous Skin Rash
Muscle Myositis
28%
51%
Pulmonary Hypertension 9%
23%
Sclerodermatous Changes 4%
19%
CNS (or peripheral) 0%
17%
Renal 2%
11%
Cohort of 47 MCTD patients.

10. Pulmonary Manifestations
Pleural Effusions
Pulmonary Hypertension
Pleuritic Pain
Intersitial Lung Disease (30-50%)
Thromboembolic Disease
Obstructive Disease
Pulmonary Vasculitis
75% of patients
Early Symptoms
Dry cough
Dyspnea
Pleuritic Chest Pain

11. Pericardial Disease Pericardial Involvement MCTD Scleroderma 59%
SLE 44%
MCTD 30%
RA 24%
MCTD
At autopsy – 56% had pericardial disease
Asymptomatic pericardial effusion – 24-38%

12. Laboratory Findings High titer, speckled ANA pattern
Leukopenia, anemia, thrombocytopenia
Elevated ESR
Very high serum immunoglobulins
Complement levels usually normal or high
Rheumatoid Factors increased in 70% of patients
Negative findings include anti-dsDNA and anti-Sm antibodies (if positive, some argue that it represents exclusion criteria for MCTD)

13. Antibody Findings Disease ANA RF dsDNA Sm Scl-70 RNP SLE 95-99 20
50-70 30
30-50 RA
15-35 85
<5 10
Diffuse
SSc
>90 40
MCTD 50
100

14. Follow-Up 39 MCTD patients at 10 year follow-up
64% “differentiated” into another syndrome
11 systemic sclerosis, 10 SLE, 2 RA, 2 overlap syndrome
Other studies have found similar results
About 40% of patients with anti-U1RNP antibodies retain the diagnosis of MCTD and others are “reclassified” within 5 years of presentation

15. Undifferentiated and Overlap Syndromes
MCTD
SLE, SSc, PM, RA
Undifferentiated Systemic Rheumatic Disease
Undifferentiated connective tissue, collagen, vascular, or autoimmune disease
Nonclassical SLE
“Atypical” rheumatic disease
Undiiferentiated Polyarthritis Syndrome
Undifferentiated Spondylparthritis
Overlap Syndromes
RA-lupus
Rhupus
Scleroderma-PM/DM
Scleroderma-lupus
Scleroderma-PBC-Sjogren’s
Scleroderma-RA
JRA-lupus
Psoriatic arthritis-lupus
Psupus
Sjogren’s overlaps
PM overlaps
Raynaud’s phenomenom overlaps

16. SLE Criteria Malar Rash Discoid Rash Photosensitivity Oral Ulcers
Arthritis
Serositis
Renal Disease
Neurologic Disease
Hematologic Disease
Hemolytic anemia
Leukopenia, lymphopenia
Immunologic
Anti-dsDNA
Anti-Sm
ANA
4/11 Criteria

17. Patient Course Prednisone 1mg/kg started on day #4
Patient became afebrile
Tachycardia and tachypnea resolved
Discharge on day #7
Few weeks later –
anti-dsDNA positive

18. References
Bennett RM. “Definition and diagnosis of mixed connective tissue disease.” UpToDate.
Bennett RM. “Clinical manifestations of mixed connective tissue disease.” UpToDate.
Kumar MS, Smith M, Pischel KD. “Case Report and Review of Cardiac Tamponade in Mixed Connective Tissue Disease.” Arthritis & Rheumatism, :
Swanton J, Isenberg D. “Mixed Connective Tissue Disease: Still Crazy After All These Years.” Rheum Dis Clin N Am, :
Venables PJW. “Mixed Connective Tissue Disease.” Lupus, :
American College of Rheumatology, classification criteria for SLE.