Mixed connective tissue disease (MCTD) is a rare autoimmune disorder with features of lupus, scleroderma, rheumatoid arthritis, and polymyositis. It is characterized by high levels of antibodies against ribonucleic proteins. Diagnostic criteria require at least 3 of 5 clinical features plus positive serology. Over time, many patients evolve features meeting criteria for other connective tissue diseases. Common clinical manifestations include Raynaud's phenomenon, arthritis, swollen hands, and lung and heart involvement. Prognosis depends on degree of organ involvement, with 5-year cumulative risks including pulmonary dysfunction in 66% and pericardial disease in 30% of patients.

1. Mixed Connective
Tissue Disease
SAMIR EL ANSARY
ICU PROFESSOR
AIN SHAMS
CAIRO

2. Global Critical Care
https://www.facebook.com/groups/1451610115129555/#!/groups/145161011512
9555/
Wellcome in our new group ..... Dr.SAMIR EL ANSARY

3. “Mixed Connective Tissue
Disease:
Still Crazy After All These
Years”

4. 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”

5. 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

6. 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

7. 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

8. 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

9. 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”

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

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

12. 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

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

14. 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)

15. Antibody Findings
Disease ANA RF dsDNA Sm Scl-70 RNP
SLE 95-99 20 50-70 30 0 30-50
RA 15-35 85 <5 0 0 10
Diffuse
SSc
>90 30 0 0 40 30
MCTD 95-99 50 0 <5 0 100

16. 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

17. 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 Spondyloarthritis

18. Undifferentiated and Overlap
Syndromes
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

19. 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

20. Global Critical Care
https://www.facebook.com/groups/1451610115129555/#!/groups/145161011512
9555/
Wellcome in our new group ..... Dr.SAMIR EL ANSARY

21. GOOD LUCK
SAMIR EL ANSARY
ICU PROFESSOR
AIN SHAMS
CAIRO
elansarysamir@yahoo.com