2. DEFINITION
• Mixed connective tissue disease (MCTD) is a disease characterised by
combination of clinical features of systemic lupus erythematosus (SLE),
systemic sclerosis, polymyositis (PM), and rheumatoid arthritis (RA).
• MCTD is considered as a distinct clinical entity because of the presence of very
high anti-U1RNP antibody.
• Mixed connective tissue disease (MCTD) was originally defined in 1972 as a
connective tissue disorder
3. EPIDEMIOLOGY
• The prevalence is four times less than that of SLE indicating an overall prevalence of
10/100,000.
• Peak onset second and third decade
• can occur in children and elderly also.
• female to male ratio is 9:1.
4. IMMUNOPATHOLOGY
• U1nRNP is a subunit of spliceosomes.
• Spliceosomes are complex nuclear particles involved in the processing of premessenger RNA into
mature spliced RNA.
• Two subunits of spliceosomes are antigenic targets in autoimmunity.
• These are:
• Small nuclear ribonucleoprotein particles (snRNPs)----contain high level of uridine (U RNA)
• Heterogenous nuclear RNP (hnRNP).
• snRNP contains small RNAs that are complexed with proteins.
5.
6. • Antibodies directed exclusively against U1 subunit are known as antiU1RNP antibodies.
• They precipitate three proteins with molecular weight of 68000, 33000, and 22000.
• Most closely associated with antibodies 68 kD and the 33000 proteins of the U1 RNP
complex.
7. • Characteristic lesions in the involved organs are intensive obliterative proliferative
vascular lesions in large, medium and small vessels with less inflammatory
infiltrates.
• Increased synthesis of type III collagen leading to abnormal type I to type III
ratio, unlike scleroderma where the ratio is maintained.
8. CLINICAL FEATURES
• MCTD develop over many months or years.
• Presenting symptoms
• Raynaud’s phenomenon, puffy hands, arthralgia, myalgia and fatigue.
• Fingers as well as the entire hand may become puffy.
• Fever may be prominent feature
• can present as pyrexia of unknown origin.
9. SKIN AND MUCOUS MEMBRANE
• Skin manifestations include
• Raynaud’s phenomenon, sclerodactyly, skin tightening, photosensitivity
• Sclerodermal changes --- usually limited to the distal extremities and sometimes the
face but spare the trunk.
• Telangiectasia and calcinosis may occur.
• Other lesions include oral uclerations, orogenital ulceration, livedo vasculitis, and nasal
septal perforation.
10.
11. Joints
• Joint pains, stiffness and non-erosive peripheral arthritis are common.
• Joint involvement in MCTD is more common and more severe than seen in SLE.
• Deformities can occur but joint erosions are uncommon.
• An overlap between SLE and RA has been called "rhupus”.
• It is characterized by a symmetric erosive polyarthritis of the small and large joints and
symptoms of SLE with high titers of antibodies to double-stranded (dsDNA) and Sm as
well as RF and anti-CCP antibodies.
12. Muscle
• Myalgia
• Myositis occurs frequently, but most often without significant demonstrable
weakness, electromyographic changes or muscle enzyme elevation.
• May present as inflammatory myositis with antiU1RNP antibody without other
features of MCTD.
13. Lung
• Asymptomatic 85%
• Low diffusion capacity for carbon monoxide may be the only abnormality.
• Pluritis common but is rarely associated with large pleural effusion.
• Interstitial lung disease (ILD).
• High-resolution computed tomography (HRCT) is a sensitive test to determine the
presence of ILD.
• HRCT findings are septal thickening, ground-glass opacities, non-septal linear opacities,
and peripheral/lower lobe predominance similar to the findings in SSc.
14. • Pulmonary hypertension is the most common cause of death in MCTD.
• Pulmonary arterial hypertension (PAH) is usually caused by a bland intimal proliferation
and medial hypertrophy of pulmonary arterioles.
15. Heart
• All three layers of heart can be involved in MCTD.
• Pericarditis may occur in 10% to 30% of cases.
• Arrhythmias, conduction disturbances and mitral valve prolapse also can
occur
16. Gastrointestinal System (70%)
• The most common manifestations are oesophageal dysmotility, lower oesophageal
sphincter laxity, and gastrooesophageal reflux.
• Abdominal pain, malabsorption syndrome, and chronic active hepatitis.
• Pseudodiverticula along the antimesenteric border of colon can occur like in
scleroderma.
17. Kidney (25%)
• Membranous glomerulonephritis is the most common (usually mild, but can
cause nephrotic syndrome)
• Diffuse proliferative glomerulonephritis (DPGN) is unusual in MCTD.
• believed to be due to the protective role played by the high titers of anti-U1RNP.
• Renal crisis secondary to malignant renovascular hypertension rarely.
18. Central Nervous System
• Central nervous system (CNS) involvement is rare in MCTD.
• Trigeminal neuropathy is the most common.
• Vascular headache, aseptic meningitis, peripheral neuropathy, transverse myelitis
and sensorineural hearing loss may be present.
19. LABORATORY FINDINGS
• The diagnosis of MCTD depends on the demonstration of antiU1RNP antibody in high
titres.
• Antinuclear antibody positivity is seen in 100% of patients in high titre
• Anti U1RNP antibodies by haemagglutination test titre > 1:1600 is characteristic
feature of MCTD.
• Absence of anti-Sm antibodies and anti-DNA antibodies in a patient seropositive for
anti U1RNP is an important finding discriminating MCTD from SLE.
20. • Other investigations show features common to connective tissue diseases in
general.
• The most frequent haematological findings
• Anemia, leucopaenia, thrombocytopaenia and a high ESR.
• Serum immunoglobulins may be extremely high, with IgG concentrations
reaching more than 40 g/l.
• Rheumatoid factors are increased approximately 70% of patients.
21. DIAGNOSIS
• The diagnosis of MCTD is clinicoserologic findings. The two diagnostic criteria for MCTD
that are widely employed are Alarcon-Segovia’s Criteria and Kahn’s Criteria. 63% sensitive;
86 % specific
22. PROGNOSIS
• Course of MCTD is unpredictable.
• Most have a benign course.
• It is the major organ involvement that decides the morbidity and mortality in an
individual case.
23. MANAGEMENT
• There is no specific treatment for MCTD.
• The treatment depends on the pattern of clinical involvement .
• Analgesics and nonsteroidal anti-inflammatory drugs alone may be needed in one-
third cases.
24. • Manifestations like aseptic meningitis, myositis, pleurisy, pericarditis and myocarditis
usually respond to corticosteroids.
• Gloves and calcium channel blockers are useful in Raynaud’s phenomenon.
• Arthritis and cutaneous manifestations respond well to antimalarial agents such as
hydroxychloroquine.
• High dose steroids are indicated for the treatment of severe systemic disease such as
vasculitis myositis, or interstitial lung disease.
25. • IV gamma globulin or danazol
• steroid-resistant thrombocytopaenia, refractory myositis and haemolytic anaemia.
• Unless contraindicated, all patients should take supplementary calcium and vitamin D.
• Immunosuppressive drugs may be useful for induction of remission or for their
corticosteroid sparing effects.
• azathioprine, cyclophosphamide and methotrexate.
26.
27. OVERLAP SYNDROMES
• Overlap syndromes occur when patients meet criteria for the diagnosis of more than one
connective tissue disease.
• Raynaud’s phenomenon, arthritis, and sclerodactyly are usually found in most of the
overlap syndromes.
• Sjögren’s syndrome commonly overlaps with RA, SLE, Systemic sclerosis, PM, primary
biliary cirrhosis.
• MCTD is a serologic subset of overlap syndrome characterised by the presence of
antibodies to U1RNP.
30. REFRENCES
• 1. UPTODATE
• 2. API TEXT BOOK OF MEDICINE
• 3. Harrison's Principles of Internal Medicine (Vol.1 & Vol.2) 20th
Editor's Notes
These RNAs contain a high content of uridine and are, therefore, called U RNAs. (snRNP)
anti-U1 ribonucleoprotein (RNP)
Five different types of URNAs are defined on the basis of immunoprecipitation (U1, U2, U4, U5, and U6).
Autoantibodies to these complexes are mainly directed to the protein components.
Fever may be traced to co-existent myositis, aseptic meningitis, serositis, lymphadenopathy or intercurrent infection.
Digit autoamputation can occur with severe Raynaud phenomenon .
Rhupus differs from of MCTD in having only mild systemic involvement, and the presence of Raynaud phenomenon is less common. Jaccoud arthropathy is another manifestation of joint involvement in SLE . It is characterized by severe deformities of the hands (ulnar deviation, swan neck deformities, and Z deformity of the thumb) and feet due to multiple nonerosive subluxations.
Approximately 60 percent of patients with MCTD develop an obvious arthritis, often with deformities characteristic of rheumatoid disease, such as boutonniere deformities and swan neck changes.
Other changes include small marginal erosions and a destructive arthritis, including arthritis mutilans.
A positive rheumatoid factor (RF) is found in approximately 70 percent of patients with MCTD , and anticyclic citrullinated peptide (CCP) antibodies are found in approximately 50 percent,
PAH may also be due to coexistent antiphospholipid (APL) antibodies.
Myocardial involvement also is described.
ECG changes are seen in 20% includes hemiblock, bundle branch block, and atrioventricular block .
This finding should prompt the measurement of antibodies to U1RNP, Sm, Ro and La.
with coarse speckled pattern.
In contrast to SLE, in MCTD the complement concentrations are usually normal or high.
Anaemia of chronic disease (75%).
In MCTD the complement concentrations are usually normal or high.
Other abnormalities noted are
leucopaenia, thrombocytopaenia, thrombotic thrombocytopaenic purpura and red cell aplasia.
Pulmonary hypertension being the most common cause of death, patients should be evaluated at regular intervals for its development--- suspected in patients with increasing breathlessness.
Echocardiogram is the most useful screening test.
A definitive diagnosis requires cardiac catheterisation showing a mean resting pulmonary arterial pressure more than 25 mmHg at rest.
Usually one syndrome gradually takes on the features of another. Sometimes, the features of both diseases may occur concurrently.
Other overlap syndromes include SLE with polymyositis in 4% to 16% of cases, SLE with RA (positive rheumatoid factor, nodules and erosive arthritis) known as ‘rhupus’.
Scleroderma can be associated with myositis and limited scleroderma with primary biliary cirrhosis (Raynold’s Syndrome).
For example, a patient with SLE who develops, erosive arthritis in a distribution similar to RA is labelled an overlap of RA and SLE.
