Mixed Connective Tissue Disease (MCTD), Undifferentiated Connective Tissue Disease (UCTD), Overlap Syndromes

Chapter: Mixed Connective Tissue Disease (MCTD), Undifferentiated Connective Tissue Disease (UCTD), Overlap Syndromes
McMaster Section Editor(s): Jonathan D. Adachi
Section Editor(s) in Interna Szczeklika: Irena Zimmermann-Górska, Aleksandra Tuchocka-Kaczmarek, Jan Sznajd
McMaster Author(s): Maggie Larché
Author(s) in Interna Szczeklika: Marzena Olesińska, Hanna Chwalińska-Sadowska†
† Deceased.
Additional Information

Etiology, Clinical FeaturesTop

Mixed connective tissue disease (MCTD) is a chronic systemic inflammatory condition with some features of systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyositis, rheumatoid arthritis, and a high titer (>8 on the BioPlex assay) of antibodies against uridine-rich nuclear ribonucleoprotein (anti-U1 RNP).

Clinical FeaturesTop

MCTD often presents with nonspecific features, including malaise, Raynaud syndrome, and positive ANAs. Over the course of months to years, patients may develop more specific features, such as hand swelling and organ involvement including arthralgia or arthritis; rashes; and gastrointestinal, pulmonary, cardiac, and renal involvement.

Undifferentiated connective tissue disease (UCTD) refers to a group of symptoms and signs that suggest a connective tissue disease (CTD) but do not fulfil any specific CTD criteria. Often these patients will “evolve” over time to develop a diagnosable CTD.

DiagnosisTop

Diagnostic Criteria

Diagnostic criteria for MCTD: Table 14.10-1.

Overlap syndrome is diagnosed in patients fulfilling diagnostic criteria for ≥2 connective tissue diseases, such as systemic lupus erythematosus and myositis (Table 14.10-2).

Diagnostic Tests

1. Antibodies to U1 RNP are found at high titers. Other antibodies are typically negative, including antibodies to Sm and to dsDNA. Complement levels are usually normal or rarely low (as found in active systemic lupus erythematosus). There may be an anemia, leukopenia, or thrombocytopenia. Inflammatory markers may be raised, and serum immunoglobulins can be very high.

2. Nail-fold capillaroscopy frequently shows dilated loops.

3. Other investigations are tailored to the internal organ involvement.

Differential Diagnosis

Differential diagnosis includes other systemic connective tissue diseases (Table 14.10-3) and other conditions characterized by positive autoantibodies. Initially, early MCTD is most frequently diagnosed as rheumatoid arthritis, systemic lupus erythematosus, or UCTD (a combination of symptoms characteristic for systemic connective tissue diseases but not fulfilling the diagnostic criteria for any of them for ≥3 years; all patients are ANA-positive, typically with an RNP antibody positive).

TreatmentTop

Treatment depends on the dominant symptoms and involves treating the internal organ manifestations of MCTD. In patients with UCTD, nonsteroidal anti-inflammatory drugs, hydroxychloroquine, and/or low-dose glucocorticoids could be used.

PrognosisTop

The prognosis in patients with MCTD is more favorable than in those with systemic lupus erythematosus and systemic sclerosis. In some patients, the clinical course is mild and remission occurs; some develop a distinct connective tissue disease; and in other cases, signs and symptoms persist, warranting long-term immunosuppressive treatment. Nevertheless, MCTD sometimes leads to fatal complications, with the main causes of death in adult patients being pulmonary hypertension and heart failure.

TablesTop

Table 14.10-1. Diagnostic criteria for MCTD

Diagnostic criteria according to Alarcón-Segovia and Villareal

1. Serologic criterion: Positive antibodies to U1 RNP antibodies at a titer ≥1:1600

2. Clinical criteria:

1) Edema of the hands

2) Synovitis

3) Myositis

4) Raynaud phenomenon

5) Sclerodactyly

Diagnosis of MCTD: Fulfilled serologic criterion and ≥3 of the clinical criteria (coexisting edema of the hands, Raynaud phenomenon, and Sclerodactyly require an additional fulfillment of the criteria 2b or 2c).

Diagnostic criteria according to Kasukawa et al

1. Common symptoms:

1) Raynaud phenomenon

2) Swollen fingers or hands

2. Positive antibodies to U1 RNP

3. Mixed findings:

1) SLE-like findings:

a) Polyarthritis

b) Lymphadenopathy

c) Facial erythema

d) Pericarditis or pleuritis

e) Leukopenia or thrombocytopenia

2) SSc-like symptoms:

a) Sclerodactyly

b) Pulmonary fibrosis, a restrictive pattern on pulmonary function tests, or reduced DLCO

c) Hypomotility or esophageal dilation

3) Polymyositis-like symptoms:

a) Muscle weakness

b) Raised serum creatine kinase levels

c) Myogenic pattern on electromyography

Diagnosis of MCTD: Presence of ≥1 common symptoms, serologic criterion, and ≥1 from each group of the mixed findings (1, 2, 3).

Adapted from: (1) Alarcón-Segovia D, Villarreal M. Classification and diagnostic criteria for mixed connective tissue disease. In: Kasukawa R, Sharp GC, eds. Mixed connective tissue disease and anti-nuclear antibodies. Amsterdam: Elsvier Science Publishers B.V. (Biomedical Division); 1987: 33-40; (2) Kasukawa R, Tojo T, Miyawaki S. Preliminary diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp GC, eds. Mixed connective tissue disease and anti-nuclear antibodies. Amsterdam: Elsevier Science Publishers B.V. (Biomedical Division); 1987: 41-7. 

DLCO, carbon dioxide diffusing capacity of the lungs; MCTD, mixed connective tissue disease; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.

Table 14.10-2. Other connective tissue disease overlap syndromes

Syndrome

Features

SSc + PM (scleromyositis)

Serologic marker: Positive anti-PM/Scl antibodies in 24% of patients

Clinical manifestations similar to antisynthetase syndrome; however, myositis and interstitial pneumonia are less frequent, the course is less severe, and the response to treatment is better

SLE + scleroderma

SLE with antibodies to histones and centromere – more frequent pulmonary, renal, and cardiac involvement

SLE with anti-Scl-70 antibodies – higher activity of the disease, more frequent pulmonary hypertension and renal involvement

SLE with Raynaud phenomenon – more frequent anti-U1 RNP antibodies, dilated nail-fold capillaroscopy with “drop-outs” (typical for scleroderma)

SLE + RA (rhupus)

Destructive arthritis, rheumatoid nodules, positive RF and/or ACPAs; these most frequently precede features of SLE: leukopenia, thrombocytopenia, positive ANAs and anti-dsDNA, decreased levels of complement components

ACPA, anti-citrullinated protein antibody; dsDNA, double-stranded DNA; PM, polymyositis; RA, rheumatoid arthritis; RF, rheumatoid factor; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.

Table 14.10-3. Features differentiating systemic connective tissue diseases

Clinical symptom

SLE

RA

SSc

PM

MCTD

Pleuritis or pericarditis

++++

+

+

+++

Arthritis with joint destruction

±

++++

+

±

+

Raynaud phenomenon

++

++++

+

++++

Myositis

+

+

+

++++

+++

Sclerodactyly

±

++++

++

Skin thickening

+++

Interstitial lung disease

+

+

+++

++

+

Pulmonary hypertension

+

±

++

+

+++

Butterfly rash

++++

++

Oral ulcers

+++

++

Seizures or psychosis

+++

Nerve V neuropathy

+

++

+++

Peripheral polyneuropathy

++

++

±

++

Transverse myelitis

+++

+

++

Aseptic meningitis

+++

+

+++

Glomerulonephritis

Proliferative

++++

+

Membranous

+++

++

Renovascular hypertension

+

++++

+++

Cutaneous (leukocytoclastic vasculitis on skin biopsy) or systemic vasculitis, including renal, neurologic, and pulmonary manifestations)

++

++

+

+

+

Noninflammatory vasculopathy

++++

+++

Impaired esophageal motility

±

±

++++

++

+++

Anti-RNP

++

+

+

++++

Anti-Sm

+++

Anti-dsDNA

++++

Anti-Scl-70, ACAs, anti-RNA polymerase III

+++

↓ levels of complement components

+++

+ or normal

Rheumatoid factor

++

+++

+

+

++

The number of pluses denotes the frequency.

↓, decreased; ACA, anticentromere antibody; dsDNA, double-stranded DNA; MCTD, mixed connective tissue disease; PM, polymyositis; RA, rheumatoid arthritis; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.

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