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

EtiologyTop

Mixed connective tissue disease (MCTD) is a chronic systemic inflammatory condition with some features of systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis, rheumatoid arthritis, and a high titer of antibodies against uridine-rich nuclear ribonucleoprotein (anti-U1 RNP).

Clinical FeaturesTop

MCTD often presents classically with Raynaud phenomenon, hand swelling (“puffy hands”), shiny tight fingers (sclerodactyly) or tightness of skin of hands and feet (acrosclerosis), arthralgia/arthritis, or myositis. It may start with nonspecific features, including fever, malaise, and fatigue. Over the course of months to years patients may develop organ involvement, including gastrointestinal (reflux or motility disorders), pulmonary (interstitial lung disease [ILD]), cardiac (pulmonary hypertension), or renal involvement (mesangial or membranous nephropathy.

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, including those for MCTD. Often these patients will “evolve” over time to develop a diagnosable CTD.

DiagnosisTop

Diagnostic Criteria

Diagnostic criteria for MCTD: Table 1.

Overlap syndrome is diagnosed in patients fulfilling diagnostic criteria for ≥2 connective tissue diseases, such as SLE and myositis. MCTD is an independent overlap syndrome rather than co-occurrence of other conditions (Table 2).

Diagnostic Tests

1. Antibodies to U1 RNP are found in 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 SLE). There may be 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 3) and other conditions characterized by positive autoantibodies. Initially, early MCTD is most frequently diagnosed as rheumatoid arthritis, SLE, 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 antinuclear antibody [ANA]-positive and typically also RNP-antibody positive).

TreatmentTop

Treatment depends on the dominant symptoms and involves treating the internal organ manifestations of MCTD, such as ILD, with immunosuppressive drugs and antifibrotics or with supportive therapies such as nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics and, depending on organ involvement, motility agents, calcium channel blockers, phosphodiesterase inhibitors (eg, tadalafil), or proton pump inhibitors (PPIs).

PrognosisTop

The prognosis in patients with MCTD is more favorable than in those with isolated SLE and isolated systemic sclerosis. In some patients the clinical course is mild and remission occurs in the absence of ILD. In the majority of cases, however, the symptoms persist and progress to involve lungs, thus warranting long-term immunosuppressive treatment. Untreated and unmonitored MCTD sometimes leads to fatal complications, with the main causes of death in adult patients being pulmonary hypertension and heart failure. Monitoring for cardiopulmonary complications is warranted.

TablesTop