Skin involvement is often the presenting feature and occurs in most patients. Raynaud’s phenomenon occurs early in the course of disease [10]. Puffy fingers and occasionally hand edema may also be noted. Superficial vasculitis of the digits, acrosclerosis, and calcinosis cutis have also been described. Skin manifestations such as discoid plaques and malar rash are indistinguishable from SLE. Mucous membrane involvement can include orogenital and buccal ulcerations, nasal septal perforation, and the sicca complex [11].

Fever of unknown origin may be the presenting feature of MCTD [12]. In this setting, the cause can be usually traced to a coexistent myositis, aseptic meningitis, serositis, lymphadenopathy, or intercurrent infection.

Articular involvement in MCTD is more common and severe than in classic SLE. Approximately 60 % of patients with MCTD develop an obvious arthritis [13], often with boutonniere deformities and swan-neck changes. In adults, rheumatoid factor is present in 70 % of patients with MCTD and anti-cyclic citrullinated peptide (CCP) antibodies in about 50 % patients [14, 15].

One of the three overlap features required for the diagnosis of MCTD is an inflammatory myopathy clinically and histologically identical to polymyositis (PM). Myalgia is a common symptom in patients with the MCTD syndrome. In the early phase, electromyographic (EMG) abnormality or elevation of muscle enzymes may be the only finding. It is unclear whether the symptoms represent a low-grade myositis or an associated fibromyalgia syndrome. However, a clinical myositis may occur over time. The histology of muscle involvement in MCTD is the same as that of idiopathic inflammatory myopathy. It is increasingly apparent that a diagnosis of “pure” PM is relatively rare, and most patients with an inflammatory myopathy evolve into an overlap syndrome [16].

Cardiac involvement accounts for 20 % of mortality in MCTD. While 30 % of MCTD patients have symptomatic heart disease, nearly 40 % have subclinical disease [17]. An abnormal electrocardiogram is noted in about 20 % of patients. The most common electrocardiographic abnormalities include hemiblock, bundle branch block, and atrioventricular block. Pericardial effusion and mitral valve prolapse are among the most common echocardiographic abnormalities. Pericarditis is the most common clinical manifestation of cardiac involvement, reported in up to 40 % of patients [18].

Lungs are commonly affected in MCTD with involvement in about 75 % of patients [19]. A wide spectrum of pulmonary problems can occur in MCTD such as pleural effusion or pain, pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), thromboembolic disease, alveolar hemorrhage, diaphragmatic dysfunction, aspiration pneumonitis/pneumonia, obstructive airways disease, pulmonary infections, or vasculitis. Early symptoms include dry cough, dyspnea, and pleuritic chest pain.

ILD occurs in about 50–66% of patients with MCTD [20]. A reduction in the single breath-diffusing capacity for carbon monoxide (DLCO) is a feature noted in the early stages of ILD. High-resolution computed tomography (HRCT) is a sensitive diagnostic modality to determine the presence of ILD. The most common HRCT findings are septal thickening, ground-glass opacities, non-septal linear opacities, and peripheral/lower lobe predominance.

A major cause of death in MCTD is PAH. This complication is caused by bland intimal proliferation and medial hypertrophy of pulmonary arterioles.

Absence of severe renal disease is a hallmark of MCTD. It is possible that high titers of anti-U1 RNP antibodies, which are characteristic of MCTD, may protect against the development of diffuse proliferative glomerulonephritis, independent of whether these antibodies occur in MCTD or in classic SLE.

Gastrointestinal involvement is the most common clinical overlap feature with SSc, occurring in about 60–80 % of patients [25]. Disordered motility in the upper gastrointestinal tract is the most common.

The original description of MCTD emphasized the lack of CNS involvement. This observation remains largely correct, since patients with MCTD do not develop severe complications such as cerebritis, psychosis, or seizures. However, approximately 25 % of patients may have some mild form of CNS disease [27]. The most frequent CNS manifestation is a trigeminal (fifth cranial) nerve neuropathy, which may be the presenting feature of the disease, and this is also the most common CNS problem in patients with SSc. Headaches which are vascular in origin are common. Aseptic meningitis may also be noted. Sensorineural hearing loss is often not recognized, but it is reported to occur in about 50 % of MCTD patients.

Nonspecific hematologic and laboratory abnormalities are common in MCTD. Approximately 75 % patients have a low-grade anemia [14]. Leukopenia, mainly affecting the lymphocyte series, is a common finding that tends to correlate with disease activity. While majority have hypergammaglobulinemia [28], rheumatoid factor is positive in 50–70 % and anti-CCP antibodies are found in about 50 % of patients. Many patients have antibodies directed against heterogeneous nuclear ribonucleoprotein (hnRNP)-A2, fibrillin-1, and nucleosomes but not against ribonucleic acid (RNA) polymerases. Antiphospholipid antibodies occur less frequently than in SLE. If present, they tend to correlate with thrombocytopenia and PAH, but not with thrombosis and/or abortions. Anti-endothelial cell antibodies (AECA) occur in 50 % adults with MCTD. The use of trimethoprim-sulfamethoxazole is a significant risk factor for the development of AECA.

Raynaud’s phenomenon is a typical early feature of MCTD. Its absence should raise a suspicion against the diagnosis of MCTD. The characteristic vascular lesion of MCTD is bland intimal proliferation and medial hypertrophy affecting medium- and small-sized vessels. These pathologic changes differ from those usually noted in SLE, in which perivascular inflammatory infiltrates and necrosis are more characteristic. Similar to SSc, abnormal fingernail capillaroscopy is a common feature of MCTD [23]. The capillary pattern is characterized by dilatation and dropout. Angiographic studies reveal a high prevalence of medium-sized arterial occlusions.