The most likely diagnosis is mixed connective tissue disease (MCTD), an overlap syndrome that includes features of systemic lupus erythematosus (SLE), systemic sclerosis, and/or polymyositis in the setting of positive anti-U1-ribonucleoprotein (RNP) antibodies. Patients with MCTD must have positive anti-U1-RNP antibodies and at least three of the following five features: Raynaud phenomenon, edema of the hands, sclerodactyly, synovitis, and myositis. Patients with MCTD usually have positive antinuclear antibodies (ANA), negative anti–double-stranded DNA antibodies, normal complement levels, and a low incidence of kidney disease. These criteria have a sensitivity of 63% and specificity of 86% in the diagnosis of MCTD. These patients are more likely to have myositis and pulmonary hypertension, an important cause of mortality, than patients with SLE.

Polymyositis is a form of inflammatory myopathy characterized by symmetric proximal muscle weakness with little or no pain, and muscle enzymes such as creatine kinase are usually elevated 10- to 50-fold the upper limit of normal. However, polymyositis is not associated with anti-U1-RNP antibodies and does not result in puffy hands or sicca symptoms.

Although the patient has a positive ANA, the diagnosis of SLE is less likely in the context of the negative anti-Smith and anti–double-stranded DNA antibodies as well as the normal complement levels, serum creatinine, and urinalysis.

The absence of sclerodactyly, sclerodermatous skin changes, and esophageal involvement makes systemic sclerosis an unlikely diagnosis.

Undifferentiated connective tissue disease (UCTD) is not an overlap syndrome but instead refers to nonspecific clinical features (such as Raynaud phenomenon and arthralgia), no disease-specific findings, and nonspecific positive autoantibodies (such as ANA). UCTD may exist for some time prior to a clear emergence of symptoms characteristic enough to define a single rheumatologic disease.