Mixed connective tissue disease, undifferentiated connective tissue disease and overlap syndromes

Abstract

Systemic lupus erythematosus, systemic sclerosis, inflammatory myopathy and rheumatoid arthritis are systemic connective tissue disorders which are characterized by heterogeneous clinical symptoms and variable course. To date, updated diagnostic criteria for early diagnosis of each of the diseases of this group have been proposed. At the same time, a proportion of patients already have at the onset of the disease or over time, a combination of signs characteristic of different diseases. Such conditions are referred to as mixed connective tissue disease, undifferentiated connective tissue disease or overlap-syndrome, whose nosological identity remains the subject of discussion. Formerly there has been a kind of terminological confusion and similar conditions were described under different names, depending on the author's preferences. It was also believed that these conditions were an early stage or a clinically "incomplete" form of a connective tissue disease. However, as the observations of large patient groups have shown, whose disease was represented by a number of individual signs of several connective tissue diseases, the clinical manifestation remains unchanged for many years in the majority of them. To recognize the right for nosological independence, one should account for the fact that only for a mixed connective tissue disease various authors and research groups have proposed four variants of diagnostic criteria. These criteria have small differences in the number of clinical signs; however, all criteria include a mandatory sign, i.e. the presence of antibodies to U1-ribonucleoprotein in high titers. Clinical signs common to all these diagnostic criteria include the Raynaud's syndrome, arthritis, myositis and finger swelling or sclerodactyly. Another patient category includes those with mono- or oligosymptomatic manifestations characteristic of systemic connective tissue diseases, but without any specific immunological markers. Some of these patients in a fairly short time, usually from several months to 1–2 years, develop other clinical symptoms and signs corresponding to a reliable diagnosis of a connective tissue disease. At the same time, a significant part of patients with the oligosymptomatic course demonstrate a long-term stability without any further evolution of the disease. Such cases are defined as an undifferentiated connective tissue disease. To avoid the erroneous diagnosis of the transient form or an early stage of any connective tissue disease, the proposed classification criteria, along with the inclusion criteria, also embrace clinical and serological exclusion criteria. A separate category consists of patients with a combination of clinical signs sufficient for a definitive diagnosis of at least two systemic connective tissue diseases. These patients are diagnosed with the overlap-syndrome with indication of the components of connective tissue diseases in each individual case, as it largely determines the individual treatment and prognosis. The possibility of such clinical variants of systemic connective tissue diseases is becoming increasingly justified due to the concept of polyautoimmunity, which has attracted great interest of researchers in the last few years.