CHAPTER 54
Mixed connective tissue disease

Mark Goodfield

Department of Dermatology, Chapel Allerton Hospital, Leeds, UK

Definition and nomenclature

Mixed connective tissue disease (MCTD) [1], or overlap syndrome, describes the clinical situation in which symptoms of a number of connective tissue diseases (CTDs) occur in one patient. There may be specific antibody profiles associated with these constellations of symptoms, such as the presence of anti-U1-ribonucleoprotein (anti-U1-RNP) in Sharp's original description of MCTD in 1972 [2]. Progression to a specific CTD may occur, but many patients continue to have a mixed and static pattern of symptomatology.

Introduction and general description

Overlap syndromes, in which there are symptoms suggestive of more than one CTD, occur relatively commonly. This may be one stage in the development of a classic CTD, or a more persistent entity. More variants are being described, both with and without the U1-RNP antibody of Sharp's original description. Hence, some authors now regard MCTD as one among many ‘undifferentiated CTDs’ or ‘overlap syndromes’, and others doubt the validity of the concept, particularly in children [3]. Nevertheless, it is important to recognize this group of patients because of the generally good prognosis and the response to corticosteroid therapy. There have been a number of attempts at defining diagnostic criteria along the lines of those used for systemic lupus erythematosus (SLE) [4]. Some associations are more frequent than others: for example, systemic sclerosis combined with dermatomyositis is more frequent than systemic sclerosis combined with SLE [5].

Epidemiology

Incidence and prevalence

In a Norwegian study of 147 adults, the point prevalence of adult MCTD patients was 3.8 (95% confidence interval (CI) 3.2–4.4) per 100 000 adults. The incidence of adult-onset MCTD in Norway during the period from 1996 to 2005 was 2.1 (95% CI 1.7–2.5) per million per year [6].

Age

The mean age at diagnosis of adult-onset MCTD was 37.9 years (95% CI 35.3–40.4 years) in the Norwegian study quoted above [6]. The condition can occur in childhood and may be more severe in children, in whom cardiac renal disease and arthritis are common, and thrombocytopenia may be marked, although the overall prognosis may be quite good [7].

Sex

The condition is more common in females, with a female to male ratio of 3.3 : 1 in Norway in 2008.

Pathophysiology

In the classic form of MCTD, all patients have the speckled type of antinuclear antibody together with a high titre of antibody to extractable nuclear antigen (ENA). Different molecular forms of U1-RNP may be associated with different clinical variants [8]. Ro and La antibodies are found frequently, usually in association with sicca symptoms [9]. Precipitating antibodies designated PM-1 and Ku occur in polymyositis/systemic sclerosis overlap [10], and SL-Ki in patients with SLE, scleroderma and sicca syndrome [11]. Immune complexes occur in 90% of patients, and T cells are decreased. Complement levels are normal. Sometimes, anti-DNA antibody occurs in low titre, but this usually disappears with corticosteroid therapy. Anti-endothelial antibodies occur in approximately 50% of cases, and are associated with abnormal pulmonary, neurological and cardiac function, particularly pulmonary hypertension [12]. They are also related significantly to spontaneous abortion in female patients [13].

Predisposing factors

No predisposing factors have been identified.

Pathology

The microscopic appearances of the skin vary with the pattern of the disease. Immunohistology of uninvolved skin, where there is basement membrane staining with immunglobulin G (IgG) or IgM, may be helpful in distinguishing MCTD from uncomplicated systemic sclerosis where staining is absent [14]. Direct immunofluorescence study of apparently normal skin reveals particulate (‘speckled’) epidermal nuclear staining, and this correlates with high titres of anti-RNP. Epidermal nucleolar staining is associated with alopecia, hyper- and hypopigmentation, swollen hands with sclerodactyly, and lesions of discoid lupus erythematosus (DLE).

Genetics

Differences in HLA antigens between patients with MCTD and SLE indicate that they are genetically separate disorders [15]. HLA-DR4 is found more commonly in patients with arthritis than in normal controls, and is associated with a young age of onset of the condition [16]. Familial cases occur.

Environmental factors

Ultraviolet radiation may be relevant in precipitating and exacerbating lupus-like elements of MCTD [17]. Vitamin D deficiency has also been associated with the condition, although its relevance is unclear [18]. The role of silicone breast implants in the pathogenesis of the overlap syndromes is controversial; there is probably no relationship [19].

Clinical features

History

Patients, predominantly female, usually present with a history of joint symptoms, Raynaud phenomenon and skin changes – either erythematous skin rashes or skin swelling and thickening.

Presentation

Patients will show features of SLE, systemic sclerosis, dermatomyositis and polymyositis in varying combinations. Raynaud phenomenon, arthritis and arthralgia, sausage-shaped fingers and swelling of the dorsa of the hands are common presenting features. More than half have the abnormal nail fold capillaries seen in systemic sclerosis [20]. There may be prominent neurological or neuropsychiatric features [21], although these are less frequent and less severe than those seen in SLE. Other less frequent features include oro-genital ulceration, panniculitis and autonomic neuropathy [22].

Clinical variants

By its very nature, the condition is variable in its features, both at presentation and as the condition progresses. Features may lead to a diagnosis of a single CTD or may remain ‘mixed’ throughout the course of the illness.

Differential diagnosis

Any of the specific CTDs need to be considered in the differential diagnosis.

Classification of severity

There has been an attempt at staging the severity of MCTD, but this is not widely used [4].

Complications and co-morbidities

Thrombocytopenia is also occasionally found in adult cases, and may occur with thrombotic thrombocytopenic purpura [23]. Livedoid vasculitis [24], ankylosing spondylitis [25] and antineutrophil cytoplasmic antibody (ANCA) related glomerulonephritis [26] are reported to occur with MTCD. There may be an increased risk of malignancy, with cancer developing in 10% of cases [28]. Peripheral gangrene may occur due to obstruction of small blood vessels (Figure 54.1). Although the presence of anti-RNP is usually associated with a good prognosis, death occurs in approximately 4% from pulmonary hypertension, nephritis, myocarditis or widespread vasculitis [29].

Image described by caption.

Figure 54.1 Gangrene of the hands in mixed connective tissue disease.

Approximately one-third of cases develop into a characteristic CTD, usually SLE or systemic sclerosis [30]. A few patients with HLA-DR4 develop rheumatoid arthritis. In patients whose disease differentiated into systemic sclerosis, there was an association with HLA-DR5 [31].

Investigations

The purpose of investigation is to establish the nature and extent of the disease. Autoantibody testing is fundamental, since the antibody profile helps to define the condition. Investigation of potential internal organ involvement should include routine assessment of renal and pulmonary function. Abnormal oesophageal motility, impaired pulmonary diffusing capacity and myositis are frequently found on investigation. The incidence of clinical renal disease is approximately 5%, but renal histology may be abnormal in 20% [32].

Management

First line

The response to treatment with corticosteroids is good and should be used early, but in controlled doses. Most reports use 0.5 mg/kg body weight or less, with rapid dose reduction [1]. As with the specific CTDs, symptomatic treatment for particular symptoms is needed: vascular symptoms should be treated with oral and intravenous vasodilators [33].

Second line

Other successful treatment options, including hydroxychloroquine and methotrexate, have been reviewed [1]. Haematological manifestations may need to be managed with anti-B-cell treatment [34]; renal and neurological disease may require treatment with plasmapheresis or more aggressive immunosuppression.

References

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