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Mixed connective tissue disease: An overview of clinical manifestations, diagnosis and treatment

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The most common clinical manifestations of mixed connective disease are Raynaud’s phenomenon, arthralgias, swollen joints, esophageal dysfunction, muscle weakness and fingers sausage-like appearance together with the presence of anti-ribonucleoprotein (RNP) antibodies. However, organ involvement is more extensive than first descriptions reported. The disease can be serious with development of pulmonary, kidney, cardiovascular, gastrointestinal and central nervous system manifestations. The worst prognosis and high mortality are associated with the presence of pulmonary disease. Although a different set of clinical criteria have been proposed, there is no consensus about the most accurate. There is no full agreement about treatment and the initial impression of a satisfactory response to low doses of steroids is not always the rule. Herein, we review available evidence to a better approach to all previous topics.

Section snippets

Mixed connective tissue disease: from the criticism to the concept

Mixed connective tissue disease (MCTD) was first described in 1972 as an entity with mixed features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA) together with the presence of high-titre anti-U1small nuclear (sn) anti-ribonucleoprotein (anti-RNP) antibodies *[1], [2]. The disease has been reported in children and in individuals over 80 years and is more prevalent in women in the third decade of life (from 80%

Overview of clinical manifestations

MCTD may begin with any clinical manifestations of SLE, SSc, PM or RA, at disease onset or during clinical course. The most common clinical features are polyarthritis, RP, sclerodactyly, swollen hands, muscle disorders and oesophageal dysmotility. Alopecia, malar rash, lymphadenopathy or kidney damage are less common but can be present [17]. Unspecific constitutional symptoms such as fever, fatigue, arthralgias or myalgias are also common. In general, a broad spectrum of signs and symptoms can

Joint and forearm manifestations

Joint involvement varies from minimal arthralgias, arthritis in small or large joints and erosions typical of RA to arthritis mutilans [16]. Although rheumatoid factor can be positive in up to 70% of patients with erosive arthritis [18], no specific findings are found. In general, polyarthralgia is an early and common symptom in MCTD, occurs in approximately 60% of patients and may be accompanied by joint deformities with changes in radiographs [19], [20]. In addition, small peritendinous

Muscle disease

Between 80% and 90% of patients develop some muscle involvement. Proximal muscles are the more frequently affected with elevation of creatine kinase. However, it does not present any peculiar pattern different from other connective tissue diseases (CTDs) with muscle involvement. Electromyography is typical of inflammatory myopathy, although, focal myositis may also occur. Histological findings reveal myositis which is reminiscent of patients with PM or SLE [19], [22]. In most patients, myositis

Skin manifestations

RP is one of the most consistent features. RP appears in approximately 75–90% of patients and may precede other clinical manifestations in months or years and correlates with vascular disease in middle-sized vessels as well [1]. Almost 70% of patients develop swollen hands and sausage-like appearance of the digits. The histological appearance of the skin of the hands is remindful greatly to findings in SSc [1]. Nailfold capillaroscopy of fingers demonstrates changes that are more evocative of

Lung manifestations

Pulmonary abnormalities are found in up to 85% of patients. Although various abnormalities have been described such as fibrosis, interstitial disease and pulmonary arterial hypertension (PAH), most of them have an asymptomatic course. In prospective studies, it has been found that PAH and congestive heart failures as well as infections are the most common causes of death in those patients. However, the clinical picture is less severe than in other conditions *[17], [24], [28]. In a recent study

Cardiovascular disease

Cardiac involvement varies between 11% and 85%, depending on the method used to detect abnormalities and the definition of cardiac involvement [34], [35]. The most frequent manifestation is pericarditis (10–29%), which is usually mild [36]. Myocarditis, conduction disturbances (heart block) and abnormal left ventricular diastolic filling failure besides mitral valve prolapsed (26%) have also been detected by echocardiography in several patients [34], [35]. Vasculopathy in MCTD is usually

Gastrointestinal disease

Gastrointestinal involvement is common (66–74%) and often represents a major feature of overlap with SSc [39]. Oesophageal dysfunction is the most prevalent gastrointestinal manifestation. It is initially subclinical, and when it is symptomatic, dysphagia the most common symptom [40]. Oesophageal dysmotility and reflux disease occur more frequently in patients who have clinical manifestations mostly related to SSc rather than to SLE. However, manometric abnormalities are not related to skin

Renal complications

Renal involvement is one of the major complications of MCTD. It has been observed in some studies in approximately 25% of patients and it is often asymptomatic [47]. Severe renal disease is rare and the presence of anti-U1-RNP antibodies may be protective against the development of diffuse proliferative glomerulonephritis (GNF) [48]. Although focal or diffuse proliferative GNF can be present, membranous and mesangial GNF are the most common presentation. Immune complex-mediated nephritis has

Haematological manifestations

Conceiving haematological manifestations; leucopenia, anaemia of chronic disease, broad-based hypergammaglobulinemia and positive Coomb’s test without haemolysis are the most frequent reported haematological features [3]. Other less common haematological features include thrombocytopenia, thrombotic thrombocytopenic purpura (TTP) and red cell aplasia [53], [54]. Although they are not specific of MCTD, anaemia and leucopenia tend to correlate with disease activity and usually improve with

Neurological disease

Although the nervous system involvement is less frequent than other organ manifestations, there are an increased number of studies suggesting that prevalence may be greater than reported before [55], [56]. The studies show that the most common manifestation of the peripheral nervous system is the trigeminal neuropathy, which may be an early manifestation of an undiagnosed MCTD [55], [57]. Headaches and peripheral neuropathies have also been reported but most likely related to a vascular origin

Autoantibodies in MCTD

The anti-U1-RNP antibodies are the hallmark of the disease. Patients with high titres without any criteria of MCTD or other defined CTD, usually evolve into MCTD over 2 years. A pathogenic role of anti-U1-RNP has not been proven, but clinical associations that have been observed in SLE and SSc patients may suggest so [66], [67]. Anti-RNP antibodies are directed against the U1-snRNP (one of the major components of the spliceosome), which is associated with three proteins, U1-A, U1-C and U1-70K;

How to approach the diagnosis of MCTD?

Due to the wide spectrum of clinical findings in MCTD, the diagnosis is not often easy [77]. Different forms of CTD such as transitory conditions and early phases of defined CTDs, which will become fully defined within a few months or years should be considered in the differential diagnosis [78]. There are also uncompleted forms of defined CTDs, where a diagnosis is possible based on clinical and serological manifestations, but classification criteria are not met [79]. Many years ago, a

Overview of treatment

Patients diagnosed of MCTD were initially described as having a good prognosis *[1], [2], being extremely responsive to corticosteroid therapy. However, subsequent long-term studies have revealed that not all patients have a benign clinical course and that not all clinical manifestations are responsive to steroids [3], [23], [24], [27], [82]. Some patients may have mild self-limited disease, whereas others may develop severe major organ involvement with life-threatening manifestations [24].

Constitutional symptoms

Fever, fatigue, unspecific arthralgias or myalgias usually respond to non-steroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine or low-dose of prednisone, it depends on the severity. The possibility of fibromyalgia or reactive depression should always be considered and treated optimally [16], [23]. However, when a patient debuts with fever, careful search of occult infection or neoplasm should also be included.

Joint involvement

Continuous evaluation of joint symptoms should be performed. All patients who have arthritis should have baseline radiographs to determine if erosive changes are present. Most of the mild joint involvement has been treated with NSAIDs, hydroxychloroquine and/or oral prednisone with good response [16], *[17], [27]. For more severe forms, methotrexate has been reported to be indicated [84]. If methotrexate is contraindicated, other disease-modifying agents used in RA, such as leflunomide or

Muscle disease

Most of patients with acute onset of severe myositis, often accompanied by fever, respond to high doses of corticosteroids [24], [27]. Some reports have suggested a more favourable prognosis for muscle disease in MCTD with less steroid requirements [23], [24]. Myalgias in the absence of myositis can be treated with NSAIDs, hydroxycloroquine and/or low-dose prednisone. Otherwise, SLE-like skin rash, oral ulcerations and photosensitivity have been treated effectively with topical steroids,

Sclerodermatous involvement

Sclerodermatous-like skin manifestations are often responsive to steroid therapy. RP in MCTD usually responds to conventional vasodilator therapies such as calcium channel blockers together with preventive measures like avoidance of cold temperatures and other triggering factors such as smoking, and sympathomimetic agents. The use of warm and protection techniques of fingers are also beneficial. In recent years, therapy with prostaglandin-analogues was considered to treat severe ischaemic

Lung involvement

Regarding treatment of patients with PAH, recent advances have expanded the therapeutic options. First, an early detection is mandatory, all patients with MCTD must undergo screening echocardiography and high-resolution computed tomography at the time of diagnosis [89]. Mild cases must be followed with serial testing monitoring for any signs of progression. Traditional regimen of calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, immunosuppression and conventional heart

Cardiovascular disease

Concerning cardiovascular involvement, pericarditis usually responds to NSAIDs and/or varying doses of corticosteroids depending on the severity. Massive pericardial effusion with cardiac tamponade rarely occurs and it may need surgical drainage. It depends of the severity. Moderate to severe myocarditis should be treated with high-dose steroid therapy together with common therapy employed to treat congestive heart failure if it is present. Patients with myocarditis often require additional

Gastrointestinal involvement

Gastrointestinal disease in MCTD can be treated following common recommendations to treat similar disorders such as SSc. In any case, the first-line therapy is the conventional treatment with proton-pump inhibitors, H2-receptor antagonists and lifestyle modifications, together with oesophageal PH monitoring in patients with persistent reflux symptoms. However, there is one remarkable difference when treating oesophageal dysfunction in patients with MCTD [39]. In contrast to SSc, it usually

Renal impairment

As previously mentioned, renal involvement can be asymptomatic and although, nephrotic syndrome can develop, this may respond to high-dose of corticosteroid therapy. Approximately, 70% of nephropathy episodes resolved or improve significantly [47], with a few percentage of progression to renal failure [47], [96]. If a patient presents SSc-like renal crisis, treatment with ACE inhibitors as well as intravenous prostacyclin (Epoprostenol) are indicated. They are believed to improve microvascular

Neurological disease

Although nervous system involvement can be serious and sometimes fatal, it is potentially treatable. Unfortunately, there is a lack of randomised clinical trials in MCTD, so clinical trials performed for SLE patients and isolated observations provide the main evidence [97], [98]. In general, to treat nervous system involvement, corticosteroids are used in low-dose oral, high-dose oral or high-dose intravenous regimens according to the severity of potential damage. Therapeutic efforts to treat

Conclusions

MCTD is a well-defined entity with a wide spectrum of clinical manifestations. Long-term studies reveal that some patients may have mild self-limited disease, whereas others may develop severe major organ involvement. Although there is a different set of clinical criteria, the most common approach for the diagnosis requires the serological criteria plus at least three clinical criteria. The worst prognosis and high mortality is associated with the presence of pulmonary arterial hypertension.

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