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.
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 . 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% to 90%) . Since 1972, the concept of MCTD has been criticised because of the following aspects: (1) the difficulty to distinguish MCTD patients from SLE, SSc or RA and (2) because many patients who have anti-U1-RNP antibodies satisfy the criteria for SLE or SSc during the clinical course, and may experience a shift of symptoms from MCTD to the true features of SLE . However, after years, other studies supported the concept of MCTD as a different disease. In this regard, different set of diagnostic criteria were proposed . MCTD has also been associated with HLA class II alleles and such linkage is distinct from that one for SLE, SSc or PM/DM. HLA-DR4, -DR1 and less frequent -DR2 are the main HLA-associated alleles . To remark, relevant similar conditions have different HLA-DR associations; SLE is mainly associated with HLA-DR2 and DR3 , whereas SSc shows an association with HLA-DR3 or DR5 . PM/DM shows association with HLA-DR3 . A murine model also suggests some genetic linkage, HLA-DR4 transgenic mice C57BL/6-derived mice immunised with UI-70k in combination with complete freund’s adjuvant developed anti-70K autoantibodies and perivascular infiltrates resembling histopathological findings in MCTD . Regarding clinical manifestations, the most common at disease onset are Raynaud’s phenomenon (RP), arthralgias, swollen hands, fingers sausage-like appearance and muscle weakness. They appear in 90% of patients and usually develop insidiously . Asthenia and myalgias are also frequent. However, organ involvement is more extensive than first descriptions reported , and the initial impression of a satisfactory response to low doses of steroids and a favourable prognosis is not the rule. MCTD can be a serious disease with development of pulmonary arterial hypertension (PAH), glomerulonephritis (GNF), vasculitis, gastrointestinal bleeding and severe central nervous involvement, which does not always have a good prognosis.
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 . Unspecific constitutional symptoms such as fever, fatigue, arthralgias or myalgias are also common. In general, a broad spectrum of signs and symptoms can be present some of which, we intent to abridge herein.
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 . Unspecific constitutional symptoms such as fever, fatigue, arthralgias or myalgias are also common. In general, a broad spectrum of signs and symptoms can be present some of which, we intent to abridge herein.
Joint and forearm manifestations
Joint involvement varies from minimal arthralgias, arthritis in small or large joints and erosions typical of RA to arthritis mutilans . Although rheumatoid factor can be positive in up to 70% of patients with erosive arthritis , 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 . In addition, small peritendinous nodules in forearms have also been reported in some patients .
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 . In most patients, myositis presents acutely in the setting of general disease activity and may be associated with fever. Nevertheless, patients may also present with a more insidious onset, and persistent myopathy .
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 . 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 . Nailfold capillaroscopy of fingers demonstrates changes that are more evocative of SSc than SLE, but bushy formations seem to be characteristic of MCTD . Dermatomyositis-like rash, orogential ulceration and sicca complex syndrome have also been reported . Although uncommon, hypocomplementemic urticarial vasculitis was informed in some patients with MCTD . In general, clinical manifestations such as SLE-like skin rash, oral ulcerations and photosensitivity may also be present .
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 . In a recent study named the ‘registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL)’, it was found that patients with MCTD with PAH had better haemodynamic and favourable right ventricular echocardiographic findings but a higher prevalence of pericardial effusions. Additional findings were higher levels of B-type natriuretic peptide and lower diffusing capacity of carbon monoxide. One-year survival and discharge from hospitalisation were lower in patients with MCTD and PAH when compared to patients with SLE, SSc and RA with PAH . Other common clinical pulmonary manifestations include dyspnea and pleuritic chest pain. Radiographic findings include interstitial changes, pleural effusions, pneumonic infiltrates and pleural thickening . Patients can also develop interstitial lung disease, which is usually mild or even asymptomatic. Cases of acute interstitial pneumonia and pulmonary haemorrhage have been reported as well .
Cardiovascular disease
Cardiac involvement varies between 11% and 85%, depending on the method used to detect abnormalities and the definition of cardiac involvement . The most frequent manifestation is pericarditis (10–29%), which is usually mild . 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 . Vasculopathy in MCTD is usually similar to SSc, and is characterised by a bland intimal proliferation and medial hypertrophy that affects small and medium-sized vessels. Other cardiovascular events, such as stroke, are rarely reported in patients with MCTD . Low levels of vitamin D have been found in patients with MCTD. Among the clinical symptoms, the cardiovascular involvement has showed an inverse correlation with vitamin D status .
Gastrointestinal disease
Gastrointestinal involvement is common (66–74%) and often represents a major feature of overlap with SSc . Oesophageal dysfunction is the most prevalent gastrointestinal manifestation. It is initially subclinical, and when it is symptomatic, dysphagia the most common symptom . 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 disorders and are less severe than in SSc . Such abnormalities consist of decreased oesophageal sphincter pressure, reduced amplitude of peristalsis in distal oesophagus and, less common, reduced upper sphincter pressure . Other gastrointestinal manifestations that have been described are mesenteric vasculitis, colonic perforation, protein-losing enteropathy, acute pancreatitis, haemoperitoneum, haemobilia, diarrhea and chronic active hepatitis . Gastrointestinal abnormalities appear to correlate with the time of disease course but not with its clinical expression .
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 . Severe renal disease is rare and the presence of anti-U1-RNP antibodies may be protective against the development of diffuse proliferative glomerulonephritis (GNF) . Although focal or diffuse proliferative GNF can be present, membranous and mesangial GNF are the most common presentation. Immune complex-mediated nephritis has also been reported . Interstitial nephropathy or renal vascular disease which is characteristic of SSc is less frequent in MCTD patients . By contrast, juvenile MCTD is associated with a higher risk of nephritis than in adults with renal involvement. Hypocomplementemia observed in those patients suggests higher frequency of GNF, including membranous lesions. A more aggressive indication of renal biopsy should be considered in children with MCTD because of the high incidence of non-clinical nephritis . Other patients with MCTD may also develop accelerated hypertension, acute renal insufficiency and microangiopathic haemolytic anaemia with similar histopathologyfindings to those of scleroderma renal crisis .
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 . Other less common haematological features include thrombocytopenia, thrombotic thrombocytopenic purpura (TTP) and red cell aplasia . Although they are not specific of MCTD, anaemia and leucopenia tend to correlate with disease activity and usually improve with therapies employed to treat other organ manifestations .
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 . 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 . Headaches and peripheral neuropathies have also been reported but most likely related to a vascular origin . Regarding central nervous system manifestations, some patients can develop aseptic meningitis with increased concentrations of interferon (IFN)-gamma, interleukin (IL)-6 and higher titres of anti-U1-RNP antibodies in cerebrospinal fluid (CSF) than in serum. Titres of anti-U1-RNP antibodies in CSF correlate well with disease activity . Sato T, et al. recently tested the presence of anti-U1-RNP antibodies in both CSF and sera of 24 patients with SLE and four patients with MCTD with neuropsychiatric symptoms. It was found that titres of anti-U1-RNP antibodies in the CSF were useful indicators of central neuropsychiatric manifestations in patients with anti-U1-RNP antibodies . Intrathecal production was predominant in patients with neuropsychiatric symptoms. Otherwise, isolated cases of intracraneal haemorrhage, transverse myelitis, cauda equine syndrome, optic neuropathy and retinal vasculitis have been reported as well .
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 . 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; all of these autoantigens may be targeted by anti-U1-RNP specific antibodies . Vlachoyiannopoulos et al. described that anti-U1-RNP IgG isotype may be characteristic of MCTD, whereas IgM isotype are more commonly found in SLE patients, although two types can be detected in both diseases. In any case, antigen recognition by anti-U1-RNP antibodies seems to be different between SLE and MCTD. In an epitope mapping study, 94% of the patients who had MCTD, but only 20% of SLE patients, recognised the 35–58 peptide of the U1-A-protein . The targeted region is different and limited to the second of the two RNA-binding domains in SLE patients while antibodies of patients who have MCTD recognise a larger epitope that contains sequences of both RNA-binding domains . In most instances, any patient with new onset of MCTD with positive anti-U1-RNP antibodies will present with new-onset RP; polyarticular joint pain with or without frank sinovitis, and swollen, together with puffy hands rater with the typical sclerodactyly and muscle weakness . Otherwise, anti-U1-RNP antibodies are not the only antibodies found in the sera of patients with MCTD. Anti-Ro/SS-A, anti-single-stranded DNA (ssDNA) , anti-Sm and anti-double-stranded DNA (dsDNA) antibodies have also been detected, nevertheless, they are not specific of MCTD. Antiphospholipid antibodies have been reported in patients with MCTD. Anticardiolipin antibodies (aCL) are present in approximately 15% of patients; however, they are less prevalent than in patients with SLE . aCL have been associated with PAH in patients with MCTD but not with thrombotic events or other manifestations of the antiphospholipid syndrome (APS). It might be explained by low titres of IgG antibodies with higher prevalence of IgM isotype when compared to APS patients . Additional autoantibodies may be associated with specific clinical manifestations in patients with MCTD. Recently, autoantibodies to angiotensin-converting enzyme 2 (ACE2) were associated with constrictive vasculopathy, PAH and persistent digital ischaemia in patients with MCTD, SLE and SSc . Consistent with this, immunosuppressive therapy given to one SLE patient with digital necrosis markedly decreased the anti-ACE2 antibody titre and restored serum ACE2 activity, together with a substantial improvement in clinical symptoms . In another study, anti-endothelial cell antibodies (AECA) were more frequently seen in patients with MCTD than in patients with SSc . Although the pathogenic role of AECA in MCTD remains uncertain, serum AECA may constitute a useful marker of endothelial activation and disease activity.
How to approach the diagnosis of MCTD?
Due to the wide spectrum of clinical findings in MCTD, the diagnosis is not often easy . 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 . 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 . Many years ago, a different set of criteria were proposed ( Table 1 ). Nowadays, the most common approach for diagnosis in clinical practice requires the serological criteria plus at least three clinical criteria. However, when only hand edema, RP or sausage-like appearance of the digits are present, four clinical criteria should be considered . In this regard, different studies have tested the accuracy of the available clinical criteria to identify patients with MCTD rightly. In one study, Alarcon-Segovia and Cardiel compared three different set of criteria in a series of 593 patients, including 80 cases of MCTD. Results revealed that criteria by Alarcón-Segovia had 100% sensitivity and with the presence of anti-RNP antibodies, the specificity raises to 99.6%. Similar findings were found for Kasukawa criteria, the sensitivity was 96.2% and specificity was 99.8%. The specificity for Sharp criteria was 87.7% . This is important to remark that testing of criteria was made internally, so results may be different in a multicentre study. In another study, it was found that the criteria that best identified patients with MCTD were those proposed by Alarcón-Segovia, with 62.5% sensitivity and 86.2% specificity, comparable to Kahn’s criteria. The overlap with other CTDs was found in 16% of patients . In a recent study performed by Capelli S. et al. , three different classification criteria for MCTD (Kasukawa, Alarcón-Segovia and Sharp) were compared together with define predictors (clinical features and autoantibodies) of potential evolution towards other CTD. It was found that after a mean of 7.9 years of disease follow-up, 57.9% of patients remained meeting the MCTD-classification criteria of Kasukawa; 17.3% evolved into SSc, 9.1% into SLE, 2.5% into RA, 11.5% was reclassified as affected by UCTD and 1.7% as suffering from overlap syndrome. Kasukawa’s criteria were more sensitive (75%) in comparison to those of Alarcón-Segovia (73%) and Sharp criteria (42%) ( Table 1 ) . In summary, the concordance between serologic features and clinical findings together with close clinical follow-up is still being the elementary strategy to approach the diagnosis of MCTD.
| Sharp (1987) | Major criteria | Minor criteria | Requirements for diagnosis | Sensitivity | Specificity | Ref. |
| 1. Myositis 2. Pulmonary involvement: a. Diffuse capacity <70% of normal values b. Pulmonary hypertension c. Proliferative vascular lesions on lung biopsy 3. Raynud’s phenomenon or esophageal hypomotility 4. Swollen hands 5. Anti-ENA > 1:10.000 amd anti-U1 RNP positive and anti-Sm negative. | 1. Alopecia 2. Leuckoepnia 3. Anemia 4. Pleuritis 5. Pericarditis 6. Arthritis 7. Trigeminal neuropathy 8. Malar rash 9. Thrombocytopenia 10. Mild myositis 11. History of swollen hands. | At least four major criteria plus anti-U1-RNP titer of at least 1:4000. Exclusion criteria: positivity for anti-Sm antibody. Two major criteria from among criteria 1, 2 and 3 plus 2 minor criteria plus anti-U1-RNP titer of at least 1:1000. | S:42% | 87.7% | ||
| Alarcón-Segovia (1987) | Serological | Clinical | Requirements for diagnosis | Sensitivity | Specificity | Ref. |
| Anti-RNP titer > 1:1.600 | Edema in hands, synovitis, myositis, raynaud’s phenomenon, acrosclerosis. | Serological criteria plus at least three clinical criteria, included either synovitis or myositis. | 62.5% | 86.2% | ||
| Kasukawa (1987) | Common symptoms | Mixed Symptoms | Requirements for diagnosis | Sensitivity/specificity | Specificity | Ref. |
| 1.Raynaud’s phenomenon 2.Swollen fingers or hands Anti-RNP antibody positive | 1. SLE-like symptoms: a. Polyarthritis b. Lymphadenopathy c. Facial erythema d. Pericarditis or Pleuritis e. Leuko-thrombocytopenia. 2. SSc-like findings: a. Sclerodactyly b. Pulmonary fibrosis, restrictive changes of lung, or reduced diffusion capacity c. Hypomotility or dilatation of esophagus. 3. PM-like findings: a. Muscle weakness b. Eleveated serum levels of muscle enzymes (CPK) c. Myogenic pattern on EMG | At least 1 of 2 common symptoms plus positive for anti-RNP plus 1 more of the mixed symptoms in at least 2 of the 3 disease categories. | S:75% | 99.8% | ||
| Kahn (1991) | Serological | Clinical criteria | Requirements for diagnosis | Sensitivity | Specificity | Ref. |
| Presence of high titer anti-RNP corresponding to speckled ANA at titer ≥1:2000 | a. Raynauds phenomenon b. synovitis c. myositis d. swollen fingers | Serological criteria plus Raynaud’s phenomenon and at least two of the three following signs (synovitis, myositis and swollen fingers). | 63% | 86. % |
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