INTRODUCTION — Mixed connective tissue disease (MCTD) is defined as a systemic rheumatic disease characterized by the presence of high titer anti-U1 ribonucleoprotein (U1 RNP) antibodies in combination with clinical features commonly seen in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), and polymyositis (PM).
It often takes several years before enough overlapping features have appeared to be confident that MCTD is the most appropriate diagnosis. The distinctive overlap features of SLE, SSc, inflammatory arthritis, and PM commonly appear sequentially over time. Thus, in its early stages, MCTD may present with features of undifferentiated connective tissue disease (UCTD). (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes".)
The clinical manifestations and diagnosis of MCTD will be reviewed here. The treatment and prognosis of this disorder are discussed separately. (See "Prognosis and treatment of mixed connective tissue disease".)
CONTROVERSY OVER DIAGNOSTIC CRITERIA — Since the disease was first defined by Sharp in 1972, there has been disagreement among experts as to whether mixed connective tissue disease (MCTD) should be considered a distinct clinical entity, or whether it might represent an early stage of another well-defined systemic rheumatic disease (eg, systemic lupus erythematosus [SLE], systemic sclerosis [SSc]) [1-5]. Four different diagnostic criteria have been proposed, reflecting the ongoing controversy over its definition [6-9]. The difference in sensitivity and specificity for each of the diagnostic criteria may determine which are to be utilized for screening (ruling out) and confirming (ruling in) the presence of the disease [10].
Across all of the four diagnostic criteria, common required features are:
●Positive anti-U1 ribonucleoprotein (U1 RNP) antibodies
Plus three or more of the following:
●Swollen hands
●Synovitis
●Myositis
●Raynaud phenomenon
●Acrosclerosis
While some argue that MCTD is a disease defined by presence of anti-U1 RNP, not all patients with anti-U1 RNP antibody meet the criteria for MCTD [11-13]. In this topic discussion, we present MCTD as a distinct clinical entity.
In support of its existence as a distinct clinical entity, the presence of antibodies targeting the U1 RNP is characteristic for MCTD and its association with distinct clinical characteristics. As examples:
●Patients with U1 RNP antibodies seldom develop diffuse proliferative glomerulonephritis, psychosis, or seizures; these abnormalities are a major source of morbidity and mortality in SLE [14,15].
●Patients with U1 RNP antibodies nearly always have an early development of Raynaud phenomenon [1,3,16] and a nailfold capillary pattern that is the same as in SSc, but that is different from classical SLE [17]. Raynaud phenomenon only occurs in approximately 25 percent of patients with classical SLE.
●Patients with U1 RNP antibodies are more likely to develop pulmonary hypertension than patients with classical SLE or SSc. Pulmonary hypertension is the major cause of death in MCTD [18-20].
●Patients with U1 RNP antibodies are more likely than SLE patients to test positively for rheumatoid factor [21,22] or anticyclic citrullinated peptide (anti-CCP) antibodies [23], and they are also more likely to develop an erosive arthritis [20-22,24]. Similarly, patients with anti-U1 RNP antibodies are more likely to have more than one autoantibody including anti-Sm and double-stranded deoxyribonucleic acid (dsDNA) compared with those with SSc only [11].
Additional information regarding antibodies to U1 RNP can be found elsewhere. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP", section on 'Anti-U1 RNP antibodies'.)
EPIDEMIOLOGY AND PATHOGENESIS — There is limited information regarding the prevalence and incidence of mixed connective tissue disease (MCTD) [25-29]. MCTD occurs worldwide and affects all races, with a peak incidence in adolescence and the 20s [10,30,31]. In a community-based study from Olmsted County, Minnesota, the annual incidence of MCTD was 1.9 per 100,000 adults [26]. Another population-based study from Norway found the incidence of MCTD to be lower, with a rate of 0.21 per 100,000 adults [25]. MCTD is much more common in females than males, although estimates of the difference range widely (from a ratio of 3.3:1 to up to 16:1) [25,32-34].
Little is known about the etiology of MCTD. Drug-induced MCTD is a rare occurrence but may be an occasional feature of anti-tumor necrosis factor (TNF) therapy [35,36]. Vinyl chloride [37] and silica [38,39] are the only environmental agents that have been associated with MCTD. Coronavirus disease 2019 (COVID-19) infections have been associated with disease flares, including diffuse lymphadenopathy and lupus nephritis [40,41], suggesting that both diseases share similar immune dysregulation mechanisms and antigen-autoantibody interactions.
Although there is limited evidence for potential environmental factors for MCTD, HLA-DRB1*04:01 has been linked with MCTD [42]. Although not specific, epigenetic signal with DNA methylation variability for genes involved in type I interferon pathways was associated with MCTD [43]. Antigen recognition by anti-U1 ribonucleoprotein (U1 RNP) antibodies may be different among autoimmune diseases. In addition, mapping of the anti-U1 RNP antibodies in patients with systemic lupus erythematosus (SLE) and MCTD demonstrated that different epitopes are recognized and there is variability among patients [44]. Epitope spreading has been proposed as a potential mechanism to account for the change in clinical disease expression [45].
Prognostically, MCTD with anti-U1 RNP positivity has better long-term survival than patients with systemic sclerosis (SSc) with positive anti-Scl70 and anti-ribonucleic acid (RNA) polymerase antibodies; this prognostic difference extends to those with pulmonary hypertension despite similar severity [11,46], and this correlates with Sharp's initial observations.
CLINICAL MANIFESTATIONS — The early clinical features of mixed connective tissue disease (MCTD) are nonspecific and may consist of puffy fingers, fatigue, arthralgias, myalgias, low-grade fever, and Raynaud phenomenon [47,48]. A clue that these symptoms may be due to a systemic rheumatic disease is the discovery of a positive antinuclear antibody (ANA) in association with Raynaud phenomenon [1].
As will be described below, almost any organ system can be involved in MCTD [49,50]. There are, however, four clinical features that suggest the presence of MCTD rather than another systemic rheumatic disease such as systemic lupus erythematosus (SLE) or systemic sclerosis (SSc):
●Raynaud phenomenon, as well as swollen hands or puffy fingers (picture 1) [51,52]
●The absence of severe kidney and central nervous system (CNS) disease [15,53]
●More severe arthritis and the insidious onset of pulmonary hypertension (not related to lung fibrosis), which differentiate MCTD from both SLE and SSc [18,21,54]
●Autoantibodies whose fine specificity is anti-U1 ribonucleoprotein (U1 RNP), especially antibodies to the 68 kD protein [55] (see "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP", section on 'Anti-U1 RNP antibodies')
Specific organ involvement
Skin involvement — Skin involvement occurs in most patients with MCTD and is often a presenting feature [52]. The most common skin change is Raynaud phenomenon, which usually presents early in the disease course [52,56] (see 'Vascular involvement' below). As one of the key features across all four diagnostic criteria, swollen digits and occasionally total hand edema are distinctive features, occurring in 53 to 72 percent of cases at presentation and 46 to 92 percent after follow-up (picture 1) [3,54,57]. The fingers may initially appear puffy, which represents an initial edematous phase mainly due to vascular (rather than articular) damage, followed by a fibrotic phase that later leads to induration. Chilblain lesions, if present, can be associated with sausage-like fingers leading to digital ulcers and infarcts, resulting in ice-pick scars, digital atrophy, and poor nail growth. Superficial vasculitis of the digits (picture 2), acrosclerosis, and calcinosis cutis are all well described [52,58,59]. Digit autoamputation can occur with severe Raynaud phenomenon (picture 3) [60].
Other skin manifestations, such as discoid plaques and malar rash (picture 4), are indistinguishable from SLE (picture 5A-C) (see "Overview of cutaneous lupus erythematosus"). Panniculitis over the abdomen, legs, and breasts has been described. Mucus membrane involvement can include orogenital and buccal ulcerations, nasal septal perforation, and the sicca complex [54,61,62].
Joint involvement — Joint involvement in MCTD is more common and frequently more severe compared with that observed in SLE. Approximately 60 percent of patients with MCTD develop an obvious arthritis, often with deformities characteristic of rheumatoid arthritis (RA), such as boutonniere deformities and swan neck changes (picture 6) [11,21,57]. Other changes include small marginal erosions (image 1) [63-65] and a destructive arthritis, including arthritis mutilans (image 2 and picture 7) [21,66].
A positive rheumatoid factor is found in approximately 70 percent of patients with MCTD [22], and anticyclic citrullinated peptide (anti-CCP) antibodies are found in approximately 50 percent, especially in those MCTD patients who also fulfill the American College of Rheumatology diagnostic criteria for RA [67].
Pulmonary involvement — The lungs are commonly affected in MCTD with involvement in approximately 75 percent of patients [68,69]. The most common pulmonary complications of MCTD are interstitial lung disease (ILD) and pulmonary hypertension, but a wide spectrum of other pulmonary complications have been described, including pleural effusions, pleuritic pain, alveolar hemorrhage, and thromboembolic disease [19].
Early symptoms that should alert one to pulmonary involvement are dry cough, dyspnea, and pleuritic chest pain [19].
●Interstitial lung disease – ILD occurs in approximately 50 to 66 percent of patients with MCTD [70-73]. MCTD-ILD accounts for 6 percent of the whole connective tissue disease (CTD)-ILDs, and 24 percent of MCTD-ILDs demonstrate progressive fibrotic phenotype [74]. Operationally, progressive fibrosing phenotype is defined to meet at least one of the following criteria for disease progression within the 24 months before screening: a relative decline in the forced vital capacity (FVC) of 10 percent or more of the predicted value, a composite of a relative decline in the FVC of 5 to 10 percent of the predicted value and worsening symptoms or an increase in disease extent on chest computed tomography (CT), or worsening symptoms and an increase in disease extent on chest CT [75].
Risk factors for the development of ILD include Raynaud phenomenon, dysphagia, and an elevated C-reactive protein (CRP) [76,77]. Digital ulceration was reported to be a risk factor for more severe lung disease, which is consistent with the association of ILD with giant capillaries on nailfold capillaroscopy [77,78]. Anti-Sm antibody and anti-Ro52 antibodies appear to be more commonly associated with MCTD-related pulmonary fibrosis [45,79].
Nonspecific interstitial pneumonia pattern accounts for most of ILD in MCTD, and therefore, the most common high-resolution CT findings are septal thickening, ground-glass opacities, nonseptal linear opacities, and peripheral/lower lobe predominance [80,81], which are most similar to the findings in SSc [72,82].
Patients with more severe fibrosis exhibit further decreases in diffusing capacity for carbon monoxide (DLCO); reduced FVC and forced expiratory volume, consistent with restrictive lung disease; reduced six-minute walk test distances; and higher (worse) mean New York Heart Association functional class [72].
Untreated ILD is usually progressive with the development of severe pulmonary fibrosis in 25 percent of patients after four years of follow-up [70]. Esophageal dilatation has been associated with a tendency to develop ILD in MCTD [83].
●Pulmonary hypertension – Systematic screening of patients with MCTD and SSc demonstrated a prevalence of 13.3 percent [84]. Pulmonary hypertension is a major cause of death in MCTD [33].
However, the prognosis of pulmonary hypertension in MCTD is better than for other CTD-pulmonary hypertensions, including SSc and SLE, despite similar histologic changes affecting the pulmonary arteries with intimal hyperplasia, medial hypertrophy, plexiform lesions, and local microthrombi (picture 8) [46].
The development of pulmonary hypertension has been correlated with a nailfold capillary pattern with low capillary density similar to that seen in SSc, with antiendothelial cell antibodies, and with anticardiolipin antibodies [85-87]. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)
Vascular involvement — Raynaud phenomenon is a typical early feature of MCTD occurring in between 50.3 to 93.2 percent of patients at presentation and 57.5 to 99 percent after follow-up [56]; its absence should cast doubt on the diagnosis. The characteristic vascular lesion of MCTD is bland intimal proliferation and medial hypertrophy affecting medium- and small-sized vessels [88]; this is also the characteristic pathology in pulmonary hypertension and renovascular crises (picture 5A-C) [33]. Angiographic studies reveal a high prevalence of medium-sized arterial occlusions (image 3) [17]. These pathologic changes differ from those usually noted in SLE, in which perivascular inflammatory infiltrates and necrosis are more characteristic.
Similar to SSc, abnormal nailfold capillaroscopy with giant capillaries, abnormal shapes, and low capillary density is a common feature of MCTD (occurring in 38 to 70 percent of cases), and this can accrue over time [89-91]. The capillary pattern is characterized by dilation and dropout (picture 9). Nailfold capillaroscopy can be performed at the bedside, a test that is useful for the prognostic stratification of those with early Raynaud phenomenon [92]. (See "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Nailfold capillary microscopy'.)
Muscle involvement — One of the three overlap features required for the diagnosis of MCTD is an inflammatory myopathy clinically and histologically identical to polymyositis (PM) [3,93,94]. Myalgia is a common symptom in patients with MCTD [95]. In most patients, there is no demonstrable weakness, electromyographic (EMG) abnormalities, or elevation of muscle enzymes. It is often unclear whether the symptom represents a low-grade myositis, a physical deconditioning, or an associated fibromyalgia syndrome. However, a true myositis may occur as an acute flare against a background of general disease activity [3]. Cases of a low-grade, insidious, and persistent inflammatory myopathy have also been described. The histology of muscle involvement in MCTD is the same as that of idiopathic inflammatory myopathy [96,97], with features of both the vascular involvement of dermatomyositis (DM) and the cell-mediated changes of PM [98]. It is increasingly apparent that a diagnosis of "pure" PM is relatively rare, and most patients with an inflammatory myopathy turn out to have an overlap syndrome [99]. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Nomenclature' and "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Polymyositis' and "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Overlap syndromes' and "Clinical manifestations of dermatomyositis and polymyositis in adults".)
Cardiac involvement — Cardiac involvement accounts for approximately 20 percent of MCTD mortality [100]. Approximately 30 percent of MCTD patients have symptomatic heart disease, and up to 40 percent have subclinical disease [100]. All three layers of the heart may be involved.
An abnormal electrocardiogram is noted in approximately 20 percent of patients. The most common electrocardiogram abnormalities include hemiblock, bundle branch block, and atrioventricular block [100]. Echocardiography may detect subclinical cardiac involvement in up to 38 percent of patients. Pericardial effusion and mitral valve prolapse are among the most common echocardiographic abnormalities and may be seen in up to 25 percent of MCTD patients.
Pericarditis is the most common clinical manifestation of cardiac involvement, being reported in up to 40 percent of patients [100]. Involvement of the myocardium is also recognized [101,102]. In some patients, myocardial involvement is secondary to pulmonary hypertension, which is often asymptomatic in its early stages [103]. (See 'Pulmonary involvement' above.)
There is also increasing recognition of accelerated atherosclerosis in MCTD [101,104]. Documented risk factors include elevated high-sensitivity CRP levels, dyslipidemia, antiendothelial antibodies, antiphospholipid antibodies, and vitamin D deficiency.
Kidney involvement — The absence of severe kidney disease is a hallmark of MCTD, with a wide range of reported frequency of 4 to 64 percent [1]. In larger series, the frequency is closer to 4 percent [101], while smaller series reported an occurrence of approximately 64 percent, leading to the wide range of frequency reported in different series [105]. It is possible that high titers of anti-U1 RNP antibodies, which are characteristic of MCTD, may protect against the development of diffuse proliferative glomerulonephritis, independent of whether these antibodies occur in MCTD or in SLE [15,20].
However, some degree of kidney involvement occurs in approximately 25 percent of patients [14,15,54]. Membranous nephropathy is the most common finding (picture 10A-E) [15,54,106], and nephrotic range proteinuria may occur [20]. Tubulointerstitial nephritis, mesangioproliferative glomerulonephritis, and hypertensive crises similar to scleroderma renal crisis have also been reported [107-109]. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis".)
The presence of a urinary abnormality defined as proteinuria and/or hematuria on urinalysis was reported in a retrospective series to be associated with poor kidney prognosis and development of other CTDs, indicating regular urinary analysis may be warranted [110].
Gastrointestinal involvement — Gastrointestinal involvement is the most common clinical overlap feature with SSc, occurring in approximately 60 to 80 percent of patients [53,68]. Disordered motility in the upper gastrointestinal tract is the most common problem, and this may be associated with development of SSc [2,83,111]. Esophageal biopsies may show severe atrophy and loss of smooth muscle cells in the muscular layer of the lower esophagus, followed by fibrosis (image 4) [112]. The atrophied tissues show deposition of immunoglobulin (Ig) G and C3 on immunofluorescence microscopy.
There have been case reports of hemoperitoneum, hematobilia, duodenal bleeding, megacolon, pancreatitis, ascites, protein-losing enteropathy, primary biliary cholangitis (previously referred to as primary biliary cirrhosis), portal hypertension, pneumatosis intestinalis, and autoimmune hepatitis [54,113-115]. Malabsorption syndrome can occur secondarily to small bowel dilation with bacterial overgrowth. Liver involvement in the form of chronic active hepatitis and Budd-Chiari syndrome has been described. Pseudodiverticulae, identical to those seen in SSc, may be seen along the antimesenteric border of the colon. Abdominal pain in MCTD may result from bowel hypomotility, serositis, mesenteric vasculitis, colonic perforation, and pancreatitis.
Central nervous system disease — The original description of MCTD emphasized the lack of CNS involvement [1]. This observation remains largely accurate, since patients with MCTD do not develop severe complications such as cerebritis, psychosis, or seizures [116]. However, approximately 25 percent of patients have some typically mild form of CNS disease [33,116].
●The most frequent CNS manifestation is a trigeminal (fifth cranial) nerve neuropathy, which may be the presenting feature of the disease [117,118]. Trigeminal neuropathy is also the most common CNS problem in patients with SSc.
●Headaches are common. They are most often vascular in origin [119] but can be caused by aseptic meningitis [120,121], due to the disease itself or to a reaction to nonsteroidal antiinflammatory drugs (NSAIDs) [122-124], and by muscle tension and myofascial trigger points.
●Sensorineural hearing loss is often not recognized, but it is reported to occur in approximately 50 percent of MCTD patients [125].
Isolated cases of cerebral hemorrhage [126], transverse myelitis [127], cauda equina syndrome [128], retinal vasculitis [129], progressive multifocal encephalopathy [130,131], demyelinating neuropathy [132,133], reversible posterior encephalopathy [134], and adhesive arachnoiditis [135] have also been reported. In general, MCTD patients have relatively mild cognitive impairment compared with patients with SLE who experience neuropsychiatric involvement [136].
Other
●Sjögren's syndrome – Prominent sicca symptoms (keratoconjunctivitis sicca) of Sjögren's syndrome have been reported in 32 percent of the patients in a small single-center series [137]. However, no histologic confirmation of salivary gland involvement was available, and there was no difference in serology for Sjögren's syndrome. Ultrasound evidence with morphologic changes of inhomogeneous parenchymal appearances with hypoechoic lesions was reported in a cohort of 10 patients with MCTD with secondary juvenile Sjögren's syndrome [138]. (See "Diagnosis and classification of Sjögren's syndrome".)
DIAGNOSIS
When to suspect mixed connective tissue disease — The diagnosis of mixed connective tissue disease (MCTD) should be suspected in a patient presenting with overlapping features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory myopathy, or rheumatoid arthritis (RA), particularly when found in association with a high titer of anti-U1 ribonucleoprotein (U1 RNP) antibody and/or with abnormal nailfold capillaroscopy.
However, in early stages of the disease, most patients who develop MCTD cannot be easily differentiated from other well-defined systemic rheumatic diseases. Presenting symptoms are often nonspecific and include constitutional symptoms of fatigue and fever with a combination of arthralgia, myalgias, Raynaud phenomenon, and puffy digits. Specific symptoms of interstitial lung disease (ILD) or myositis may be present at onset.
The diagnosis is often complicated by the fact that the simultaneous presence of overlap features of SLE, SSc, inflammatory myopathy, and RA is seldom seen early on in the disease. More commonly, the overlapping features occur sequentially over several years [139].
Rarely, some patients present acutely with trigeminal neuropathy, severe polymyositis (PM), acute arthritis, aseptic meningitis, digital gangrene, acute abdomen, or high fever [116,118,140,141].
Many patients present with nondiagnostic features, which are considered to represent an undifferentiated connective tissue disease (UCTD), before displaying clinical characteristics most consistent with MCTD. Thus, the initial diagnostic considerations are broad. (See 'Differential diagnosis' below.)
Evaluation — The initial evaluation should include a thorough history, physical examination, and laboratory testing. Early referral to specialists, depending on organ involvement and severity of disease, is often appropriate, and multidisciplinary involvement (eg, by rheumatology, pulmonology) may be required.
History and physical examination — A comprehensive history and physical examination should be performed in all patients and should include nailfold capillary microscopy (see "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Nailfold capillary microscopy'). Pertinent history and physical examination findings are described below:
●History – Patients should be questioned about the presence of any of the following:
•Constitutional symptoms, such as fever, fatigue, lymphadenopathy, or weight loss
•Dysphagia
•Painless oral or nasal ulcers
•Raynaud phenomenon or digital puffiness
•Joint pain or swelling
•Chest pain suggestive of pericarditis
•Dyspnea or pleuritic chest pain suggestive of serositis or interstitial lung disease
•Lower-extremity edema and hypertension
•Weakness when climbing stairs, getting out of a chair, or carrying heavy objects
●Physical examination – Pertinent physical examination findings include the following:
•Puffy or swollen fingers and/or nonpitting edema of the hands
•Skin thickening, either diffuse or limited to the hands, face, feet, and forearms
•Abnormal nailfold capillaroscopy with SSc pattern
•Skin lesions consistent with a malar rash or discoid lesions
•Polyarticular arthritis
•Decreased or abnormal breath sounds that may indicate a pleural effusion, pneumonitis, or ILD
•Proximal muscle weakness
Laboratory testing — We obtain the following routine laboratory tests to help exclude other processes and/or determine the extent of disease involvement:
●Complete blood count – Common abnormalities include leukopenia (mainly affecting lymphocytes), mild anemia, and/or thrombocytopenia [54,141].
●Serum creatinine level and urinalysis with urine sediment – A serum creatinine and urinalysis with urine sediment may help identify the presence of kidney involvement and the degree of injury if present. Patients with evidence of abnormal kidney function, microscopic hematuria, proteinuria, or an active urinary sediment (eg, with dysmorphic red cells [acanthocytes] and/or red cell casts) may need further evaluation with a kidney biopsy.
In addition to the routine laboratories described above, we preform the following autoantibody tests in all patients:
●Antinuclear antibody (ideally by human epidermoid carcinoma cell line [HEp-2] indirect immunofluorescence testing) – Patients with MCTD typically have a positive antinuclear antibody (ANA) with a high titer coarse speckled pattern (commonly >1:1000 and often >1:10,000) [142]. However, autoantibodies to U1 RNP, Sm, Ro/SSA, and La/SSB all produce a speckled pattern, and antibodies to double-stranded DNA (dsDNA), Sm, and Ro/SSA are occasionally seen transiently in patients with MCTD. If dsDNA, Sm, or Ro/SSA are the dominant and persistent autoantibody system, then the patient is more likely to develop a systemic rheumatic disease other than MCTD. If, on the other hand, antibodies to U1 RNP remain dominant, then the patient is likely to continue to have the clinical characteristics of MCTD.
●Anti-U1 RNP antibodies – As part of the routine extractable nuclear antigen profile, the presence of anti-U1 RNP antibodies remains a sine qua non for the diagnosis of MCTD. Nevertheless, anti-U1 RNP antibodies alone do not guarantee that a patient either has MCTD or will continue to display the MCTD phenotype.
U1 RNP consists of RNA plus three proteins (A', C, and a 68-70 kD protein). Additional information regarding antibody measurement and clinical utility is presented separately. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP", section on 'Anti-U1 RNP antibodies'.)
Other testing should be performed to help identify overlap conditions or exclude alternative diagnoses. Additional testing may include the following:
●Rheumatoid factor – Rheumatoid factor is positive in 50 to 70 percent of patients with MCTD [22]. (See "Rheumatoid factor: Biology and utility of measurement", section on 'Rheumatic disorders'.)
●Anticyclic citrullinated peptide (anti-CCP) antibody – Anti-CCP antibodies are present in approximately 50 percent of patients with MCTD [67]. (See "Biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Positive anti-CCP in other diseases'.)
●Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels – An elevation in ESR and CRP may be present.
●C3 and C4 complement levels – Complement levels may decrease in patients with SLE.
●Anti-dsDNA autoantibodies – Anti-dsDNA autoantibodies are more specific for SLE. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP", section on 'Anti-dsDNA antibodies'.)
●Anti-Ro/SSA and anti-La/SSB autoantibodies – Anti-Ro/SSA and anti-La/SSB may be present in a range of autoimmune disorders including Sjögren's syndrome, SLE, inflammatory myopathies, SSc, MCTD, and RA, as well as primary biliary cholangitis. (See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems".)
●Creatine kinase and myositis-specific autoantibodies panel – Creatine kinase (CK) may be elevated in cases of myositis or inflammatory myopathy. Myositis-specific autoantibodies are often available as a panel and are associated with particular clinical syndromes within the idiopathic inflammatory myopathy spectrum. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Muscle enzymes' and "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Myositis-specific autoantibodies'.)
Other nonspecific laboratory abnormalities that may be present in MCTD include hypergammaglobulinemia [3,143].
Additional testing — Since cardiopulmonary involvement can be a prominent characteristic of MCTD, screening and monitoring for pulmonary hypertension are warranted. A transthoracic echocardiogram (TEE) to evaluate tricuspid regurgitant jet velocity and right ventricular systolic pressure is important. Lung imaging is often required at baseline. High-resolution CT is a sensitive test to determine the presence of ILD. Lung function tests (for forced vital capacity [FVC] and diffusing capacity for carbon monoxide [DLCO]) should be undertaken at regular intervals (eg, annually) to evaluate for development of ILD.
Other tests that may be necessary are typically determined by the clinical presentation and associated differential diagnostic possibilities. As an example, musculoskeletal ultrasonography may be appropriate to examine painful joints to detect synovitis and tenosynovitis in the hands and wrists.
Establishing the diagnosis — We diagnose MCTD in patients who present with at least three of the following clinical features:
●Digital swelling
●Raynaud phenomenon
●Synovitis
●Myositis
●Acrosclerosis
This approach is generally in accordance with accepted diagnostic criteria [6-9] (see 'Diagnostic criteria' below). Notably, these characteristic features develop over time, and they may include at least two systemic rheumatic diseases, which include SLE, SSc, inflammatory myopathy, and RA in the presence of anti-U1 RNP antibodies and/or abnormal nailfold capillaroscopy. The diagnosis is complicated by the fact there is significant heterogeneity in terms of disease presentations.
Affected patients are prone to develop pulmonary hypertension and a SSc-like vasculopathy, but serious kidney or central nervous system (CNS) disease is uncommon.
Diagnostic criteria — Several attempts have been made to standardize the diagnostic criteria for MCTD [6-8,144-146]. The Alarcon-Segovia and Kahn criteria have comparable sensitivity and specificity, and comparison of the four diagnostic criteria suggest that the Kasukawa criteria provides the highest sensitivity while both Alarcon-Segovia and Kahn criteria provide the maximum specificity [10]. Thus, the Kasukawa criteria may be useful for screening patients while either the Alarcon-Segovia or Kahn criteria may be used to rule in the diagnosis of MCTD. While misdiagnosis is common, the utility of antibody identification may be more accurate at prognostication than classification to disease groups.
Differential diagnosis — The distinction of MCTD from other systemic rheumatic diseases including overlap syndrome is a clinical challenge, particularly given the heterogeneity of disease presentations. Misdiagnosis at disease presentation is therefore common in up to 61 percent from one cohort from a single center [147]. While cases of MCTD have been reported to evolve into other systemic rheumatic diseases over time [2,26,148], other reports indicate that true phenotypic conversion is rare [147]. It is likely that one of the key reasons for these differences is the definition of MCTD and other systemic rheumatic diseases.
One study followed the clinical course of 118 patients initially diagnosed with MCTD [149]. Twelve percent developed another well-defined rheumatic condition over the course of 17 years; puffy hands predicted a stable MCTD phenotype. Remission occurred in 13 percent of patients, and disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K]) became lower with disease progression. A relatively low SLEDAI-2K score over the course of observation suggested that MCTD has a generally milder course than SLE and SSc.
On the other hand, many clinically stable patients fulfill criteria for both SLE and MCTD. In 1 study of 20 MCTD patients, 47 percent also satisfied SLE criteria [148]. In total, 37 out of 38 (97 percent) patients who satisfied MCTD criteria met Systemic Lupus International Collaborating Clinics (SLICC) SLE criteria, while 37 out of 79 (47 percent) RNP-positive patients who satisfied SLICC SLE criteria met MCTD criteria.
While it is not the scope of this review to provide a comprehensive list of all possible alternative diagnoses, we present several important mimics below. However, one of the distinguishing laboratory features for the diagnosis of MCTD is the presence of anti-U1 RNP antibodies. (See 'Laboratory testing' above.)
Consideration must be given to the individual diseases (and their respective differential diagnoses) that are required to present as overlapping as part of the diagnosis of MCTD:
●SLE (see "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults")
●RA (see "Clinical manifestations of rheumatoid arthritis" and "Diagnosis and differential diagnosis of rheumatoid arthritis")
●Inflammatory myopathy (see "Overview of and approach to the idiopathic inflammatory myopathies")
●SSc (see "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults")
●Primary Raynaud phenomenon (see "Clinical manifestations and diagnosis of Raynaud phenomenon")
In addition, some patients may have other types of overlap syndromes or undifferentiated disease. The following conditions should be considered:
●Overlap syndromes (see "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes")
●Rhupus (see "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Rhupus')
●UCTD (see "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes")
CONSIDERATIONS DURING PREGNANCY — The risk of medical and obstetric complications is similar to what has been reported for other systemic rheumatic diseases, and prepregnancy counseling to optimize disease control may improve outcomes [150-153].
The mechanism for pregnancy complications is probably an autoimmune reaction against placental tissues, as immunostaining studies show deposits of fibrinogen, IgG, IgM, IgA, and C3 localized to the trophoblast basement membrane [154]. Furthermore, there is an association of antiendothelial antibodies with spontaneous abortion in mixed connective tissue disease (MCTD) [155]. Controlled ovarian hyperstimulation in an MCTD patient undergoing in vitro fertilization resulted in a severe flare accompanied by respiratory failure [156].
Patients with severe Raynaud phenomenon in general often have low-birthweight infants [157], presumably due to placental ischemia. This relationship has also been described in patients with MCTD [158].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mixed connective tissue disease".)
SUMMARY
●Definition – Mixed connective tissue disease (MCTD) is defined as a systemic rheumatic disease characterized by the presence of high titer anti-U1 ribonucleoprotein (U1 RNP) antibodies in combination with clinical features commonly seen in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), and polymyositis (PM). (See 'Introduction' above and 'Controversy over diagnostic criteria' above.)
●Clinical manifestations – The early clinical features are nonspecific and may consist of puffy fingers, fatigue, arthralgias, myalgias, low-grade fever, and Raynaud phenomenon. A clue that these symptoms may be due to a systemic rheumatic disease is the discovery of a positive antinuclear antibody (ANA) in association with Raynaud phenomenon. Symptoms of interstitial lung disease (ILD) or myositis may be present at onset. (See 'Clinical manifestations' above and 'When to suspect mixed connective tissue disease' above.)
●Specific organ involvement – Almost any organ system can be involved in MCTD:
•Skin involvement – Skin involvement occurs in most patients and is often a presenting feature, particularly swollen digits. (See 'Skin involvement' above.)
•Joint involvement – Joint involvement is more common and severe compared with that observed in SLE. Approximately 60 percent of patients develop an obvious arthritis, often with deformities characteristic of RA. (See 'Joint involvement' above.)
•Pulmonary involvement – The lungs are commonly affected with involvement in approximately 75 percent of patients. The most common pulmonary complications of MCTD are ILD and pulmonary hypertension. (See 'Pulmonary involvement' above.)
•Vascular involvement – Raynaud phenomenon is a typical early feature, and its absence should cast doubt on the diagnosis. Similar to SSc, abnormal nailfold capillaroscopy with giant capillaries, abnormal shapes, and low capillary density is common. (See 'Vascular involvement' above.)
•Muscle involvement – Myalgia is a common symptom. In most patients, there are no demonstrable weakness, electromyographic (EMG) abnormalities, or elevation of muscle enzymes. However, a true myositis may occur as an acute flare against a background of general disease activity. (See 'Muscle involvement' above.)
•Cardiac involvement – Cardiac involvement accounts for approximately 20 percent of MCTD mortality. Approximately 30 percent of MCTD patients have symptomatic heart disease, and up to 40 percent have subclinical disease. All three layers of the heart may be involved. (See 'Cardiac involvement' above.)
•Kidney involvement – The absence of severe kidney disease is a hallmark of MCTD. However, some degree of kidney involvement may occur in approximately 25 percent of patients. (See 'Kidney involvement' above.)
•Gastrointestinal involvement – Gastrointestinal involvement is the most common clinical overlap feature with SSc, occurring in approximately 60 to 80 percent of patients, and it typically manifests as disordered motility in the upper gastrointestinal tract. (See 'Gastrointestinal involvement' above.)
•Central nervous system disease – Patients with MCTD generally do not develop severe central nervous system (CNS) complications, but some may have mild CNS involvement manifesting as trigeminal (fifth cranial) nerve neuropathy, headaches, or sensorineural hearing loss. (See 'Central nervous system disease' above.)
●Evaluation – The initial evaluation should include a thorough history, physical examination, and laboratory testing. Early referral to specialists, depending on organ involvement and severity of disease, is often appropriate, and multidisciplinary involvement (eg, by rheumatology, pulmonology) may be required. (See 'Evaluation' above.)
We obtain laboratory tests to help exclude other processes and/or determine the extent of disease involvement. Laboratory testing may include a complete blood count, serum creatinine level and urinalysis with urine sediment, ANA, and anti-U1 RNP autoantibodies as part of the routine extractable nuclear antigen profile. Additional testing may include rheumatoid factor, anticyclic citrullinated peptide (anti-CCP) antibodies, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and C3 and C4 levels. (See 'Laboratory testing' above.)
Since cardiopulmonary involvement can be a prominent characteristic of MCTD, screening and monitoring for pulmonary hypertension and ILD are warranted. A transthoracic echocardiogram (TEE) to evaluate tricuspid regurgitant jet velocity and right ventricular systolic pressure is important. Lung imaging is often required at baseline. High-resolution CT is a sensitive test to determine the presence of ILD. Lung function tests (for forced vital capacity [FVC] and diffusing capacity for carbon monoxide [DLCO]) should be undertaken at regular intervals (eg, annually) to evaluate for development of ILD. (See 'Additional testing' above.)
●Establishing the diagnosis – We diagnose MCTD in patients who present with at least three of the following clinical features:
•Digital swelling
•Raynaud phenomenon
•Synovitis
•Myositis
•Acrosclerosis
Notably, these characteristic features develop over time, and they may include at least two systemic rheumatic diseases, which include SLE, SSc, inflammatory myopathy, and RA in the presence of anti-U1 RNP antibodies and/or abnormal nailfold capillaroscopy. The diagnosis is complicated by the fact there is significant heterogeneity in terms of disease presentations. (See 'Establishing the diagnosis' above.)
●Differential diagnosis – The distinction of MCTD from other systemic rheumatic diseases including overlap syndrome is a clinical challenge, particularly given the heterogeneity of disease presentations. Consideration must be given to the individual diseases that are required to present as overlapping as part of the diagnosis of MCTD, which include SLE, RA, inflammatory myopathy, SSc, and Raynaud phenomenon. Rhupus and undifferentiated connective tissue disease (UCTD) should also be considered. (See 'Differential diagnosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert M Bennett, MD, FRCP, MACR, now deceased, who contributed to an earlier version of this topic review.
