Version May 2024
INTRODUCTION — Mixed connective tissue disease (MCTD) is a systemic rheumatic disease characterized by the presence of high-titer anti-U1 ribonucleoprotein (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).
This topic will review the clinical manifestations, diagnosis, treatment and prognosis of MCTD. UCTD is discussed separately. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes".)
EPIDEMIOLOGY AND PATHOGENESIS
●Epidemiology – There is limited information regarding the prevalence and incidence of mixed connective tissue disease (MCTD) [1-5]. MCTD occurs worldwide and affects all races, with a peak incidence in adolescence and the 20s [6-8].
Estimates of the annual incidence of MCTD range from 0.2 to 1.9 per 100,000 adults [1,2]. MCTD is much more common in females than males, although estimates of the difference range widely (from 3:1 to 16:1) [1,9-11].
●Pathogenesis – Little is known about the etiology of MCTD.
•Exposures – Drug-induced MCTD is a rare occurrence but has been associated with anti-tumor necrosis factor (TNF) therapy [12,13]. Vinyl chloride [14] and silica [15,16] 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 [17,18].
•Genetics – Although there is limited evidence for potential environmental factors for MCTD, HLA-DRB1*04:01 has been linked with MCTD [19]. Although not specific, MCTD has been associated with variations of DNA methylation of genes in the type I interferon pathway [20].
•Target epitope – Anti-U1 ribonucleoprotein (RNP) antibodies associated with MCTD target a different epitope than anti-U1 RNP antibodies associated with systemic lupus erythematosus (SLE). This implies that anti-U1 RNP antibodies may play different roles in the pathogenesis of MCTD versus SLE [21].
Epitope spreading has been proposed as a potential mechanism to account for the change in clinical disease expression [22].
●Controversy regarding diagnosis – Since the disease was first defined in 1972, there has been disagreement among experts as to whether MCTD should be considered a distinct clinical entity or whether it might represent an early stage of another well-defined systemic rheumatic disease (eg, SLE or systemic sclerosis [SSc]) [23-27]. Four different diagnostic criteria have been proposed, reflecting the ongoing controversy over its definition [28-31]. (See 'Establishing the diagnosis' below.)
The following observations support the concept of MCTD as a distinct clinical diagnosis:
•Raynaud phenomenon – Patients with MCTD nearly always have an early development of Raynaud phenomenon [23,25,32] and a nailfold capillary pattern that is the same as in SSc but different from classical SLE [33]. Raynaud phenomenon only occurs in approximately 25 percent of patients with SLE. (See 'Raynaud phenomenon' below.)
•Pulmonary arterial hypertension – Patients with MCTD are more likely to develop pulmonary arterial hypertension (PAH) than patients with SLE or SSc. (See 'Pulmonary arterial hypertension' below.)
•Autoantibodies – Patients with MCTD are more likely than SLE patients to test positively for rheumatoid factor [34,35] or anti-citrullinated peptide antibodies (ACPA) [36]. MCTD patients with RF or ACPA are more likely to develop an erosive arthritis [34,35,37,38]. (See 'Arthritis' below.)
Similarly, these patients are more likely to have more than one autoantibody including anti-Sm and double-stranded deoxyribonucleic acid (dsDNA) compared with those with SSc [39].
CLINICAL MANIFESTATIONS — The early clinical features of mixed connective tissue disease (MCTD) may include puffy fingers, fatigue, arthralgias, myalgias, low-grade fever, and Raynaud phenomenon [40,41].
Lupus-like features
Cutaneous — Skin involvement occurs in most patients with MCTD and is often a presenting feature [42]. MCTD may share many of the cutaneous features of systemic lupus erythematosus (SLE), including chilblains (pernio), discoid plaques, malar rash, panniculitis, and mucosal ulcerations.
●Chilblains – Chilblains presents as erythematous to violaceous macules, papules, plaques, or nodules in sites of cold exposure, generally in the fingers and toes. 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 (picture 1 and picture 2). (See "Pernio (chilblains)", section on 'Clinical manifestations'.)
●Discoid plaques – Discoid plaques present as discrete, erythematous, indurated plaques covered by scale (picture 3 and picture 4). (See "Overview of cutaneous lupus erythematosus", section on 'Discoid lupus erythematosus'.)
●Malar rash – Malar rash is a form of acute cutaneous lupus erythematosus that presents as an erythematous rash across the cheeks and nose and is sometimes called a “butterfly rash” (picture 5). (See "Overview of cutaneous lupus erythematosus", section on 'Acute cutaneous lupus erythematosus'.)
●Panniculitis – Panniculitis over the abdomen, legs, and breasts has been described (picture 6 and picture 7). (See "Overview of cutaneous lupus erythematosus", section on 'Lupus profundus (lupus panniculitis)'.)
●Mucus membrane involvement – Mucus membrane involvement can include orogenital and buccal ulcerations [43-45]. All of these skin manifestations are indistinguishable from SLE (picture 8A-C). (See "Overview of cutaneous lupus erythematosus", section on 'Mucosal manifestations'.)
The management of chilblains is discussed elsewhere. The other disease manifestations mentioned above are managed using the same approach used for subacute cutaneous lupus erythematosus:
●(See "Pernio (chilblains)", section on 'Management'.)
Cardiac — Approximately 30 percent of MCTD patients have symptomatic heart disease, and up to 40 percent have subclinical disease [46]. Cardiac involvement accounts for approximately 20 percent of MCTD mortality [46].
MCTD may share many of the cardiac features of SLE:
●Pericarditis – Pericarditis is the most common clinical manifestation of cardiac involvement, being reported in up to 40 percent of patients [46].
Pericarditis typically presents with pleuritic substernal chest pain, which may be accompanied by an audible rub on auscultation. It may be accompanied by evidence of serositis at other sites (eg, pleural effusion). (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults", section on 'Pericardial disease'.)
As with acute idiopathic pericarditis, some patients may respond to nonsteroidal antiinflammatory drugs (NSAIDs) (table 1) and/or a moderate-dose glucocorticoid taper (table 2) However, for patients with MCTD, we generally add hydroxychloroquine. We reserve colchicine for patients with recurrent pericarditis despite hydroxychloroquine.
The management of acute pericarditis is discussed in detail elsewhere. (See "Acute pericarditis: Treatment and prognosis", section on 'Medical therapies'.)
●Myocarditis – Myocarditis is an uncommon manifestation of MCTD [47,48].
Myocarditis may present with tachycardia, electrocardiographic abnormalities (eg, diffuse ST and T wave abnormalities), cardiomegaly, or heart failure. Myocarditis may also present as an asymptomatic troponin/creatinine kinase elevation in a patient with other signs of systemic inflammation (eg, pericarditis, arthritis). Echocardiography may demonstrate systolic and/or diastolic dysfunction. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults", section on 'Myocarditis'.)
Myocarditis is managed using the same strategies developed for lupus myocarditis.
The management myocarditis is discussed in detail elsewhere. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults", section on 'Treatment of myocarditis'.)
●Accelerated atherosclerosis – There is also increasing recognition of accelerated atherosclerosis in both SLE and MCTD [47,49].
Atherosclerosis in MCTD may present with symptoms typical of ischemic heart disease (eg, exertional chest pain) or with nonspecific symptoms (eg, dyspnea, diaphoresis).
For patients with SLE, risk factors for accelerated atherosclerosis include elevated high-sensitivity C-reactive protein (CRP) levels, dyslipidemia, antiendothelial antibodies, antiphospholipid antibodies, and vitamin D deficiency. (See "Coronary artery disease in systemic lupus erythematosus", section on 'Clinical manifestations'.)
The management of the accelerated atherosclerosis associated with SLE is discussed elsewhere. (See "Coronary artery disease in systemic lupus erythematosus", section on 'Prevention and treatment'.)
●Conduction abnormalities – An abnormal electrocardiogram is noted in approximately 20 percent of patients. The most common electrocardiogram abnormalities include hemiblock, bundle branch block, and atrioventricular block [46].
SLE-associated conduction abnormalities are discussed elsewhere. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults", section on 'Conduction abnormalities'.)
Renal — Some degree of kidney involvement occurs in approximately 25 percent of patients [43,50,51]. Membranous nephropathy is the most common finding (picture 9A-E) [43,50,52], and nephrotic range proteinuria may occur [37]. Tubulointerstitial nephritis and mesangioproliferative glomerulonephritis has also been reported [53-55]. (See "Lupus nephritis: Diagnosis and classification", section on 'Histopathologic classification of LN' and "Lupus nephritis: Diagnosis and classification", section on 'Tubulointerstitial lesions'.)
Early kidney disease is generally asymptomatic. Proteinuria and/or hematuria may be the first sign of kidney disease, occurring prior to an increase in the serum creatinine. (See "Lupus nephritis: Diagnosis and classification", section on 'Clinical features'.)
The absence of severe kidney disease is a hallmark of MCTD [23,47,56]. High titers of anti-U1 ribonucleoprotein (RNP) antibodies may protect against the development of diffuse proliferative glomerulonephritis, independent of whether these antibodies occur in MCTD or in SLE [37,50]. However, the presence of hematuria or proteinuria is associated with a poor kidney prognosis and an increased risk of progression to SLE [57].
The treatment of both lupus-associated membranous nephropathy and lupus nephritis are discussed elsewhere:
●(See "Lupus nephritis: Therapy of lupus membranous nephropathy", section on 'Initial therapy'.)
Neurologic — Approximately 25 percent of patients have some mild form of central nervous system (CNS) disease [10,58]. Compared with patients with SLE, the cognitive impairment associated with MCTD is mild [59].
Patients with MCTD do not develop severe neurologic complications such as cerebritis, psychosis, or seizures [23,58]. The neurologic manifestations of MCTD include:
●Trigeminal neuralgia – The most frequent CNS manifestation is a trigeminal (fifth cranial) nerve neuralgia, which may be the presenting feature of the disease [60,61]. Trigeminal neuralgia is also the most common CNS problem in patients with SSc. (See "Trigeminal neuralgia", section on 'Clinical features'.)
●Headaches – Headaches are common. They are most often vascular in origin [62] but can be caused by aseptic meningitis [63,64], due to the disease itself or to a reaction to NSAIDs [65-67], and by muscle tension and myofascial trigger points. (See "Evaluation of headache in adults", section on 'Evaluation'.)
●Sensorineural hearing loss – Sensorineural hearing loss is often not recognized, but it is reported to occur in approximately 50 percent of MCTD patients [68]. There is no association between sensorineural hearing loss and age or disease duration. (See "Sudden sensorineural hearing loss in adults: Evaluation and management", section on 'Clinical manifestations'.)
●Other neurologic manifestations – Isolated cases of cerebral hemorrhage [69], transverse myelitis [70], cauda equina syndrome [71], retinal vasculitis [72], progressive multifocal encephalopathy [73,74], demyelinating neuropathy [75,76], reversible posterior encephalopathy [77], and adhesive arachnoiditis [78] have also been reported. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus", section on 'Clinical syndromes'.)
The management of trigeminal neuralgia, headache, autoimmune sensorineural hearing loss, and other features of neuropsychiatric lupus are discussed elsewhere:
●(See "Trigeminal neuralgia", section on 'First-line therapy'.)
Hematologic — Autoimmune thrombocytopenia and autoimmune hemolytic anemia are uncommon manifestations of MCTD. When these manifestations occur, they are managed using the same strategies developed for the hematologic manifestations of SLE.
Early thrombocytopenia and anemia are generally asymptomatic and are often detected through routine laboratory testing. There are multiple causes of thrombocytopenia and anemia, many of which are not immune mediated. (See "Hematologic manifestations of systemic lupus erythematosus", section on 'Causes of anemia' and "Hematologic manifestations of systemic lupus erythematosus", section on 'Thrombocytopenia'.)
The management of SLE-associated thrombocytopenia and autoimmune hemolytic anemia are discussed elsewhere. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Initial management' and "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Overview of decision-making'.)
Pulmonary — Patients with MCTD may rarely develop a wide spectrum of pulmonary complications associated with SLE, including pleural effusions, pleuritic pain, alveolar hemorrhage, and thromboembolic disease [79]. (See 'Interstitial lung disease' below.)
●Pleural effusions – Plural effusions are often bilateral and may be associated with a cough, dyspnea, or fever. Pleuritic chest pain may occur in the absence of a pleural effusion and may be associated with a pleural rub on examination. (See "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)
●Alveolar hemorrhage – Alveolar hemorrhage may be associated with hemoptysis, dyspnea, or anemia, developing over a few days. (See "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)
●Thromboembolic disease – Thromboembolic disease may present as a pulmonary embolism (with cough, dyspnea, and pleuritic chest pain) or a deep venous thrombosis (with unilateral lower extremity edema). (See "Epidemiology and pathogenesis of acute pulmonary embolism in adults", section on 'Clinical presentation'.)
The management of the pulmonary manifestations of SLE is discussed elsewhere:
●(See "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Pleural disease'.)
Scleroderma-like features
Raynaud phenomenon — Raynaud phenomenon is an early feature of MCTD in most patients [80]. The absence of Raynaud phenomenon should cast doubt on a diagnosis of MCTD.
In Raynaud phenomenon, vasospasm leads to a sharply demarcated color change of the digits (initially white, due to constricted blood flow, then blue, due to cyanosis). Rarely, patients with Raynaud phenomenon may also develop digital ischemia. (See "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Clinical features'.)
As with systemic sclerosis (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 [81-83]. The capillary pattern is characterized by dilation and dropout (picture 10). Nailfold capillaroscopy can be performed at the bedside and can be used to determine which patients with Raynaud phenomenon are at higher risk of developing a rheumatic disease, such as MCTD [84]. (See "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Nailfold capillary microscopy'.)
The management of Raynaud phenomenon and scleroderma-associated digital ischemia is discussed elsewhere:
●(See "Treatment of Raynaud phenomenon: Initial management", section on 'Initial management'.)
Gastrointestinal dysmotility — Gastrointestinal involvement is a common clinical overlap feature with SSc, occurring in approximately 60 to 80 percent of patients [85,86]. Disordered motility in the upper gastrointestinal tract is the most common problem, and this may be associated with development of SSc [24,87,88].
Dysmotility of the upper gastrointestinal tract most commonly presents with heartburn, dysphagia, or odynophagia. Advanced dysphagia may lead to regurgitation of food or fluids. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)", section on 'Esophageal involvement'.)
Esophageal biopsies may show severe atrophy and loss of smooth muscle cells in the muscular layer of the lower esophagus, followed by fibrosis (image 1) [89]. The atrophied tissues show deposition of immunoglobulin G (IgG) and C3 on immunofluorescence microscopy.
Gastrointestinal dysmotility is managed according to the treatment guidelines established for similar disorders in scleroderma [90]. (See "Treatment of gastrointestinal disease in systemic sclerosis (scleroderma)".)
Interstitial lung disease — Interstitial lung disease (ILD) occurs in approximately 50 to 66 percent of patients with MCTD [91-94]. Six percent of patients with connective tissue disease (CTD)-ILD have MCTD [95].
Nonspecific interstitial pneumonia (NSIP) accounts for most of ILD in MCTD. The most common high-resolution computed tomography (CT) findings are septal thickening, ground-glass opacities, non-septal linear opacities, and peripheral/lower lobe predominance [96,97], which are similar to the findings in SSc-ILD [93,98].
NSIP commonly presents with dyspnea and cough, developing over weeks to months, associated with bibasilar fine inspiratory crackles. Clubbing and right heart failure are uncommon manifestations of NSIP. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Clinical manifestations' and "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia", section on 'Clinical features'.)
Risk factors for the development of MCTD-ILD include [22,87,99-102]:
●Raynaud phenomenon
●Dysphagia
●Elevated CRP
●Giant capillaries on nailfold capillaroscopy
●Anti-Sm or anti-Ro52 antibodies
●Patulous esophagus
Additionally, digital ulceration was reported to be a risk factor for more severe lung disease [100,101].
Untreated MCTD-ILD is usually progressive, with the development of severe pulmonary fibrosis in 25 percent of patients after four years of follow-up [91].
The assessment and management of scleroderma lung disease are discussed elsewhere:
Digital vasculopathy — Swollen digits and occasionally total hand edema are present in 53 to 72 percent of cases at presentation and 46 to 92 percent after follow-up (picture 11) [25,43,103]. The fingers may initially appear puffy, which represents an initial edematous phase due to vascular (rather than articular) damage, followed by a fibrotic phase that leads to induration (figure 1). Acrosclerosis leading to digital autoamputation have also been described (picture 12) [104]. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'Suggestive findings' and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Digital vasculopathy'.)
The characteristic vascular lesion of MCTD is bland intimal proliferation and medial hypertrophy affecting medium- and small-sized vessels [105]; this is also the characteristic pathology in pulmonary arterial hypertension (PAH) and renovascular crises (picture 8A-C) [10]. Angiographic studies reveal a high prevalence of medium-sized arterial occlusions (image 2) [33]. These pathologic changes differ from those usually noted in SLE, in which perivascular inflammatory infiltrates and necrosis are more characteristic.
The management of digital ischemia is discussed elsewhere. (See "Treatment of Raynaud phenomenon: Refractory or progressive ischemia", section on 'Severe acute ischemia'.)
Pulmonary arterial hypertension — PAH is present in 13.2 percent of patients with MCTD [106].
PAH commonly presents with dyspnea, fatigue, and symptoms of right heart failure (eg, exertional chest pain, exertional syncope, abdominal pain/swelling due to hepatic congestion). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)
PAH is a major cause of death in MCTD [10,107]. However, the prognosis of PAH-MCTD is better than the prognosis of PAH associated with SSc or SLE, despite similar histologic changes affecting the pulmonary arteries (eg, intimal hyperplasia, medial hypertrophy, plexiform lesions, and local microthrombi (picture 13)) [108].
Risk factors of PAH-MCTD include low capillary density on nailfold capillaroscopy and antiendothelial or anticardiolipin antibodies [109-111].
The use of immunosuppression for the management of MCTD-associated PAH is controversial [112-115]. A systematic review indicated that 19 percent of patients with MCTD-associated PAH responded to immunosuppression [116]. However, scleroderma-associated PAH is generally thought to be refractory to immunosuppressive therapies.
The management of scleroderma-associated PAH is discussed separately. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis", section on 'General measures'.)
Cutaneous sclerosis and calcinosis cutis — Patients with MCTD rarely develop the cutaneous manifestations of scleroderma, such as cutaneous sclerosis and calcinosis cutis [117,118].
●Cutaneous sclerosis – Cutaneous sclerosis presents as thickening of the skin of the extremities and the face, sparing the back (figure 2). (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Cutaneous manifestations'.)
●Calcinosis cutis – Cutaneous cutis presents as hard deposits just below the surface of the skin, most commonly affecting the hands and feet (picture 14 and picture 15). (See "Calcinosis cutis: Etiology and patient evaluation", section on 'Autoimmune connective tissue disease'.)
When these disease manifestations occur, they are managed using the same strategies used for scleroderma.
The management of scleroderma-associated sclerosis and calcinosis cutis are discussed elsewhere:
●(See "Calcinosis cutis: Management", section on 'Treatment of calcinosis'.)
Scleroderma renal crisis — Scleroderma renal crisis (SRC) is an uncommon manifestation of MCTD. The diagnosis of SRC should be considered in any patient with MCTD presenting with new or worsening hypertension.
SRC is characterized by acute kidney injury with abrupt onset (or worsening) of hypertension. It is accompanied by a thrombotic microangiopathy, which is associated with thrombocytopenia, anemia, and schistocytes.
SRC, including risk factors and management, is discussed in detail elsewhere. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Clinical presentation'.)
The management of SRC is discussed elsewhere. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis", section on 'Treatment'.)
Cardiac fibrosis — In patients with SSc-like phenotype, myocardial fibrosis may be a predominant feature and therapeutic strategies would follow the management of SSc. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Cardiac involvement'.)
Other features
Arthritis — Joint involvement occurs in approximately 60 percent of patients with MCTD. The arthritis resembles rheumatoid arthritis (RA), rather than the less severe arthritis associated with SLE. Like RA, it may be associated with boutonniere deformities and swan neck changes (picture 16) [34,39,103]. Other changes include small marginal erosions (image 3) [119-121] and a destructive arthritis, including arthritis mutilans (image 4 and picture 17) [34,122]. (See "Clinical manifestations of rheumatoid arthritis", section on 'Symptoms and physical findings'.)
Rheumatoid factor is found in approximately 70 percent of patients with MCTD [35], 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 [123].
Management of inflammatory arthritis is discussed elsewhere. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Pharmacologic therapy'.)
Musculoskeletal
●Myalgias – Myalgia is a common symptom in patients with MCTD [124]. 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. (See "Approach to the patient with myalgia", section on 'Diagnosis'.)
Management of myalgias is discussed elsewhere. (See "Approach to the patient with myalgia", section on 'Management'.)
●Myositis – Patients with MCTD may develop an inflammatory myopathy and may have features of polymyositis (PM), dermatomyositis (DM), or immune-mediated necrotizing myopathy (IMNM). Myositis most commonly presents as an acute flare associated with proximal muscle weakness and creatinine kinase elevation but can also present as a low-grade, insidious, inflammatory myopathy [25]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Clinical manifestations'.)
The histology of muscle involvement in MCTD is the same as that of idiopathic inflammatory myopathy [125,126], with features of both the vascular involvement of DM and the cell-mediated changes of PM [127]. Some patients may also present with mechanic’s hands or extramuscular features of IMNM.
Management of inflammatory myopathy and the cutaneous manifestations of DM are discussed elsewhere:
•(See "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Initial therapy'.)
Sicca — Prominent sicca symptoms (ie, keratoconjunctivitis sicca) are typically associated with Sjögren’s disease. However, 32 percent of the patients with MCTD also complain of sicca symptoms [128].
Sicca is characterized by dry eyes and dry mouth.
●Dry eyes – Dry eyes often lead to complaints irritation, grittiness, itching, or a foreign-body sensation in the eye, associated with reduced tear flow. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease", section on 'Dry eye'.)
●Dry mouth – Dry mouth is associated with oral dryness or difficulty swallowing dry foot without liquids. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease", section on 'Clinical features of dry mouth'.)
The management of sicca is discussed elsewhere:
Gastrointestinal — 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 [43,129-131].
Liver involvement in the form of chronic active hepatitis and Budd-Chiari syndrome has been described.
Abdominal pain in MCTD may result from bowel hypomotility, serositis, mesenteric vasculitis, colonic perforation, and pancreatitis.
The management of all of these issues is discussed in the separate topic reviews.
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). However, overlapping features of SLE, SSc, inflammatory myopathy, and RA are seldom seen early in the disease. The overlapping features occur sequentially over several years [132].
Therefore, 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. Rarely, MCTD may present with interstitial lung disease (ILD) or myositis. Feature that are atypical for MCTD are described below. (See 'Differential diagnosis' below.)
Because the treatment of MCTD is driven by the individual manifestations, rather than the overall diagnosis, differentiating MCTD from other rheumatic diseases may not significantly affect patient outcomes.
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'.)
The following history and physical examination findings are common in MCTD although are not specific to MCTD:
●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 [43,133].
●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 perform the following autoantibody tests in all patients:
●Antinuclear antibody (ideally by human epidermoid carcinoma cell line 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) [134]. However, a speckled pattern may also be associated with autoantibodies to U1 ribonucleoprotein (RNP), Sm, Ro/SSA, and La/SSB.
Antibodies to double-stranded DNA (dsDNA), Sm, and Ro/SSA are occasionally seen transiently in patients with MCTD. If these autoantibodies remain detectable after repeat testing, the patient is more likely to develop another systemic rheumatic disease, such as SLE.
●Anti-U1 ribonucleoprotein antibodies – 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 ribonucleic acid (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'.)
●Erythrocyte sedimentation rate and/or C-reactive protein levels – An elevation in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be indicative of disease manifestations requiring immunosuppression.
It is important to note that the presence of autoantibodies typically associated with RA does not preclude a diagnosis of MCTD. Rheumatoid factor in particular is common among patients with MCTD. In a series of 300 patients with MCTD, rheumatoid factor and anti-cyclic citrullinated peptide antibodies (ACPA) were reported in 28 percent and 7 percent, respectively [135]. Hypergammaglobulinemia may also be present [25,136].
Establishing the diagnosis — We diagnose MCTD in patients who have:
●Anti-U1 RNP antibodies; and
●Have 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 [28-31].
Challenges to diagnosing MCTD include the following:
●Heterogeneity of presentation – There is significant heterogeneity in disease presentations. MCTD may present with features of multiple rheumatic diseases, including SLE, SSc, inflammatory myopathy, and RA.
●Evolution to alternate diagnoses – While cases of MCTD have been reported to evolve into other systemic rheumatic diseases over time [2,24,137], other reports indicate that true phenotypic conversion is rare [138]. These differences may be due to the use of different classification criteria in these studies.
One study followed the clinical course of 118 patients initially diagnosed with MCTD [139]. Twelve percent developed another well-defined rheumatic condition over the course of 17 years; puffy hands predicted a stable MCTD phenotype.
Other studies indicate that one in five patients initially diagnosed as having MCTD evolve into another rheumatic disease (eg, SSc, SLE, RA, Sjögren’s disease, and vasculitis) within five years of the MCTD diagnosis [24,137,140].
●Simultaneous diagnosis with lupus – Many clinically stable patients fulfill criteria for both SLE and MCTD. In one study of 20 MCTD patients, 47 percent also satisfied SLE criteria [137]. 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.
●Published diagnostic criteria – While some argue that MCTD is a disease defined by presence of anti-U1 RNP, not all patients with anti-U1 RNP antibody have MCTD [39,141,142].
Several attempts have been made to standardize the diagnostic criteria for MCTD [28-30,143-145]. The Alarcón-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 Alarcón-Segovia and Kahn criteria provide the maximum specificity [6]. Thus, the Kasukawa criteria may be useful for screening patients while either the Alarcón-Segovia or Kahn criteria may be used to rule in the diagnosis of MCTD. However, this approach is not validated.
DIFFERENTIAL DIAGNOSIS — The distinction of mixed connective tissue disease (MCTD) from other systemic rheumatic diseases including overlap syndrome is a clinical challenge, particularly given the heterogeneity of disease presentations. In a single-center study, 61 percent of patients with MCTD was not correctly diagnosed at disease presentation [138].
An alternate diagnosis should be considered under the following circumstances:
●Features atypical for MCTD – Multiple features are rarely found in association with MCTD, and their presence should prompt a thorough evaluation for systemic lupus erythematosus (SLE) (see "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Diagnosis'). These features include the following:
•Neurologic – Cerebritis, psychosis, or seizures
•Pulmonary – Pleurisy, pulmonary hemorrhage
•Hematologic – Pleural effusions, pleuritic pain, and alveolar hemorrhage, and thromboembolic disease
•Renal – Diffuse proliferative glomerulonephritis
Additionally, the presence of cutaneous sclerosis or scleroderma renal crisis (SRC) should prompt a thorough evaluation for scleroderma, since these features are rarely associated with MCTD. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Diagnosis'.)
●Absence of U1 ribonucleoprotein antibodies – Patients with U1 ribonucleoprotein (RNP) antibodies cannot be diagnosed with MCTD. Patients who have some of the clinical features of MCTD but lack U1 RNP antibodies should be evaluated for alternative diagnoses:
•Digital swelling, Raynaud phenomenon, and acrosclerosis should prompt an evaluation for scleroderma. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Diagnosis'.)
•Synovitis should prompt an evaluation for rheumatoid arthritis (RA) or another inflammatory arthritis. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Differential diagnosis' and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Evaluation and diagnosis'.)
•Myositis should prompt an evaluation for an idiopathic myopathy. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Diagnostic approach'.)
Finally, it is important to remember that patients may meet criteria for MCTD and another rheumatic disease simultaneously. Therefore, a prior diagnosis of another rheumatic disease (eg, SLE) does not preclude an additional diagnosis of MCTD. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes", section on 'Early undifferentiated systemic rheumatic disease'.)
MANAGEMENT
Monitoring — The management of patients with mixed connective tissue disease (MCTD) requires continual reassessment for new or evolving disease manifestations. In general, the distinctive clinical characteristics of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and polymyositis (PM) appear sequentially over time. It is unusual for patients to exhibit overlapping features in the early stages of MCTD [23,146-149]. Later in the disease course, patients may develop a true overlap syndrome, which simultaneously incorporates features of SLE, scleroderma, PM, rheumatoid arthritis (RA), and Sjogren’s disease.
Since cardiopulmonary involvement can be a prominent characteristic of MCTD, we suggest obtaining a baseline transthoracic echocardiogram, high-resolution CT scan of the chest, and pulmonary function tests (including forced vital capacity and diffusing capacity for carbon monoxide) for all patients.
In patients who have no evidence of cardiopulmonary disease at baseline, we recommend repeating an echocardiogram and pulmonary function tests on an annual basis to monitor for incident disease manifestations.
Slow interstitial lung disease (ILD) progression may occur. Male gender and lack of arthritis are possible risk factors for ILD progression [16]. High-titer anti-ribonucleoprotein (RNP) and/or anti-Ro52 antibodies have also been reported as risk factors for ILD progression; however, this antibody profile is more consistent with SLE rather than MCTD. Patients who have pulmonary arterial hypertension (PAH) or ILD should be monitored using the same algorithms developed for scleroderma. These issues are discussed in other topics. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Subsequent monitoring'.)
Treatment — Treatment is usually directed at the specific disease manifestations. Specific links are provided in the sections above. (See 'Clinical manifestations' above.)
The treatment of MCTD is largely extrapolated from treating similar symptoms in other rheumatic diseases [150]. When first described, MCTD was treated predominantly with long-term glucocorticoids, but this strategy is inappropriate for most patients [151-153].
In general, features of MCTD that are also associated with SLE are managed with hydroxychloroquine in addition to other immunosuppressive agents, including glucocorticoids, which are selected based on the severity of the disease manifestations. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Approach to drug therapy'.)
However, the SSc-like features of MCTD, with the exception of ILD, are not generally responsive to immunosuppressive therapies. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'General principles of management'.)
Glucocorticoids are typically contraindicated in patients with early, diffuse SSc because of their association with SRC. Because SRC has rarely been observed among patients with MCTD, glucocorticoids are not contraindicated for this patient population in the absence of other risk factors for SRC (eg, concomitant anti-U3 RNP or anti-RNA polymerase III antibodies).
Considerations during pregnancy — There are no specific guidelines for patients with MCTD considering pregnancy. However, we suggest counselling similar to that used for patients with SLE. (See "Pregnancy in women with systemic lupus erythematosus", section on 'Pregnancy planning'.)
We also suggest screening patients contemplating pregnancy for ILD, PAH, and the antiphospholipid syndrome, since these diagnoses may raise additional management considerations [154]. The evaluation of these diagnoses is discussed in other topics. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Evaluation for lung disease at time of SSc presentation' and "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing'.)
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 [154-157].
Data from retrospective series indicate that use of immunosuppression including steroids was reported to be associated with better pregnancy outcomes. This is likely related to better disease activity control with immunosuppression [154,157].
Patients with severe Raynaud phenomenon in general often have low-birthweight infants [158], presumably due to placental ischemia. This relationship has also been described in patients with MCTD [159].
The mechanism for other pregnancy complications is probably an autoimmune reaction against placental tissues, as immunostaining studies show deposits of fibrinogen, immunoglobulin G (IgG), IgM, IgA, and C3 localized to the trophoblast basement membrane [160]. Furthermore, there is an association of antiendothelial antibodies with spontaneous abortion in MCTD [161].
Issues pertaining to the safety of immunosuppressive drugs during pregnancy and lactation are discussed elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Risk categories and treatment context'.)
PROGNOSIS
●Mortality – Estimates of the mortality associated with mixed connective tissue disease (MCTD) ranges from 16 to 28 percent at 10 to 12 years [162-165]. The largest study of mortality in MCTD patients reported survival rates of 98, 96, and 88 percent at 5, 10 and 15 years after diagnosis among 280 patients [47].
MCTD with anti-U1 ribonucleoprotein (RNP) positivity has better long-term survival than patients with systemic sclerosis (SSc) with positive anti-Scl70 and anti-RNA polymerase antibodies; this prognostic difference extends to those with pulmonary arterial hypertension (PAH) despite similar severity [39,108]. Patients with MCTD also have a low prevalence of serious kidney disease and life-threatening neurologic manifestations [10,133,166].
PAH is the major cause of death in MCTD [37,79,167]. Other risk factors for morality include:
•Interstitial lung disease (ILD) [168]
•Anticardiolipin antibodies [10]
•Myocarditis [48]
•Renovascular hypertension [169,170]
•Cerebral hemorrhage [169,170]
●Morbidity – Morbidity is quite high in patients with MCTD.
•As in patients with systemic lupus erythematosus (SLE), it is not uncommon for patients with MCTD to develop fibromyalgia. This can often become more debilitating than the primary disease [151,152]. (See "Clinical manifestations and diagnosis of fibromyalgia in adults".)
•Patients with severe Raynaud phenomena can rarely develop ischemic ulcers and even outright gangrene of the fingers. Such patients generally have a higher mortality [164].
•A small subset of patients with MCTD develops a deforming arthritis and even arthritis mutilans [34,120,122].
•Esophageal dysmotility can progress over time; as a result, some patients must undergo regular bougie dilatation. Gastroesophageal acid reflux may lead to Barrett's esophagus and, eventually, to carcinoma.
●Clinical course – Long-term follow-up of patients with MCTD demonstrates that approximately one-third have a favorable outcome, one-third have a good outcome with treatment, and one-third have a more aggressive course. In a follow-up report of the original 25 patients, for example, nine (36 percent) required repeated courses of glucocorticoids [162].
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 AND RECOMMENDATIONS
●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.)
●Epidemiology – The annual incidence of MCTD is 0.2 to 1.9 per 100,000 and is more common among females than males. MCTD affects patients of all races and ages. (See 'Epidemiology and pathogenesis' above.)
●Clinical manifestations – The early clinical features are nonspecific and may consist of puffy fingers, fatigue, arthralgias, myalgias, low-grade fever, and Raynaud phenomenon. Patients with MCTD may have multiple features of systemic lupus erythematosus (SLE) and scleroderma (SSc).
The SLE-like features include:
•Cutaneous – Chilblains, discoid plaques, malar rash, panniculitis, and mucosal ulcerations are all associated with MCTD. (See 'Cutaneous' above.)
•Cardiac – Approximately 30 percent of MCTD patients have symptomatic heart disease, which may include pericarditis, myocarditis, accelerated atherosclerosis, and conduction abnormalities. (See 'Cardiac' above.)
•Renal – Membranous nephropathy is the most common renal manifestation of MCTD; severe kidney disease is uncommon. (See 'Renal' above.)
•Neurologic – Approximately 25 percent of patients with MCTD have a mild form of central nervous system (CNS) disease, most commonly trigeminal neuralgia or headache. Severe CNS disease is rare. (See 'Neurologic' above.)
The most common SSc-like features include Raynaud phenomenon, gastrointestinal dysmotility (particularly of the upper gastrointestinal tract), interstitial lung disease (ILD), and pulmonary arterial hypertension (PAH). (See 'Scleroderma-like features' above.)
Patients may also a destructive arthritis, myalgias, myositis, and sicca. (See 'Other features' 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 may be required. (See 'Evaluation' above.)
We obtain a complete blood count, serum creatinine level and urinalysis with urine sediment, antinuclear antibody (ANA), and anti-U1 RNP autoantibodies. (See 'Laboratory testing' above.)
We suggest obtaining a baseline echocardiogram, pulmonary function tests, and high-resolution CT scan in all patients due to the prevalence of cardiopulmonary manifestations, which are associated with significant morbidity and mortality. (See 'Monitoring' above.)
●Establishing the diagnosis – We diagnose MCTD in patients with:
•Anti-U1 RNP antibodies; and
•At least three of the following features:
-Digital swelling
-Raynaud phenomenon
-Synovitis
-Myositis
-Acrosclerosis
The diagnosis is complicated by the fact there is significant heterogeneity in terms of disease presentations. Additionally, some patients will evolve into other diagnoses, while other patients may simultaneously be diagnosed with another concomitant rheumatic disease (eg, SLE). (See 'Establishing the diagnosis' above.)
●Differential diagnosis – The distinction of MCTD from other systemic rheumatic diseases including overlap syndrome is a clinical challenge, given the heterogeneity of 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.
The absence of an anti-U1 RNP antibody or the presence of clinical features not typically associated with MCTD (eg, cerebritis, psychosis, seizure, diffuse proliferative glomerulonephritis) should prompt a search for alternate diagnoses. (See 'Differential diagnosis' above.)
●Management – Treatment of MCTD is directed at the specific disease manifestations. The approach for each is extrapolated from treating similar symptoms in SLE, SSc, and other rheumatic diseases:
•(See "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Initial therapy'.)
●Prognosis – The 10-year mortality associated with MCTD ranges is approximately 20 percent. Risk factors for mortality include PAH, ILD, anticardiolipin antibodies, myocarditis, renovascular hypertension, and cerebral hemorrhage.
Approximately one-third of patients have progressive disease. Patients with MCTD have high levels of morbidity due to concomitant pain syndromes, severe Raynaud phenomenon, deforming arthritis, esophageal dysmotility, and the complications of therapy with glucocorticoids. (See 'Prognosis' 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.
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