General Features

In the absence of a universally accepted classification criteria and with the current understanding of MCTD having evolved over the past 3 decades, a review of the literature on MCTD poses some challenges. This is particularly true for rare complications of the disease described as case reports or small series of patients in the literature. Despite these challenges, numerous well-characterized clinical series are now reporting on substantial numbers of patients from across the world that define the clinical features of MCTD.^{1,3–9,28–34} A summary of the most common clinical features of MCTD is shown in Table 41-1.^3–9

TABLE 41-1 Clinical Features of Mixed Connective Tissue Disease*

^* From Burdt MA, Hoffman RW, Deutscher SL, et al: Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum 42(5):899–909, 1999.

The primary clinical features of MCTD are Raynaud phenomenon, swollen fingers or hands, arthralgia with or without associated arthritis, esophageal reflux or dysmotility, acrosclerosis (also known as sclerodactyly), mild myositis, and pulmonary involvement of a variety of forms (see Table 41-1). Additional clinical features that have been commonly reported include malar rash, alopecia, anemia, leukopenia, lymphadenopathy, and trigeminal neuralgia. The characteristic serologic findings are a high-titer fluorescent antinuclear antibody (FANA) test result with a speckled pattern and the presence of antibodies to RNP at moderate to high levels in the serum; some authors require the absence of antibodies to Sm to classify patients as having MCTD.⁷ In patients with major end-organ manifestations of SLE that are uncommon in historical MCTD cohorts, such as diffuse proliferative nephritis, MCTD may also frequently be excluded from the diagnosis.

Epidemiologic Characteristics

Currently, a paucity of epidemiologic data exist on MCTD. A nationwide multicenter collaborative survey on MCTD from Japan reported a prevalence of 2.7%.³³ MCTD prevalence has been reported to be appreciably lower elsewhere in the world. Sharp and colleagues⁷ have reported that at a tertiary referral center known for its expertise in MCTD observed the disease less frequently than SLE or rheumatoid arthritis (RA) but more commonly than polymyositis, dermatomyositis, or scleroderma. Although ethnic differences have been identified in the rates of development of anti-RNP antibodies and ethnic differences appear to exist in the prevalence of MCTD, the rate at which specific clinical manifestations appear among patients with MCTD from different ethnic groups has been quite consistent.³⁴

Sex Distribution

MCTD is more common in women than it is in men. It appears to have a sex distribution similar to that observed in SLE.⁷ In a Japanese nationwide survey, MCTD was found to have a female-to-male ratio of 16 : 1,³³ whereas the longitudinal prospective clinical series of Burdt and others⁸ reported an 11 : 1 ratio of women to men among patients from a tertiary referral center in the midwestern United States. Lundberg and Hedfors³² reported a 4 : 1 ratio among patients selected for presence of anti-RNP antibodies rather than MCTD, per se, who were studied at Huddinge University Hospital in Stockholm, Sweden.

Skin

Raynaud phenomenon is one of the most common manifestations of MTCD in all clinical series.^{1,3–9,28–34} It has been reported to be present at diagnosis in 90% to 95% of patients.^3–9 It may diminish in severity or resolve over time in some patients. A small number of patients will have associated digital infarcts. Pathologic and radiographic studies have reported the presence of an obliterative vasculopathy in these patients. Digital infarcts appear to correlate with the presence of severe obliterative vasculopathy. As in other organs, the vascular endothelium appears to be a major target of the pathologic process in MCTD.

Swollen fingers or swelling of the hand is very common in patients with MCTD, particularly at the onset of disease.^{1,3–9,28–34} Total hand edema can occur but is less common. Acrosclerosis (also known as sclerodactyly) occurs with or without proximal scleroderma and is typically a later manifestation of the disease. Nail-fold vascular changes identified by unaided direct visual inspection or by one of several methods of capillary microscopy occur in those with MCTD. These changes are characterized by vascular dilation and vessel loss or dropout.

Rashes are present in 50% to 60% of patients.^{1,3–9,28–34} Photosensitive and malar rashes similar to those typical of SLE have been reported to be common. Discoid lesions are also occasionally present. The scleroderma-like features of squared telangiectasia over the hands and face or periungual telangiectasia and sclerodactyly with or without calcinosis cutis also occur in some patients with MCTD. In contrast, truncal scleroderma is rare or absent in most series.^{1,3–9,28–34}

Gottron papules or a heliotrope rash, typical of dermatomyositis, is also seen in MCTD. Erythema nodosum, hyperpigmentation, or hypopigmentation of the skin is uncommon but has been reported. Nodules appear to be uncommon, despite the fact that arthritis and rheumatoid factor are common features of the disease.

The sicca complex has been found to be present in approximately one fourth to as high as one half of all patients with MCTD.⁹ Although many patients with MCTD have anti–Sjögren syndrome antigen A (anti-SSA/Ro) and anti–Sjögren syndrome antigen B (anti-SSB/La) antibodies, a poor correlation exists between the presence of these antibodies and clinical sicca.⁹

Oral and genital ulcers have been reported to occur in patients with MCTD.^{1,3–9,28–34} More severe lesions resulting in nasal septal perforation have also been described.

Joints

Arthralgia, like Raynaud phenomenon, is reported by almost all patients with MCTD.^{1,3–9,28–35} Inflammatory arthritis is also very common in MCTD. Arthritis ultimately develops in 50% to 60% of patients. Rheumatoid factor is also common in MCTD, occurring in 50% to 75% of patients. In fact, despite the fact that MCTD was initially observed among patients with overlapping features of SLE (e.g., scleroderma, polymyositis), patients with MCTD are now recognized as also having many features in common with RA. This includes an increased frequency of the HLA-DR4 susceptibility gene and immune responses against serum immune globulin (i.e., rheumatoid factor), as well as immunity against hnRNP in the form of antibodies and T cells.^16–19 Some patients with MCTD may fulfill the classification criteria for RA. In contrast to patients with RA, however, most patients with MCTD have no bony erosions or only small marginal erosions with well-demarcated edges. Occasionally, patients will develop RA-like deformities, including boutonnière and swan neck deformities. More severe erosive arthropathy has been reported to be associated with HLA-DR4. A severe destructive arthritis including arthritis mutilans has been reported in MCTD. A Jaccoud-like arthropathy, similar to that observed in patients with SLE with or without erosions has also been reported.

Muscles

Myalgias are common in MCTD and are reported in 25% to 50% of patients. Myositis has been reported in 20% to 70% of patients.^{1,3–9,28–34,36,37} The majority of patients with MCTD, however, do not develop clinical weakness.^3–9 Mild myositis with normal or modest elevation of muscle enzymes and normal electromyographic findings are most common in patients with MCTD; however, patients may be completely asymptomatic.^3–9 In contrast, however, myositis can be severe in some patients and can be indistinguishable from classic dermatomyositis. Patients such as these may meet the criteria for the classification of myositis. Lundberg and others³⁷ have published findings of a longitudinal study comparing patients with myositis with or without RNP antibodies. They found that patients with anti-RNP antibodies and myositis appeared to respond quickly to treatment with corticosteroids and that their myositis rarely relapsed after the initial treatment. The pathologic muscle findings reported in MCTD include lymphocytic infiltrates that may be either perivascular (i.e., within the endomysium vessel wall) or perimysial focal fiber necrosis and occasionally perifascicular atrophy.

As in other chronic diseases, patients with MCTD may develop fibromyalgia; in some patients, this condition can be a clinically dominant aspect of the course and management.³⁸

Pulmonary System

Pulmonary involvement can be a serious complication of MCTD and is the most common disease-related cause of death in those with MCTD.^{1,3–9,28–34,39} Symptoms can include cough, dyspnea on exertion or at rest, and pleuritic chest pain. The physical examination may reveal basilar rales or a cardiac finding compatible with pulmonary hypertension. Often, however, the physical examination of the lungs is normal. More sensitive testing may be required to detect early pulmonary disease, such as pulmonary function testing with measurement of carbon monoxide diffusing capacity (DLCO).^7,8

Decreased DLCO has been shown to be a helpful measurement for detecting pulmonary involvement in MCTD and appears to be effective when used for periodic screening of patients as an approach to identify those with early pulmonary disease.^7,8 Some patients may have an abnormal chest x-ray result. The most common radiographic findings are small, irregular opacities of the basilar or, less commonly, the middle lung fields, although changes can include interstitial abnormalities, pleural effusions, infiltrative lesions, or pleural thickening.

High-resolution computed tomography of the chest may reveal findings of fibrosis or alveolitis that are not detectable using plain-film radiography of the chest. Pathologic changes that may be found on biopsy or at autopsy include interstitial pneumonitis with or without fibrosis, obliterative vasculopathy of pulmonary vessels with intimal proliferation and medial hypertrophy of the pulmonary arteries and arterioles along with plexiform lesions, and either frank vasculitis or inflammatory perivascular cuffing. Although a diversity of patterns has been reported, clinical patterns of interstitial lung disease have most frequently been characterized as nonspecific interstitial pneumonitis or usual interstitial pneumonitis. Significant fibrosis is observed in only approximately one half of the patients with MCTD lung disease.

Pulmonary hypertension is the most common disease-related cause of death in those with MCTD.⁸ In the longitudinal study of Burdt and others,⁸ 13% (6 out of 47) of the patients died of pulmonary hypertension. In addition, evidence suggested that treatment of pulmonary hypertension in MCTD can result in prolonged survival in some patients; therefore early identification and proper treatment of pulmonary hypertension are very important (see “Treatment” section later in this chapter).³⁹ In the REVEAL (Randomized EValuation of the Effects of Anacetrapib through Lipid-modification) trial, pulmonary hypertension in patients with MCTD was found to have features distinct from those of pulmonary hypertension in scleroderma but a mortality rate similar to that of scleroderma-associated pulmonary hypertension.⁴⁰ In other studies, however, a subset of patients has been reported that responds to immunosuppressive therapy.^7,8,39,40 Rare pulmonary manifestations that have been reported in MCTD include pulmonary hemorrhage and diaphragm dysfunction.

Gastrointestinal System

Esophageal motility disorders with symptomatic esophageal reflux, including heartburn or regurgitation of food, are very common in patients with MCTD.^{1,3–9,28–34,41} Less commonly, patients may experience pain or difficulty swallowing. Uncommon features of gastrointestinal involvement in MCTD that have been reported include pseudodiverticula along the antimesenteric border (similar to that described in scleroderma), mesenteric vasculitis, pancreatitis, bacterial overgrowth syndrome, malabsorption, protein-losing enteropathy, pseudoobstruction, serositis, colonic perforation, and gastrointestinal bleeding. In addition, reports in the literature describe chronic active hepatitis, biliary cirrhosis, and Budd-Chiari syndrome in patients with MCTD.

Cardiac System

Evidence of cardiac abnormalities is not uncommon in those with MCTD and is confirmed with methods such as electrocardiography or echocardiography.^{1,3–9,28–34,42} Approximately 20% of patients will have abnormalities when examined with either electrocardiography or echocardiography. As previously discussed, pulmonary involvement is common in MCTD and may result in cardiopulmonary disease, such as pulmonary hypertension. Pulmonary hypertension can result in associated cardiac changes, such as right ventricular hypertrophy, right atrial enlargement, and intraventricular or atrioventricular electrical conduction abnormalities. Pericarditis has been reported to occur in 10% to 30% of patients with MCTD. Myocardial involvement may be found with severe myopathy or when pulmonary hypertension is present. Additional cardiac abnormalities that have been described include septal hypertrophy, various left ventricular abnormalities, mitral valve prolapse, intimal hyperplasia of the coronary arteries, and endocardial abnormalities. Although atherosclerotic heart disease has now been recognized as a significant complication of other rheumatic diseases, including SLE and RA, similar findings have not yet been reported in longitudinal studies on MCTD.

Nervous System

Although MCTD was initially described to be notable for the absence of serious neurologic involvement, practitioners now recognize that neurologic disease can occur in some patients with MCTD.^{1,3–9,28–34,43–45} The presence of neuropsychiatric manifestations of MCTD was first emphasized by Bennett and colleagues. They reported that over one half of the 20 patients whom they studied with MCTD had findings including aseptic meningitis, psychosis, seizures, peripheral neuropathy, trigeminal neuropathy, or cerebella ataxia.⁴³ The prevalence of neuropsychiatric manifestations in MCTD has been reported to be lower in other subsequently reported cohorts.^3–9

Vascular headaches have been frequently described in MCTD.⁴⁴ Aseptic meningitis has been reported to be associated with the use of nonsteroidal antiinflammatory agents, particularly ibuprofen, in patients with MCTD. A peripheral, predominantly sensory polyneuropathy can occur in MCTD.

Rarely, trigeminal neuralgia can be the presenting feature of MCTD.⁴⁵ Trigeminal neuralgia can manifest as neuralgic pain or as partial or complete anesthesia over the distribution of one or more branches of the trigeminal nerve. Cerebellar dysfunction, psychosis, and seizure have been infrequently reported in patients with MCTD. Other neurologic problems that have been rarely reported (most often in the form of case reports) in MCTD include cauda equina syndrome, transverse myelitis, stroke, and cerebral hemorrhage. The relationship of these entities with MCTD has not been clearly established.

Renal Disease

Subtle renal involvement can be detected in approximately 25% of patients with MCTD⁴⁶ but infrequently leads to significant clinical sequelae. In patients with MCTD who undergo renal biopsy, focal proliferative glomerulonephritis may be observed.^{1,3–9,28–34,46,47} Diffuse proliferative glomerulonephritis is uncommon in MCTD. Patients with diffuse renal involvement often initially have or subsequently develop anti-Sm or anti–double stranded DNA (anti-dsDNA) antibodies or both.^3,8 The development of anti-Sm antibodies (particularly against the Sm-D peptide) appears to occur when ongoing immune spreading and more severe disease are observed.

In MCTD, membranous glomerulonephritis (with or without nephrotic syndrome) may rarely occur. Intimal proliferation in arteries and ischemic changes have been observed in MCTD. Scleroderma-like renal crisis has also been infrequently reported to occur in MCTD. Patients with MCTD and concomitant Sjögren syndrome may develop interstitial nephritis and have associated findings such as renal tubular acidosis.

Hematologic Disorders

Hematologic abnormalities are common in MCTD.^{1,3–9,28–34} Mild lymphadenopathy occurs in approximately 25% to 50% of patients. Lymphadenopathy is often an initial feature of the disease and tends to decrease over time, although it may re-appear with a flare of disease. The development of massive lymphadenopathy and pseudolymphoma has been observed.

Anemia, lymphopenia, and leukopenia are all common in MCTD, occurring in 50% to 75% of patients. Antilymphocyte antibodies have been found to be common and have been reported to correlate with disease activity. Anemia of chronic disease is one of the most common findings in several series of MCTD. Coombs-positive immune-mediated hemolytic anemia has been reported to be a rare feature of MCTD.

Thrombocytopenia occurs in MCTD but appears less commonly than leukopenia or anemia.^{1,3–9,28–34} Finally, case reports describe idiopathic thrombocytopenic purpura, red-cell aplasia, and thrombotic thrombocytopenic purpura in MCTD. Coagulation abnormalities appear to be rare but have been described.

Miscellaneous Systemic Features

Malaise and low-grade fever may occur in MCTD. The disease has been reported to develop an elevated body temperature of unknown origin.^{1,3–9,28–34} Rarely, patients may have high-grade fever without an identifiable infection agent as the cause of the elevated temperature. In these patients, the inference is that MCTD is the cause of the fever, recognizing that a careful search for infection should always be completed before an elevated body temperature is attributed to the underlying disease.

Sicca symptoms are common in MCTD, occurring in 25% to 50% of patients.⁹ Those with MCTD frequently have antibodies to SSA/Ro, and these may develop after the onset of MCTD. Anti-SSB/La is found in a small number of patients with MCTD, occurring in less than 5%.^1,3–9 However, the presence of SSA/Ro and/or SSB/La antibodies does not correlate with clinical manifestations of sicca in MCTD. Photosensitivity and malar rash appear to be increased among patients with MCTD who are positive for SSA/Ro antibodies.⁹ Orofacial and ocular vascular involvement has been described in MCTD,⁴⁸ as well as autoimmune thyroiditis and persistent hoarseness.