Clinical manifestations of mixed connective tissue disease

Author Robert M Bennett, MD, FRCP, FACP, MACR

Section Editor John S Axford, DSc, MD, FRCP, FRCPCH

Deputy Editor Paul L Romain, MD

Disclosures All topics are updated as new evidence becomes available and our peer reviewprocess is complete.

Literature review current through: Apr 2012. | This topic last updated: May 12, 2011.

INTRODUCTION — Mixed connective tissue disease (MCTD) is defined as a generalizedconnective tissue disorder characterized by the presence of high titer anti-U1 ribonucleoprotein(RNP) antibodies in combination with clinical features commonly seen in systemic lupuserythematosus (SLE), scleroderma (Scl), and polymyositis (PM) [1,2]. It often takes severalyears before enough overlapping features have appeared to be confident that MCTD is the mostappropriate diagnosis [3]. The distinctive overlap features of SLE, Scl and PM commonly appearsequentially over time. Thus, in its early stages, MCTD is often referred to as an undifferentiatedconnective tissue disease (UCTD) [4,5]. (See "Undifferentiated systemic rheumatic (connectivetissue) diseases and overlap syndromes".)

This topic will review the major clinical manifestations that can occur in patients with MCTD.The pathogenesis and diagnosis of this disorder are discussed separately. (See "Definition anddiagnosis of mixed connective tissue disease".)

CLINICAL MANIFESTATIONS — The early clinical features of MCTD are nonspecific andmay consist of general malaise, arthralgias, myalgias, and low-grade fever [6,7]. A specific cluethat these symptoms are caused by a connective tissue disease is the discovery of a positiveantinuclear antibody (ANA) in association with the Raynaud phenomenon [1].

As will be described below, almost any organ system can be involved in MCTD. There are,however, four clinical features that suggest the presence of MCTD rather than anotherconnective tissue disorder such as SLE or Scl:

Raynaud phenomenon and swollen hands or puffy fingers [8,9]. The absence of severe renal and central nervous system (CNS) disease [10,11] More severe arthritis and the insidious onset of pulmonary hypertension (not related to

lung fibrosis) differentiate MCTD from both SLE and Scl [12-14] Autoantibodies whose fine specificity is anti-U1 RNP, especially antibodies to the 68 Kd

protein [15].

General features — MCTD is much more common in women than in men (ratio of 16 to 1) [16].Most patients present in the second or third decades of life. Unlike SLE, however, sun exposureis not a precipitating factor. Drug-induced MCTD is a rare occurrence, but may be an occasionalfeature of anti-TNF therapy [17,18]. Vinyl chloride [19] and silica [20] are the onlyenvironmental agents that have so far associated with MCTD.

In the early phases of the MCTD many patients complain of easy fatigability, poorly definedmyalgias, arthralgias, and the Raynaud phenomenon; and diagnostic considerations include theearly stages of RA, SLE or undifferentiated connective tissue disease (UCTD) [21]. Most, if notall, of the major organ systems may be involved at some time during the course of MCTD,including the skin, joints, muscles, heart, lungs, gastrointestinal tract, kidneys, central nervoussystem, and hematologic system [3,4]. A high titer of anti-RNP antibodies in a patient withUCTD is a powerful predictor for a later evolution into MCTD [22].

Skin — Skin involvement occurs in most patients with MCTD. The most common skin change isthe Raynaud phenomenon, which usually presents early in the course of the disease [8,23].Swollen digits and occasionally total hand edema are also distinctive features (picture1) [13,24,25]; sclerodactyly and calcinosis cutis have been observed [26,27].

Other skin manifestations, such as discoid plaques and malar rash, are indistinguishable fromSLE (picture 2A-C). (See "Mucocutaneous manifestations of systemic lupus erythematosus".)Mucous membrane involvement can include orogenital and buccal ulcerations, nasal septalperforation, and the sicca complex [13,28,29].

Fever — Fever of unknown origin may be the presenting feature of MCTD [24]. In this setting, itcan usually be traced to a coexistent myositis, aseptic meningitis, serositis, lymphadenopathy, orintercurrent infection.

Arthritis — It is now apparent that joint involvement in MCTD is more common and frequentlymore severe than in classic SLE. Approximately 60 percent of patients with MCTD develop anobvious arthritis, often with deformities characteristic of rheumatoid disease, such as boutonnieredeformities and swan neck changes (picture 3) [12,25]. The radiographic appearance oftenresembles Jaccoud's arthropathy [30].

Other changes that can occur include small marginal erosions [31-33] (picture 4) and, in a fewpatients, destructive arthritis, including arthritis mutilans (picture 5 and picture 6) [12,34].

A positive rheumatoid factor is found in about 70 percent of patients with MCTD [35]. Anti-cyclic citrullinated peptide (CCP) antibodies are found in about 50 percent, especially in thoseMCTD patients who also fulfill the American College of Rheumatology diagnostic criteria forrheumatoid arthritis (RA) [36].

Myositis — One of the three overlap features required for the diagnosis of MCTD is aninflammatory myopathy clinically and histologically identical to PM [24,37,38]. (See "Clinicalmanifestations and diagnosis of adult dermatomyositis and polymyositis".) Myalgia is a commonsymptom in patients with the MCTD syndrome [39]. In most patients there is no demonstrable

weakness, EMG abnormalities or elevation of muscle enzymes. It is often unclear whether thesymptom represents a low-grade myositis, physical deconditioning or an associated fibromyalgiasyndrome. Sometimes myositis occurs as an acute flare against a background of general diseaseactivity [24]. Cases of a low grade, insidious, and persistent inflammatory myopathy have alsobeen described. The histology of muscle involvement in MCTD is the same as idiopathicinflammatory myopathy [40,41] with features both of the vascular involvement ofdermatomyositis and the cell-mediated changes of PM [42]. It is increasingly apparent that adiagnosis of "pure" PM is relatively rare, and most patients with an inflammatory myopathy turnout to have an overlap syndrome [43].

Cardiac disease — All three layers of the heart may be involved in MCTD [44]. An abnormalelectrocardiogram is noted in about 20 percent of patients. The most common EKG changes are:right ventricular hypertrophy, right atrial enlargement, and inter-ventricular conduction defects.Pericarditis is the commonest clinical manifestation of cardiac involvement being reported in 10to 30 percent of patients; pericardial tamponade is rare. Involvement of the myocardium isincreasingly recognized [45,46]. In some patients myocardial involvement is secondary topulmonary hypertension (PAH); this is often asymptomatic in its early stages [47]. (See'Pulmonary hypertension' below.)

Pulmonary involvement — The lungs are commonly affected in MCTD with involvement inabout 75 percent of patients [48,49]. There is a wide spectrum of pulmonary problems that canoccur in MCTD [50]:

Pleural effusions Pleuritic pain Pulmonary hypertension Interstitial lung disease Thromboembolic disease Alveolar hemorrhage Diaphragmatic dysfunction Aspiration pneumonitis/pneumonia Obstructive airways disease Pulmonary infections Pulmonary vasculitis

Early symptoms that should alert one to pulmonary involvement are dry cough, dyspnea andpleuritic chest pain [50].

Interstitial lung disease — Interstitial lung disease (ILD) occurs in 30 to 50 percent of subjects[51]. A reduction in the single breath-diffusing capacity for carbon dioxide (DLCO) iscommonly found on lung function testing in the early stages of ILD [50].

High resolution computed tomography (HRCT) is a sensitive test to determine the presence ofILD. The commonest HRCT findings are septal thickening, ground-glass opacities, nonseptallinear opacities and peripheral/lower lobe predominance [52,53], which are similar to thefindings in Scl [54]. Rapid clearance of technetium labeled diethylenetriamine pentaacetate

(DTPA lung scan) is closely correlated with CT evidence of interstitial lung disease and with adecreased DLCO [55].

Based upon a combination of high resolution CT (HRCT) and DTPA scans, the prevalence ofinterstitial lung disease in MCTD was found to be 66.6 percent [55]. Untreated ILD is usuallyprogressive with the development of severe pulmonary fibrosis in 25 percent of subjects afterfour years of follow-up [51]. Esophageal dilatation has been associated with a tendency todevelop interstitial lung disease in MCTD [56].

Pulmonary hypertension — A major cause of death in MCTD is pulmonary hypertension [57].This complication is caused by a bland intimal proliferation and medial hypertrophy ofpulmonary arterioles (picture 7).

The presence of pulmonary hypertension may be suspected from the history, physical findings,and laboratory tests, particularly if the patient has four or more of the following [58]:

Exertional dyspnea Systolic pulsation at the left sternal border An accentuated second pulmonary sound Dilation of the pulmonary artery on x-ray (picture 8) Right ventricular hypertrophy on electrocardiogram Right ventricular enlargement on echocardiogram

The early detection of pulmonary hypertension is increasingly important, as there are now moreeffective therapeutic options. PAH is probably under-diagnosed, its prevalence in a communityrheumatology practice was 13 percent, based on echocardiography to estimate right ventricularsystolic pressure [59].

Two-dimensional echocardiography with Doppler flow studies is the most useful screening test[60], with a definitive diagnosis requiring cardiac catheterization showing a mean restingpulmonary artery pressure greater than 25mm Hg at rest [61]. The development of pulmonaryhypertension has been correlated with a nail-fold capillary pattern similar to that seen in Scl,anti-endothelial cell antibodies and anticardiolipin antibodies [62-64]. (See "Overview ofpulmonary hypertension".)

Renal disease — The absence of severe renal disease is a hallmark of MCTD [1]. It is possiblethat high titers of anti-U1 RNP antibodies, which are characteristic of MCTD, may protectagainst the development of diffuse proliferative glomerulonephritis, independent of whetherthese antibodies occur in MCTD or classic SLE [10,65].

However, some degree of renal involvement occurs in about 25 percent of patients [10,13,66].Membranous nephropathy is the most common finding (picture 9A-E) [10,13,67] and nephroticrange proteinuria may occur [65]. Hypertensive crises similar to Scl kidney have also beenreported [68,69]. (See "Scleroderma renal crisis".)

Gastrointestinal disease — Gastrointestinal involvement is the commonest clinical overlapfeature with Scl, occurring in about 60 to 80 percent of patients [11,48]. Disordered motility inthe upper gastrointestinal tract is the commonest problem [56,70,71]. There have been casereports of hemoperitoneum, hematobilia, duodenal bleeding, megacolon, pancreatitis, ascites,and protein loosing enteropathy, primary biliary cirrhosis, portal hypertension, pneumatosisintestinalis and autoimmune hepatitis [13,72-74]. Malabsorption syndrome can occur secondarilyto small bowel dilation with bacterial overgrowth. Liver involvement in the form of chronicactive hepatitis and Budd-Chiari syndrome has been described. Pseudodiverticulae, identical tothose seen in Scl, may be seen along the anti-mesenteric border of the colon. Abdominal pain inMCTD may result from bowel hypomotility, serositis, mesenteric vasculitis, colonic perforationand pancreatitis.

Central nervous system disease — The original description of MCTD emphasized the lack ofCNS involvement [1]. This observation remains largely correct since patients with MCTD do notdevelop severe complications such as cerebritis, psychosis, or seizures [75]. However,approximately 25 percent of patients have some, typically mild form of CNS disease [57,75].

The most frequent CNS manifestation is a trigeminal (fifth cranial) nerve neuropathy,which may be the presenting feature of the disease [76,77]. Trigeminal neuropathy is alsothe most common CNS problem in patients with Scl.

Headaches are also common. They are most often vascular in origin [78], but can becaused by aseptic meningitis [79,80], due to the disease itself or to a reaction tononsteroidal anti-inflammatory drugs [81,82] and by muscle tension and myofascialtrigger points.

Sensorineural hearing loss is often not recognized, but is reported to occur in about 50percent of MCTD patients [83].

Isolated cases of cerebral hemorrhage [84], transverse myelitis [85], cauda equina syndrome[86], retinal vasculitis [87], progressive multifocal encephalopathy [88,89], and demyelinatingneuropathy [90] have also been reported.

Hematologic and laboratory abnormalities — Nonspecific hematologic and laboratoryabnormalities are common in MCTD:

Approximately 75 percent of patients have a low-grade anemia [13]. As in classic SLE, leukopenia, mainly affecting the lymphocyte series, is a common

finding that tends to correlate with disease activity [13,91]. (See "Hematologicmanifestations of systemic lupus erythematosus in adults".)

The majority of patients have hypergammaglobulinemia [24,92]. The rheumatoid factor is positive in 50 to 70 percent of patients [35]. Anti-cyclic citrullinated peptide (CCP) antibodies are found in about 50 percent of

patients [36]. Many patients also make antibodies directed against hnRNP-A2, fibrillin-1, and

nucleosomes, but not to RNA polymerases [93] or proteasome [94]. Antiphospholipid antibodies occur less frequently than in SLE [95,96]. If present, they

tend to correlate with thrombocytopenia and pulmonary hypertension, but not with

thrombosis and/or abortions. Anti-beta(2)-glycoprotein I antibodies are fairly uncommonin MCTD, occurring in about 10 percent of patients. Their presence is often associatedwith the development of pulmonary hypertension [64].

Anti-endothelial cell antibodies occur in some 50 percent of MCTD patients [97], andappear to be reactive with a voltage-dependent anion-selective channel 1 (VDAC-1) [98].Their occurrence tends to be associated with microvascular injury in the lung and kidneys[99].

Less common problems include thrombocytopenia, thrombotic thrombocytopenic purpura[100,101], Coombs positive hemolytic anemia [102], and red cell aplasia [103].

The one specific serological finding is that, by definition, all patients with MCTD have a positiveANA whose fine specificity is anti-U1 RNP, especially antibodies to the 68 Kd protein [104].(See "Definition and diagnosis of mixed connective tissue disease".)

Vasculopathy — The Raynaud phenomenon is a typical early feature of MCTD [23]; thus, anabsence of Raynaud argues against this diagnosis. The characteristic vascular lesion of MCTD isbland intimal proliferation and medial hypertrophy affecting medium and small size vessels[105]; this is also the characteristic pathology in pulmonary hypertension and renovascular crises(picture 2A-C) [57]. This pathologic changes differs from that usually noted in SLE, in whichperivascular inflammatory infiltrates and necrosis are more characteristic.

Similar to Scl, abnormal fingernail capillaroscopy is a common feature of MCTD [106,107]. Thecapillary pattern is characterized by dilation and drop-out (picture 10). Nailfold capillaroscopycan be performed at the bedside, a test that is useful for the prognostic stratification of those withearly Raynaud phenomenon [108]. (See "Clinical manifestations and diagnosis of the Raynaudphenomenon", section on 'Nailfold capillary microscopy'.)

Angiographic studies reveal a high prevalence of medium-sized arterial occlusions (picture11) [109].

Pregnancy — Conflicting reports describe the effects of pregnancy on the course of MCTD andthe effects of MCTD on the fetus [110,111]. One study described increased fetal wastage and a40 percent prevalence of flares during pregnancy [112]. Another report, however, did notconfirm disease exacerbations associated with pregnancy or the postpartum period [24,113].Small for gestational age infants occurred in 50 percent and 63 percent of pregnancies in oneseries of 20 patients [111]. The mechanism for pregnancy complications is probably anautoimmune reaction against placental tissues, as immunostaining studies show deposits offibrinogen, IgG, IgM, IgA, and complement 3 (C3) localized to the trophoblast basementmembrane [114]. Furthermore, there is an association of anti-endothelial antibodies withspontaneous abortion in MCTD [115].

Patients with severe Raynaud phenomenon in general often have low birth weight infants [116],presumably due to placental ischemia. This relationship has also been described in patients withMCTD [117].

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