Connective tissue diseases (CTDs) are inflammatory conditions with characteristic signs and symptoms defining specific disorders. Classification criteria developed by the American College of Rheumatology have provided guidelines for diagnosis in adult patients and have been used to some extent in children. The criteria were developed initially to ensure diagnoses for clinical investigations. Some children, however, simultaneously manifest signs and symptoms characteristic of two or more of the major rheumatic disorders, such as juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), juvenile dermatomyositis (JDM), cutaneous systemic scleroderma (CSS), and vasculopathy. Children with these disorders are often difficult to categorize under existing classification criteria and are properly referred to as having overlap syndromes . The most studied of these conditions is mixed connective tissue disease (MCTD), which will be further discussed in this chapter.
Mixed Connective Tissue Disease
Definition and Classification
MCTD was initially described by Sharp and colleagues in 1972 in 25 adults as a disorder with an excellent initial response to relatively low-dose glucocorticoid therapy and a favorable prognosis. The syndrome included clinical features of rheumatoid arthritis (RA), scleroderma, SLE, and dermatomyositis in conjunction with a high antibody titer to an extractable nuclear antigen (ENA). However, reassessment of the original patients indicated that the inflammatory manifestations (e.g., arthritis, serositis, fever, myositis) tended to become less evident over time, whereas sclerodactyly and esophageal disease, which were less responsive to treatment with glucocorticoids, persisted and began to dominate the clinical picture. Severe renal disease continued to remain an unusual feature. Although the concept of MCTD as a clinical entity separate from the other CTDs has remained controversial, classifications employing more precise serological criteria and human leukocyte antigen (HLA) typing have confirmed the uniqueness of this disorder ( Table 29-1 ).
| Clinical Signs of at Least Two of the Following Diseases |
| Juvenile rheumatoid arthritis |
| Systemic lupus erythematosus |
| Juvenile dermatomyositis |
| Systemic scleroderma |
| Positive Serological Findings |
| High-titer of antibodies to U1 snRNP and the 70-kD A and C polypeptides |
| Anti-U1-RNA antibodies |
| Presence of HLA-DR4 |
Criteria for MCTD have been evaluated for adults but not for children ( Table 29-2 ). These criteria are summarized in the review by Smolen and colleagues. Shen and co-workers studied 50 patients from China during a 2- to 8-year period and indicated that Sharp’s criteria were the most reliable for the diagnosis of MCTD. Among 23 patients fulfilling these criteria, only one (4.3%) developed scleroderma. Among 23 patients satisfying the criteria of Kasukawa and colleagues, 7 (30.4%) developed another CTD. Of the 27 who met the criteria of Alarcón-Segovia and colleagues, 12 (44%) fulfilled classification criteria for another major rheumatic disease. The frequencies of HLA-DR4 and HLA-DR5 were significantly higher among the patients whose disease fulfilled Sharp’s criteria. Different conclusions were reached, however, in a comparative study of four diagnostic criteria from France by Amigues and co-workers. These investigators analyzed the criteria developed by Sharp, Kasukawa and colleagues, Alarcón-Segovia and co-workers, and Kahn and associates, respectively, in 45 patients with anti-uridine rich (U1) ribonucleoprotein (RNP) antibodies who were classified as having MCTD. They found that the criteria of Alarcón-Segovia and co-workers had the highest sensitivity (62.5%) and specificity (86.2%), with an overlap of 16% with other major CTDs. These results were comparable with those obtained with the criteria of Kahn and associates.
| SHARP | ALARCÓN-SEGOVIA | KASUKAWA | KAHN |
|---|---|---|---|
| Criteria | |||
| Major | |||
|
|
SLE
|
|
| Minor | |||
| SSc
| ||
| Diagnosis | |||
| MCTD Certain | MCTD | MCTD | MCTD |
| 4 major criteria, no anti-Sm, anti-U1-RNP >1 : 4000 | If serological criterion above is met, and at least 3 clinical criteria are identified [if (a), (d), and (e) are present, (b) or (c) are also required] | If presence of at least 1 of the 2 common symptoms, anti-RNP antibodies, and the presence of at least 1 sign of at least 2 of the following connective tissue diseases: SLE, SSc, and PM | If serological criteria fulfilled, and Raynaud phenomenon, and at least 2 of the 3 following signs are present: synovitis, myositis, and swollen fingers |
| MCTD Probable | |||
| 3 major criteria and no anti-Sm, or 2 major criteria and 1 minor criterion, anti-U1-RNP >1 : 1000 | |||
Epidemiology
MCTD is one of the least common disorders in a pediatric rheumatology clinic. It had a frequency of 0.1% in a Finnish nationwide prospective study and 0.3% in the U.S. Pediatric Rheumatology Database. Data from the British Pediatric Rheumatology Association Disease Registry and the Canadian Pediatric Rheumatology Association Disease Registry showed frequencies of 0.5% and 0.2%, respectively. The median age at onset was approximately 11 years (range: 4 to 16 years). MCTD occurred three times more frequently in girls than in boys. There was one report of this disorder occurring in siblings.
Immunogenetic Background
In studies from several continents, including North and South America, Japan, and Europe, the predominant HLA class II specificity associated with MCTD has been DR4; association with HLA-DR2 is less well established. Individuals with DR4 or DR2 have a region of homology of seven amino acids (numbers 26, 28, 30, 31, 32, 70, and 73) in the highly polymorphic antigen-binding segment of the DRB1 gene (HLA-DRB1). These HLA specificities are also linked to antibodies to the uridine-rich small nuclear ribonucleoprotein (U1snRNP) that are characteristic of the disorder. It is notable that major histocompatibility complex (MHC) haplotypes most commonly associated with CSS (DR5) or SLE (DR3) are uncommon.
Etiology and Pathogenesis
MCTD is characterized immunologically by the presence of autoantibodies and T cells reactive with U1-RNP and polypeptides of the spliceosome complex, including their associated uridine-rich (U) small nuclear ribonucleic acids (RNAs). A number of immunological factors have been associated with MCTD and may contribute to disease pathogenesis. The 70-kD peptide of the U1-RNP antigen appears to be a dominant autoantigen in MCTD and consists of a 437 residue polypeptide, which noncovalently associates with U1-RNA through an RNA binding domain on the polypeptide spanning residues 92-202. There are a variety of potential and proven structural modifications, which occur to the U1 70-kD polypeptide and RNP, any of which might influence antigenicity of the RNP complex. The apoptotically modified 70-kD has been shown to be antigenically distinct from intact 70-kD, which may have clinical implications in breaking immune tolerance to the autoantigen. One study reported that autoantibodies reactive with apoptotic 70-kD are superior markers to those against intact 70-kD for MCTD.
Various independent observations over the years have led to the conclusion that the innate and adaptive immune systems play a central role in the development of many systemic autoimmune diseases, including MCTD. As noted previously, the dominant epitopes recognized in MCTD reside within the RNA binding domains of the peptide. These observations coincided with the discovery of a series of pathogen-associated pattern recognition receptors, including the Toll-like receptors (TLRs), especially those that recognize double-stranded RNA or single-stranded RNA, and normally play a vital role in host defense through their recognition of bacterial and viral cell products. These findings led to a series of studies examining TLRs in autoimmunity. Studies have shown that U1-RNA can activate cells of a TLR3 using U1-RNA and TLR-deficient mutant endometrial cell lines.
Autoantibodies are widely recognized as a hallmark of many of the rheumatic diseases, including MCTD. Two studies have supported a role for anti-RNP antibodies in the pathogenesis of MCTD by providing linkage between the emergence of antibodies and clinical disease. B cells can function in several other key immunological pathways beyond antibody production; these include functioning as antigen-presenting cells, secreting pathological cytokines, and mediating tissue injury through a variety of antibody-directed mechanisms.
T cells appear to have a central role in the pathogenesis of MCTD. RNP-reactive CD4 + T cells have been identified from peripheral blood of MCTD patients. Both anti-RNP and anti-U1-RNA antibodies found in patients’ sera have, in most instances, undergone isotope switching to immunoglobulin G (IgG) subtypes. Also, there is dense lymphocyte infiltration, with many T cells found in the sites of tissue injury at autopsy and in biopsy specimens from patients. Findings have also shown that human RNP reactive T cells can provide B-cell help in vitro to anti-RNP autoantibody production.
Vascular alterations result in some of the most severe clinical manifestations in patients with MCTD. Uncontrolled overexpression of angiogenic and angiostatic factors (vascular endothelial growth factor [VEGF] and endostatin) were found in adult MCTD patients. Levels of VEGF were higher in MCTD patients with pulmonary arterial hypertension (PAH) and myositis, possibly characterizing patients with a more severe course of disease.
A murine model for MCTD has been developed, and it will assist in advancing preclinical and translational research in MCTD.
Clinical Manifestations
MCTD has been recognized with increasing frequency in childhood. These children present with features of more than one CTD, a speckled antinuclear antibody (ANA) pattern, and high titers of antibody to RNP (see Table 29-1 ). The condition characteristically evolves over time from a more limited presentation of clinical disease to one with overlapping features of JRA, SLE, CSS, or JDM. Manifestations develop sequentially, but not in any predictable order or over any circumscribed period. The rashes of SLE or JDM are common at onset. Sclerodermatous skin changes are slow to develop but may become the most prominent feature of the disease late in its course. Moderately asymptomatic involvement, such as myositis with minimal weakness, mild atrophy, and minimal to moderate increases in the serum muscle enzyme concentrations, is common. Van der Net et al. showed that proximal muscle strength, as well as aerobic capacity, was significantly impaired in one cohort. Dysphagia and bowel dysmotility also may occur. Manifestations of the sicca syndrome with xerostomia, keratoconjunctivitis sicca, or parotid gland enlargement occur in one third of the children. Although children typically do not complain of shortness of breath (depending on cognitive development or unconsciously self-imposed restriction of activity), they often have pulmonary functional impairments.
Clinical characteristics of children from selected studies are summarized in Table 29-3 . Polyarthritis (93%) and Raynaud phenomenon (85%) are the most common manifestations at onset ( Fig. 29-1 ). The arthritis may be relatively painful; erosive disease is uncommon, but deformity may develop with flexion contractions or swan-neck deformities. The arthritis is often associated with rheumatoid factor (RF) seropositivity, which often presents early, in approximately two thirds of the children. Cutaneous changes include scleroderma-like disease in one half of MCTD patients, the rash of SLE in one third, and the rash of JDM in one third. Nailfold capillary abnormalities are similar to those in CSS. Cardiopulmonary disease and esophageal dysmotility occur more frequently than clinical symptoms indicate. Vasculitis can occur and be severe (i.e., transverse myelopathy). Although nephritis occurs in about one fourth of the patients with MCTD, it is less common and is usually less severe than in those with SLE. However, children with MCTD may have more frequent and more severe renal disease, more hematological complications, such as thrombocytopenia, and less pulmonary hypertension than do adults with MCTD. Trigeminal neuropathy has been reported as a presenting symptom.
| CHARACTERISTIC | NUMBER REPORTED * | NUMBER PRESENT † | PERCENT |
|---|---|---|---|
| Arthritis | 72 | 67 | 93 |
| Raynaud phenomenon | 72 | 61 | 85 |
| Sclerodermatous skin | 67 | 33 | 49 |
| Rash of systemic lupus erythematosus | 67 | 22 | 33 |
| Rash of dermatomyositis | 67 | 22 | 33 |
| Fever | 61 | 34 | 56 |
| Abnormal esophageal motility | 56 | 23 | 41 |
| Cardiac disease | 67 | 20 | 30 |
| Pericarditis | 67 | 18 | 27 |
| Muscle disease | 72 | 44 | 61 |
| Sicca syndrome | 66 | 24 | 36 |
| Central nervous system disease | 61 | 14 | 23 |
| Lung | |||
| Abnormal diffusion | 56 | 24 | 43 |
| Restrictive disease | 56 | 8 | 14 |
| Hypertension | 56 | 4 | 7 |
| Effusion | 56 | 13 | 23 |
| Radiographic changes only | 56 | 1 | 2 |
| Splenomegaly | 63 | 18 | 29 |
| Hepatomegaly | 68 | 19 | 28 |
| Renal disease | 72 | 19 | 26 |
| Anti-dsDNA positive | 64 | 13 | 20 |
| Anti-Sm positive | 58 | 6 | 10 |
| Anti-RNP positive | 72 | 72 | 100 |
| Rheumatoid factor positive | 57 | 39 | 68 |
* The number of children in whom the characteristic was identified.
Pulmonary disease is a major source of morbidity and mortality among adults who have MCTD. In a prospective longitudinal study, 31 of 34 adults with high titers of RNP antibody had typical MCTD in which pulmonary disease, often initially asymptomatic, was common. Pulmonary hypertension was the most frequent serious complication. One retrospective study in pediatric patients found restrictive pulmonary disease in up to 35% and abnormal carbon monoxide diffusion (DLCO) in up to 42%. This retrospective data may represent a select patient population. A cross-sectional study focusing on chest manifestations in juvenile-onset MCTD patients identified interstitial lung disease in 25% of the cohort. All but one had mild disease affecting 5% or less of the parenchyma. DLCO was abnormal in 33%. The authors concluded that the prevalence of interstitial lung disease in childhood-onset MCTD was lower than previously thought.
Pathology
Widespread intimal proliferation and medial hypertrophy of vascular walls have been described in four children with MCTD who died. Renal biopsies in eight additional patients confirmed abnormalities of the glomerular basement membrane or vascular sclerosis. These investigators commented that although the histopathology of MCTD resembled that of CSS, the extent of fibrosis was less, and intimal vascular abnormalities in larger vessels such as the aorta, and the coronary, pulmonary, and renal arteries, were more prominent. Another study reported pulmonary hypertension and proliferative vasculopathy in the virtual absence of interstitial fibrosis in patients with MCTD, in contrast to those with CSS.
Histological analysis of esophageal muscular layers was reported from 27 autopsy cases in adults with MCTD. The most striking change observed was atrophy and loss of smooth muscle cells followed by fibrosis. Immunohistochemically, the degenerated muscular tissues of the esophagus were positive for anti-IgG and anti-C3 antibodies, but not for IgM antibodies. The IgG fractions isolated from MCTD patients reacted with smooth muscle from nonconnective tissues disease cases, suggesting that serum antibodies may be involved in tissue damage.
Laboratory Examination
Very high titers of ANAs are usually present initially, often in a speckled pattern on HEp-2 cell substrate. These antibodies react specifically with an RNase-sensitive component of ENA and RNP. Anti-RNP antibodies in high titers have been the serological hallmark of MCTD, but these antibodies may be present in low titers in other diseases, such as SLE. Further investigations confirmed that the most characteristic specificities of the anti-RNP antibodies in MCTD were directed against a uridine-rich (U1), small nuclear RNP (snRNP) complex (U1 snRNP) of the spliceosome consisting of U1-RNA and the associated 70-kD, A, and C polypeptides ( Fig. 29-2 ). The anti-U1 snRNP profile of patients with MCTD is characterized by a high-titer antibody response, predominantly or solely of IgG antibodies, and specificity for an epitope different from that of SLE sera ; a false-positive anti-U1 snRNP antibody response may be observed in cases of SLE. IgM-specific anti-U1 snRNP responses have been shown to distinguish SLE from MCTD patients. Reports indicate that antibodies to U1-RNA are even more closely associated clinically with disease activity during the course of MCTD than are U1-RNP antibodies, although assays for U1-RNA antibodies themselves are poorly standardized and of limited availability to clinicians in most areas; this makes this observation primarily one of research relevance.
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