Chapter 38 Overlap Syndromes, Mixed Connective Tissue Disease, and Undifferentiated Connective Tissue Disease

INTRODUCTION

Classification of the rheumatic diseases continues to be challenging for a number of reasons, including the fact that clinical features of these diseases can be protean and overlapping and that despite advances in our understanding of disease pathogenesis the etiology of most autoimmune rheumatic diseases remains elusive. The presence of features of more than one well-defined connective tissue disease “overlapping” in the same patient is widely recognized to occur. Such patients are frequently identified as suffering overlap syndrome. The term overlap syndrome has been used in the literature to describe patients with features of more than one distinctive rheumatic disease, either simultaneously or sequentially. In addition, there are a number of so-called overlap syndromes that have distinctive autoantibodies associated with them. A summary of some of these overlap syndromes and autoantibodies is presented in Table 38.1.

TABLE 38.1 AUTOANTIBODIES AND OVERLAP SYNDROMES ^a

Antibody	Antigen Specificity	Clinical Features
PM/Scl or PM-1	Complex nuclear antigen with multiple proteins	Polymyositis-scleroderma overlap
20-110kD of unknown function	Complex nuclear antigen with multiple proteins	Polymyositis-scleroderma overlap
Ku	70kD/80kD peptides involved in repair of DNA double helix breaks	Overlap syndrome, SLE, MCTD & scleroderma
RNA polymerase	RNA polymerase I, II, III	SLE & scleroderma
Heterogeneous nuclear	hnRNP A2 and other species	MCTD, SLE & RA ribonucleoprotein (hnRNP)
SSA/Ro	Ro antigen	Primary or secondary sub-acute cutaneous lupus & apparently normal individuals
U1-RNP (nRNP, RNP)	U1-70kD, A & C polypeptides	MCTD & less commonly scleroderma or other rheumatic disease

a. Systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), heterogeneous nuclear ribonucleoprotein (hnRNP), rheumatoid arthritis (RA).

Mixed connective tissue disease (MCTD) is a distinctly identifiable rheumatic disease characterized clinically by the presence of overlapping features of SLE, scleroderma, and polymyositis and characterized serologically by the presence of high levels of antibodies against U1-ribonucleoprotein (U1-RNP).¹ Although there is no uniformly accepted diagnostic criteria for MCTD, validated classification criteria have been published for MCTD.²^–⁷ Two of the most widely recognized classification criteria for MCTD are outlined in Table 38.2.

TABLE 38.2 CLASSIFICATION CRITERIA FOR MIXED CONNECTIVE TISSUE DISEASE ^a

Criteria of Alarcon-Segovia and Villarreal

Serologic Criteria

• Anti-RNP ^b antibody must be present at a moderate-high level in serum

Clinical Criteria
There must be at least 3 out of the 5 of the following clinical findings (and this must include either synovitis or myositis):

Criteria of Sharp^c

Major Criteria

• Severe myositis

• Pulmonary involvement with diffusion capacity for carbon monoxide below 70% of predicted for age or pulmonary hypertension or proliferative vascular lesion

• Raynaud’s phenomenon or esophageal hypomotility

• Swollen hands observed or sclerodactyly

• Highest observed anti-U1 RNP anti-extractable nuclear antigen by passive hemagglutination testing of at least 1:10,000 with positive anti-U1 RNP by immunodiffusion and negative for anti-Sm antibodies by immunodiffusion testing

Minor Criteria

• Trigeminal neuropathy

• Malar rash

• Thrombocytopenia

• Mild myositis

• History of swollen hands

a. Alarcon-Segovia and Cardiel (6).

b. Anti-RNP was defined in this study using hemagglutination. A titer equal to or greater than 1:1,600 was required in their study to be considered “moderate or high.”

c. Requires four major criteria filled with anti-U1 RNP of at least 1:4,000 by passive hemagglutination assay for definite MCTD or three major criteria for probable or two major criteria from 1, 2, and 3 and two minor criteria with anti-U1 RNP at least 1:1,000 by passive hemagglutination assay.

The term undifferentiated connective tissue disease (UCTD), as introduced in the literature by LeRoy and colleagues, was used to describe the early phase of connective tissue disease when the features of the disease were nonspecific or “undifferentiated.”⁸ Currently, there is no uniformly accepted definition of the term UCTD and various investigators have applied it quite differently.⁸^–¹⁹ It would, however, appear to remain a potentially useful designation for the large number of patients who initially fail to meet established classification or diagnostic criteria for another rheumatic disease. Furthermore, longitudinal epidemiologic studies have demonstrated that many patients initially classified as UCTD remain undifferentiated without progression to another currently identifiable rheumatic disease despite careful observation over time.¹⁰^–¹² See Chapter 34.

OVERLAP SYNDROMES

As previously stated, the presence of features of more than one well-defined connective tissue disease (including SLE, scleroderma, polymyositis/dermatomyositis, Sjogren’s syndrome, and rheumatoid arthritis) overlapping in the same patient is widely recognized to occur and such patients have frequently been described in the literature using the term overlap syndrome.²⁰^–²⁴ An alternative approach to classification of such patients has been the identification of patients by the presence of a distinctive autoantibody.²⁵^–³⁶

It has been proposed that the combination of autoantibodies and genetics may be more precise methods of classification of patients with rheumatic disease, including those with overlapping clinical features.²⁵ As shown in Table 38.3, a number of distinct autoantibodies have been recognized that define groups of patients that can have clinically overlapping features of more than one systemic rheumatic disease (Fig 38.1).

TABLE 38.3 COMMON CLINICAL FEATURES OF MCTD

Fig. 38.1 Schematic of the U1-RNP. The U1-70kD protein binds specifically to the first stem loop of the U1 RNA. The U1-A protein binds similarly to the second stem loop. The Sm proteins bind to an area on a fourth stem loop. The signal recognition (SR) and U1-C proteins participate in protein-protein interactions with other members of the U1-RNA. Sera from patients with MCTD, SLE, and scleroderma have been found that react with various components of the U1-RNP.

Anti-tRNA Synthetase Syndrome

Antibodies directed against the Jo-1 antigen (later shown to be anti-histidyl-tRNA synthetase antibodies) were the first anti-synthetase antibodies identified.^26,²⁷ These anti-synthetase antibodies were reported to occur in patients with overlapping clinical features of myositis, arthritis, and intestinal lung disease.²⁶^–²⁸

Some patients have had an erosive arthritis that mimics rheumatoid arthritis, and some patients have had features of scleroderma (including Raynaud’s phenomenon, sclerodactyly, dysphagia, and telangiectasias). Although antibodies to the Jo antigen (or histidyl-tRNA synthetase) were the first reported for an anti-synthetase antibody (the Jo antigen appearing to be the most common), patients have been described with similar clinical features and antibodies directed against other tRNA synthetases [including threonyl (PL-7), alanyl (PL12), isoleucyl (OJ), and glycyl (EJ)] have been reported.²⁸

PM/Scl

Antibodies against the PM/Scl (also known as PM1) antigen are found in patients that exhibit features of both polymyositis and scleroderma.^29,³⁰ These patients typically have Raynaud’s phenomenon, arthralgia, and myositis. They frequently have tendon involvement, mechanic’s hands, and skin lesions of dermatomyositis.^29,³⁰ They may have interstitial lung disease and have a risk of severe renal disease with renal crisis.^29,³⁰ Diffuse scleroderma skin involvement is uncommon in patients with this antibody reactivity, however (Fig. 38.2).

Fig. 38.2 A model of MCTD pathogenesis. Constituents of dead cells (apoptotic debris) that fail to be cleared through noninflammatory pathways provide pro-inflammatory innate immune signals (including through toll-like receptors, TLRs) and are recognized by autoantibodies, thus activating B cells and opsonizing the dead cell material for more efficient uptake and presentation by antigen-presenting cells (potentially including dendritic cells and B cells themselves). Through antigen-specific signals with MHC-bound autoantigen and nonspecific pro-inflammatory second signals, T cells become activated, resist apoptosis, and mature into memory and effector cells. These in turn produce pro-inflammatory mediators, induce differentiation and maturation of B cells, and directly mediate cell injury. B cells under these influences avoid apoptosis and produce high quantities of avid complement-fixing antibodies that induce tissue injury at sites of autoantigen recognition.

(From Greidinger EL, Hoffman RW. Autoantibodies in the pathogenesis of mixed connective tissue disease. Rheum Dis Clin North Am 2005;31(3): 437-450.)

Ku

Anti-Ku antibodies were first described by Mimori and colleagues, who reported that patients with this antibody specificity had features of both scleroderma and polymyositis.³¹ Subsequently, anti-Ku reactivity has also been detected in patients classified as having SLE, Sjogren’s syndrome, polymyositis, autoimmune thyroid disease, and MCTD.^31,³² Anti-Ku antibodies appear to be uncommon.

RNA Polymerase

There is a series of RNA polymerases that have been identified, and autoantibodies variously reactive with RNA polymerases I, II, and III have been described.^33,³⁴ Patients with antibodies to RNA polymerases I and III have been described as having features of scleroderma, whereas patients with isolated antibodies to RNA polymerase II have been reported to have an SLE-overlap syndrome.^33,³⁴ Testing for these antibodies has revealed that it appears to be a common reactivity in patients with features of diffuse scleroderma.³⁴

Heterogeneous Nuclear RNP

Antibodies and T cells reactive with heterogeneous nuclear ribonucleoprotein (hnRNP) antigens have been reported among patients with SLE, rheumatoid arthritis, and MCTD.³⁵^–³⁶ Recently, Skriner, and colleagues have identified autoantibodies reactive with different epitopes on hnRNP A2 antigen that appear to distinguish patients with MCTD from those with RA or SLE.³⁶ Greidinger and colleagues have reported that T cells reactive with hnRNP could be cloned from MCTD patients and that these T cells could provide help for autoantibody production in vitro.³⁷

SS-A (Ro)

Anti-SS-A/Ro antibodies may be detectible in patients with primary or secondary Sjogren’s syndrome, in subacute cutaneous lupus, and in some cases in apparently otherwise healthy individuals.³⁸^–⁴¹ Sjogren’s syndrome has been found to frequently coexist in overlap patients or in patients classified as having another connective tissue disease such as SLE, MCTD, RA, scleroderma, autoimmune liver disease, and others.

U1-RNP

As reviewed in material following, the presence of high levels of anti-U1-RNP antibodies is a characteristic feature of MCTD and is required for classification of patients with MCTD.¹^–⁷ The presence of high levels of antibodies reactive with the U1-70kD polypeptide of U1-RNP has been reported to occur early in the course of disease and to have particularly strong association with MCTD.⁴²^–⁴⁴ Low levels of anti-U1-RNP antibodies and antibodies against other RNP polypeptides [particularly Smith (Sm)-B/B′ and Sm-D] have been observed in a number of other rheumatic diseases, including SLE and scleroderma.⁴³^–⁴⁵

MIXED CONNECTIVE TISSUE DISEASE

Clinical Features

The primary clinical features of MCTD include Raynaud’s phenomenon, swollen fingers or hands, arthralgia or arthritis, sclerodactyly, myositis (typically mild), and pulmonary dysfunction that can take a variety of forms.^1,⁴⁶^–⁵⁶ These are outlined in Table 38.4. Clinical features of MCTD that may also frequently be present include trigeminal neuralgia, lymphadenopathy, mild anemia, leukopenia, malar rash, and mild anemia. The initial presentation of MCTD often includes swollen fingers or swelling of the hands. Raynaud’s phenomenon is an early and characteristic feature of MCTD, being present in over 90% of patients. Sclerodactyly may often appear as a later manifestation of disease, and telangiectasias over the hands and face may also be seen. A variety of rashes may occur, including the malar rash of SLE and dermatomyositis-like rashes with Gottren’s papules or a heliotrope rash. Sicca complex has been found to occur in up to a quarter of patients.⁵⁵

TABLE 38.4 SEROLOGIC AND IMMUNOLOGIC FEATURES OF MCTD

• High levels of antinuclear antibodies in a speckled patter of staining by immunofluorescence

• High levels of antibodies reactive with extractable nuclear antigen (ENA) (this complex antigenic mixture contains U1-RNP and Smith [Sm] antigens)

• Anti-U1-RNP antibodies present at high levels and generally remain stable over time

• Reactivity with U1-70kD polypeptide of U1-RNP complex has a strong association with MCTD in many studies

• Anti-U1-RNA antibodies present and changes in levels of these in the serum may correlate with disease activity (not routinely available in clinical laboratories at this time, however)

• Absence of antibodies to Smith (Sm) antigen (including Sm-D polypeptides) or double-stranded DNA is typical of MCTD

• Leukopenia and mild anemia often present

• Rheumatoid factor present in approximately 25% of patients and may be present at high levels

Arthralgia is present in most patients, and some develop a nonerosive polyarthritis. Less commonly, an erosive arthritis may occur.⁵² Myalgias are common, occurring in a quarter to half of all patients. In most patients, myositis is mild (although it can be severe in some patients).^52,⁵⁴ Pulmonary involvement can be a serious complication of MCTD, with pulmonary hypertension the most ominous problem. This is the main disease-related cause of death in MCTD.⁵² Pulmonary symptoms can be absent until pulmonary hypertension is advanced. Pulmonary symptoms can include cough, the sensation of shortness of breath (at rest or with exertion), and pleuritic chest pain. The single breath diffusion of carbon monoxide has been shown to be a sensitive indictor of pulmonary disease in MCTD, including pulmonary hypertension in some patients.⁵⁶ Patients can also experience pleuritis, or less commonly interstitial lung disease.

There is reasonable evidence in MCTD that the treatment of pulmonary hypertension can prolong survival, and based on this it has been felt that careful monitoring to identify and treat pulmonary hypertension is warranted. The performance of annual pulmonary function testing and two-dimensional echocardiography have been advocated as screening tests for early identification of pulmonary hypertension in MCTD.^52,^54,⁵⁶ Esophageal motility abnormalities, including symptomatic esophageal reflux, are very common in MCTD.⁵⁷^–⁵⁸ In contrast to SLE, serious renal involvement in MCTD is distinctly uncommon, although mild renal abnormalities have been commonly recognized to be present. In a small percentage of patients classified as MCTD, serious membranoproliferative glomerulonephritis can occur.⁵⁹^–⁶⁵