Approach
The overlap syndromes are a diverse group of conditions that usually present subacutely with clinical manifestations that can include different organ systems. The pattern of organ involvement reflects the characteristic features of the well-defined rheumatic diseases occurring together.
History and examination
For many patients, nonspecific symptoms are often present for many months before a diagnosis is made. Any organ system can be involved, and the pattern of involvement is defined by the underlying rheumatic conditions occurring together. No one historical symptom defines any of the overlap syndromes; diagnostic suspicion should be raised when patients present with a constellation of findings affecting multiple organ systems with simultaneous features of more than one rheumatic disease. Apart from mixed connective tissue disease (MCTD), for most other overlap syndromes small numbers have limited the ability to define an evidence-based diagnostic approach, and these are best considered in the context of specific clinical features, autoantibody profiles, and immunogenetics.
MCTD: The characteristic pattern of presentation is relatively well defined by diagnostic criteria and includes overlapping features of systemic lupus erythematosus (SLE), scleroderma, myositis, and rheumatoid arthritis in the setting of a high titer of autoantibodies to a defined nuclear antigen, known as U1 ribonucleoprotein (U1 RNP, also called RNP or nRNP). Clinical features are highly variable, involving predominantly arthritis, Raynaud phenomenon (RP), sclerodermatous skin changes, and myositis. Approximately 90% of patients with MCTD have RP on presentation. Severe central nervous system and renal diseases are rare manifestations.[6][12]
Antisynthetase syndrome: This syndrome forms a distinct group characterized by the presence of antibodies directed against various aminoacyl-tRNA synthetase enzymes with anti-Jo-1 being the most common; overlapping clinical features of myositis, arthritis, and interstitial lung disease are seen.[3]
Polymyositis/scleroderma (PM/Scl) overlap syndrome: This is characterized by overlapping features of scleroderma and polymyositis, and the PM/Scl antibody, and by the presence of RP, tendon inflammation, and interstitial lung disease.[2][4] Sclerodactyly may occur, but the truncal sclerodermatous skin changes characteristic of systemic sclerosis are absent.
Physical exam should focus on identifying patterns of organ system involvement, with particular attention to detecting classic findings of well-defined rheumatic diseases such as sclerodactyly, synovitis, myopathy, and rashes typical of SLE. Many patients show lymphadenopathy on presentation.
Musculoskeletal manifestations: Joint symptoms are present in almost all patients with MCTD and are a common presenting symptom. Frank arthritis develops in 50% to 60% of patients during follow-up. A small-joint polyarthritis is the most common pattern of involvement, but deformities are uncommon. Swollen hands are very common at presentation in MCTD and may progress to swelling of the entire hand. Sclerodactyly is also common but tends to occur as a later manifestation of disease.[5] Myalgias occur in 25% to 50% of MCTD patients, but myositis is less common, usually without frank weakness on physical examination. However, myositis is a key component of patients with antisynthetase syndrome. In this instance they may present with weakness (usually in the proximal muscles).
Pulmonary manifestations: Evaluation for pulmonary disease is important, as this is the largest cause of death in patients with MCTD.[6] Pulmonary involvement in MCTD will eventually affect up to 66% of patients.[13][14] Both pulmonary hypertension (in 20% to 25% of patients) and interstitial lung disease (in 50% of patients) may be seen. Among patients with antisynthetase syndrome, interstitial lung disease is even more common, found to occur in 86% of patients.[15][16] Physical exam may demonstrate signs of elevated right-sided heart pressures or bibasilar rales. Pleural effusions occur uncommonly.
Neurologic manifestations: A full neurologic exam should be performed. A predominantly sensory polyneuropathy may be seen and should be further evaluated with nerve conduction studies and electromyography (EMG). Trigeminal neuralgia may very rarely be the presenting feature of MCTD, presenting as neuropathic pain or anesthesia over the distribution of 1 or more of the branches of the trigeminal nerve. Neuropsychiatric diseases including psychosis and seizures are rare manifestations of MCTD. Uncommonly in MCTD, headaches (due to aseptic meningitis) may be a presenting complaint.
Cutaneous manifestations: Skin lesions may be evident, present in 50% to 60% of patients. Approximately 90% of patients with MCTD have RP on presentation.[6] Abnormal nail fold capillaroscopy (the pattern of blood vessels visible under low magnification) has been shown to have predictive value for an underlying rheumatic disease. Giant capillaries and loss of the normal architecture with dropout of vessels are patterns that may suggest underlying systemic sclerosis or polymyositis.[17][18] In MCTD, malar rashes and discoid lesions similar to those characteristic of SLE may be seen occasionally. Acrosclerosis with telangiectasias and occasionally calcinosis may be seen, but truncal sclerodermatous skin changes are very rare. Skin changes typical of dermatomyositis, including Gottron papules and a heliotrope rash, may occur in MCTD, but the nodules of rheumatoid arthritis are rarely seen.[6] Alopecia may also be seen in MCTD.
Gastrointestinal manifestations: GERD is common in MCTD. Patients with MCTD may present with symptoms of esophageal dysmotility, with reflux symptoms, dysphagia, or regurgitation.
Initial laboratory investigations
No single blood test, or combination of tests, is diagnostic. Initial blood tests include the following tests.
With CBC, BUN, and serum creatinine, and inflammatory markers such as erythrocyte sedimentation rate (ESR) or CRP, nonspecific findings such as anemia, leukopenia, and hypergammaglobulinemia may be seen. Inflammatory markers (ESR or CRP) may or may not be elevated.
For most patients, measurement of antinuclear antibodies (ANAs) is an appropriate initial test when the clinical evaluation reveals symptoms or signs suggestive of an underlying rheumatic disease. ANA titers are seen in almost all patients with MCTD but are also present in other conditions such as SLE and scleroderma, and so are not diagnostic for an overlap syndrome.
Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody levels should be measured. Both are markers of rheumatoid arthritis, and may be elevated in patients with overlap syndrome.
Muscle enzymes may be elevated in patients who have MCTD, antisynthetase syndrome, or polymyositis as one of the rheumatic conditions. The most sensitive indicator enzyme is creatine kinase.
Significant proteinuria or hematuria on urinalysis is indicative of renal involvement.
High-titer of anti-U1 ribonucleoprotein (U1 RNP) is a requirement for diagnosis of MCTD. Absence of anti-U1 RNP indicates an alternative overlap syndrome or separate autoimmune disease.
Antibodies to various aminoacyl-tRNA synthetase enzymes are the defining antibodies of antisynthetase syndrome, with the anti-Jo-1 antibody the most common.
Additional autoantibody serology
When there is clinical suspicion of an autoimmune overlap syndrome, with or without the initial finding of a positive ANA, additional tests should be considered to evaluate for the presence of serologic markers more specific for the rheumatic diseases. In the absence of anti-U1 RNP antibodies, serologic tests provide additional evidence for an underlying variant of overlap syndrome or for an alternative autoimmune process.
Antibodies to double-stranded (ds) DNA or the Smith antigen may suggest SLE; in MCTD Smith antigen is negative, although a subset of patients with MCTD may be positive for anti-dsDNA.
Anti-Scl 70, anticentromere antibodies and anti-RNA polymerase III, anti-Ku, or anti-PM/Scl antibodies suggest scleroderma overlap syndrome.
Anti-Ro (SS-A) and anti-La (SS-B) antibodies are evaluated for coexistent Sjogren syndrome.
Anti-Jo-1 antibodies are highly specific for antisynthetase syndromes and are sought in patients with myositis.
Other antisynthetase antibodies (including PL7, PL12, OJ, EJ, KS, Ha and others) may be present in antisynthetase syndromes, but are less common than anti-Jo1.
The finding of these autoantibodies is highly suggestive of their associated diseases, and further investigations then follow the protocols for those conditions.
In the absence of any of the specific serologic findings, some patients who do not meet criteria for any well-defined disease should remain classified as having undifferentiated connective tissue disease (UCTD). The diagnosis can only be further clarified with follow-up over time for the development of additional clinical or serologic findings. One study estimated that, of patients initially classified as having UCTD, 64% retained that diagnosis at 1 year and 47% at 5 years of follow-up.[19] Another study among Hungarian patients suggested that one third of patients with UCTD progressed to another rheumatic diagnosis, and that this was most likely to happen within the first 2 years of follow-up.[20]
Additional investigations
Additional investigations are required to define the pattern and severity of organ involvement.
Complaints of dyspnea, dry cough, or decreased exercise tolerance should prompt further evaluation for pulmonary or cardiac involvement by CXR, ECG, and echocardiogram. Complete pulmonary function tests (PFTs) with spirometry, lung volumes and diffusion capacity, and a CXR are also performed. A high-resolution CT scan of the lungs is more sensitive than CXR for early interstitial lung disease and should be considered in those with abnormal PFTs indicative of restrictive lung disease. High-resolution CT may also be performed if lung volume or functional status declines. If echocardiogram findings are suggestive of pulmonary hypertension (e.g., elevated right ventricular systolic pressure), referral for right-heart catheterization and full evaluation should be considered.
A barium swallow can be helpful to look for features consistent with GERD, including dysmotility and reflux. It is also indicated when symptoms of heartburn worsen, or do not improve, with appropriate therapy. Symptoms and signs of dysphagia may require investigation with upper gastrointestinal endoscopy.
Patients with polyneuropathy should be further evaluated with nerve conduction studies and EMG.
In patients with symptoms of arthralgia or arthritis, plain x-rays of affected joint(s) may show evidence of inflammation, nonerosive arthritis, or bony erosions.
Tissue biopsy is not generally done as part of the diagnostic evaluation. Occasionally clinical suspicion of particular organ involvement may prompt tissue examination, such as muscle biopsy to confirm the autoimmune nature of myositis, lung biopsy to better characterize the nature of lung infiltrates, or kidney biopsy to evaluate for immune-mediated glomerular disease.
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