Overlap syndromes

Introduction

Overlap syndromes are conditions in which patients have concurrent clinical manifestations of multiple distinct immune diseases. A relatively common example of an overlap syndrome is mixed connective tissue disease (MCTD), in which antismall nuclear ribonucleoprotein (snRNP, or RNP) antibodies occur along with manifestations of at least two of the following: lupus, myositis, rheumatoid arthritis, and/or scleroderma. Patients with overlap syndromes need not meet classification criteria for any or all of the underlying conditions, though. Thus a patient with an undefined connective tissue disease (or UCTD), who does not meet classification criteria for any individual condition, may also have a rheumatic overlap syndrome. The relationships among the general category of overlap syndromes, the specific overlap syndrome MCTD, and the entity of UCTD are shown in a Venn diagram ( Fig. 50.1 ).

Clinical and laboratory manifestations of overlap syndromes

Many of the manifestations of inflammatory rheumatic diseases are nonspecific for any particular clinical syndrome. Inflammatory arthritis, for example, is a common manifestation of either lupus or rheumatoid arthritis and is not uncommon in scleroderma or myositis. Requiring that the joint involvement be symmetrically distributed in the fingers and wrists excluding the distal interphalangeal joints, while more typical for rheumatoid arthritis, would still be a manifestation seen with at least modest frequency in other inflammatory rheumatic diseases. Rather, to be regarded as “rheumatoid arthritis-like,” inflammatory arthritis would typically also imply additional features distinctive to rheumatoid arthritis, such as the presence of typical joint erosions, rheumatoid nodules, and/or relatively specific autoantibodies (such as anticitrullinated peptide antibodies).

Distinctions of this sort may be reflective both of differences in underlying disease pathogenesis and of patterns of human perception and cognition: If particular clinical manifestations occur frequently enough in the setting of an otherwise well-defined clinical syndrome, they will likely be regarded as part of the same syndrome rather than as a secondary phenomenon, unless there is a preexisting cognitive schema that conflicts with such a conceptualization. The tendency for disparate clinical manifestations to be lumped together into a unifying diagnosis can be recognized particularly aptly in the case of systemic lupus, where classification criteria can be satisfied by multiple patients in whom zero clinical or laboratory manifestations are shared. If manifestations that are regarded as aspects of an overlap syndrome occurred more frequently in the setting of an individual disease, those manifestations might either be regarded as additional canonical aspects of that disease or, at least, as nonspecific findings that would not raise the question of whether a “second disease process” was also present.

The point prevalence of MCTD is approximately 3.8 cases per 100,000 adults, roughly 20-fold less prevalent than SLE. In analyses of two substantial single center cohorts of patients with antiRNP autoantibodies, including dozens of patients clinically classified as MCTD, we have found that lupus criteria were satisfied in an overwhelming majority. This difference in the prevalence of “pure” lupus versus the prevalence of this “lupus overlap” syndrome may explain why MCTD overlap features are not themselves regarded as canonical aspects of lupus. However, it is also worth noting that distinguishing MCTD from SLE has been controversial. This 20-fold difference in prevalence may thus represent an approximate upper limit of the prevalence of an adjunctive syndrome (in the setting of uncertain underlying pathological differences) before it would be considered as a more integral aspect of the more common diagnosis.

Other relatively common clinical manifestations of inflammatory rheumatic diseases that can be associated with multiple individual conditions and are thus difficult to use as evidence for the presence of any particular component of an overlap syndrome include fatigue, serositis, small vessel vasculitis, and interstitial lung disease. Sicca complaints in association with another inflammatory rheumatic disease are generally regarded as secondary Sjogren’s syndrome and are typically also not regarded as a classical overlap syndrome.

Likewise, common laboratory findings in multiple inflammatory rheumatic diseases that thus are not incongruous in the absence of an overlap syndrome include anemia and other cytopenias, elevated acute phase reactants (such as sedimentation rate or C-reactive protein), the presence of antinuclear antibodies, and rheumatoid factor positivity. Additional autoantibodies including Ro/SS-A, La/SS-B, and antiphospholipid antibodies are also relatively nonspecific for any particular rheumatic condition.

Clinical manifestations that are more suggestive of specific diagnoses that if present concurrently could suggest an overlap syndrome include the following. Typical malar, photosensitive, or discoid rashes (except in dermatomyositis), typical patterns of alopecia, and glomerulonephritis are suggestive of a lupus-like component. For scleroderma-like overlap, suggestive findings include cutaneous or visceral fibrosis, gut hypomotility (including severe GERD), and severe Raynaud’s phenomenon with ischemic changes. For myositis-like overlap, suggestive findings include clinically significant proximal muscle weakness and classic skin manifestations including heliotrope eyelid rashes, Gottron’s papules, and mechanic’s hands. While relatively pathognomonic clinical findings exist in additional inflammatory rheumatic syndromes (such as pathergy in Behcet’s syndrome, amaurosis fugax in giant cell arteritis, or sausage digits in psoriatic arthritis), the predominance of reports of clinical rheumatic overlap syndromes are confined to the four cardinal conditions (lupus, rheumatoid arthritis, scleroderma, and/or myositis) seen in overlap in MCTD. A summary of rheumatic overlap syndromes (excluding overlap syndromes involving a rheumatic disease with other nonrheumatic conditions) has been provided ( Table 50.1 ).

Clinical overlap syndromes are often less dangerous and may respond better to treatments than classical cases of the underlying diseases. For example, MCTD has been associated with a more benign prognosis than classic lupus, even though the presence of antiRNP antibodies in classic lupus has been linked to more aggressive disease. We have recently found that in antiRNP+ patients meeting classification criteria for systemic lupus erythematosus, the patients who also meet classification criteria for MCTD do have a dramatically lower risk of nephritis compared to those who do not also meet MCTD criteria [odds ratio 4.3 (95% confidence interval 1.3–14.0)]. The lung disease in MCTD has likewise been found to be more responsive to immunosuppressive therapy than has typically been observed in scleroderma or myositis.

However, the modulation of risk associated with an overlap syndrome is not always in a favorable direction. In MCTD, the rate of development of lung disease including pulmonary hypertension may be as high as 40%, substantially higher than that reported in unselected cohorts of SLE.

Laboratory studies that may contribute to the suspicion of an individual condition (which could then be a component of an overlap syndrome with other conditions) encompass other relatively specific lab findings, typically specific autoantibodies. Thus for lupus-like overlap, antidouble-stranded DNA (or antinative DNA) and antiSmith antibodies are suggestive, as are classic immunofluorescence and/or electron microscopic patterns on renal biopsy assessment of glomerulonephritis. For scleroderma-like overlap, antiScl-70 or other scleroderma-associated antinucleolar antibodies may be suggestive. For myositis-like overlap, antibodies including Mi-2 and antisignal recognition particle may be suggestive. The findings of classic autoantibodies associated with other rheumatic diseases may also lead to consideration of an overlap syndrome, even outside of the four classic rheumatic syndromes described earlier. This can occur, for example, with antineutrophil cytoplasmic antibodies, when confirmed by ELISA for vasculitis-associated specificities and in the clinical context of vasculitic features. As newer rheumatic syndromes become established that have distinctive clinical and serological manifestations, cases of overlap between these and other rheumatic conditions can likewise be anticipated. This is now is beginning to occur with IgG4-related disease.

An additional set of autoantibodies has been associated with specific overlap syndromes. These include antiRNP (with MCTD), antiPM-Scl (with a scleroderma-myositis overlap syndrome), and antiJo-1 or similar antitRNA synthetase antibodies (with the antisynthetase syndrome, typically characterized by features including myositis, interstitial lung disease, Raynaud’s phenomenon, and erosive polyarthritis). Antisynthetase syndrome is a notable case of overlap syndrome, since antiJo-1 antibodies (and aspects of the associated syndrome) are the most common myositis-specific antibody system present in myositis cohorts, potentially contradicting the idea that overlap syndromes are always uncommon manifestations of cardinal rheumatic diseases. This can be explained in part by the fact that the high prevalence of overlap features was identified many years after Jo-1 was linked to myositis, and potentially by the fact that the conditions that occur in overlap with myositis in antisynthetase syndrome are themselves more prevalent. While anticentromere antibodies are most typical of the CREST syndrome form of scleroderma, these have also been linked to a scleroderma/primary biliary cirrhosis overlap syndrome.

When can a systemic inflammatory rheumatic disease presenting along with second organ-specific autoimmune process be considered an overlap syndrome? There is no clear consensus. Entities such as inflammatory bowel disease-associated arthropathy, for example, in which features of a seronegative spondyloarthropathy and inflammatory enteritis coexist, have not been typically regarded as overlap syndromes. Considering the relatively high prevalence of autoimmune thyroid disease in the general population, there has been a hesitancy to regard thyroid disease plus an inflammatory rheumatic disease as an overlap syndrome, even if highly linked temporally in onset. Multiple sclerosis can be difficult to diagnose as in overlap with lupus, since the clinical and immunological manifestations of neuropsychiatric lupus could be difficult to distinguish from those of MS. On the other hand, the cooccurrence of myositis and myasthenia gravis may be identified clinically, and has recently been found to be associated with a common autoimmune target, cortactin. Thus recognizing the cooccurrence of multiple seemingly distinct immune conditions as potentially due to an overlap syndrome may lead to insight regarding the pathogenesis of each.