Overlap Syndromes and Unclassified or Undifferentiated Connective Tissue Disease
Iris Navarro-Millán
Graciela S. Alarcón
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A 48-year-old Hispanic woman with symmetric polyarthritis, anemia, myalgias, and proximal muscle weakness. Over time she developed sclerodactyly and skin thickening over arms, hands, and face. She was found to be antinuclear antibody (ANA), anti-double stranded DNA (anti-dsDNA), anti-Smith, anti-Sjogren’s syndrome A (SSA), Sjogren’s syndrome B (SSB), and anticardiolipin IgG and IgM antibodies positive, without a history of thrombosis or miscarriages. Rheumatoid factor (RF) and anti-CCP antibodies were negative; however, radiographs of the hands and feet showed large erosions on both hands and feet. Her CK was elevated and a muscle biopsy was consistent with an inflammatory myopathy. Because of progressive dyspnea, a high-resolution computed tomography was performed, which demonstrated interstitial lung disease (ILD).
Introduction
Despite significant gains in the understanding of the immunopathogenesis of the different connective tissue diseases (CTDs), their etiology remains elusive. The diagnosis of the different CTDs is thus a matter of clinical judgment as patients present with constellations of symptoms, physical findings, and laboratory features that permit their recognition (1). Oftentimes, however, patients present with manifestations of more than one different CTD or with manifestations that defeat classification. The term “overlap” is used in this chapter for the first group of patients, whereas the terms “unclassified” or “undifferentiated” are used for the second group; the term mixed (M) CTD is reserved for patients with a defined overlap syndrome (vide infra). As our understanding of the etiopathogenesis of the CTDs improves, more precise labels will certainly be used.
The term atypical (A) CTD has arisen from the consensus reached by nonphysicians working with patients with silicone breast implants; the “legal” definition of ACTD is such that almost any individual presenting with some (subjective, for the most part) neuropsychologic or musculoskeletal manifestation may be diagnosed with this “entity.”
The rheumatologic community has not validated the existence of such disorder; thus, ACTD is not discussed.
The rheumatologic community has not validated the existence of such disorder; thus, ACTD is not discussed.
Table 16.1 Terminology or Nomenclature | ||||||||||||||
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The terminology or nomenclature used in this chapter is summarized in Table 16.1.
The Overlap Syndromes
The following overlap syndromes have been described in the literature: rhupus or the overlap between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE); sclerodermatomyositis (or scleromyositis) or the overlap between scleroderma and myositis; and MCTD or the overlap between poly/dermatomyositis, scleroderma, SLE, and RA in the presence of anti-U1RNP antibodies and HLA-DR4. Other “overlaps” are considered subsets of defined CTDs rather than overlaps; such is the case for patients with SLE or RA who also have myositis or vasculitis, as well as for patients with SLE who have clinical and laboratory features of the antiphospholipid antibody syndrome (APS). Other patients with a defined CTD present overlapping manifestations with non-CTD disorders; such is the case of patients with luposclerosis as the overlapping clinical syndrome of SLE, and multiple sclerosis has been called. Finally, patients with primary APS may also present with manifestation of multiple sclerosis. Table 16.2 summarizes these different conditions by categories.
Clinical Points
While there are patients with an autoimmune rheumatic disease who may develop manifestations of another, there are some patients who fully develop two or more diseases simultaneously or sequentially.
These patients may be classified as having an overlap syndrome.
Common overlap syndromes include rhupus, sclerodermatomyositis or scleromyositis, and MCTD.
Mixed connective tissue disease is a term coined nearly 40 years ago to refer to patients with features of more than one disease (arthritis, scleroderma, lupus, myositis) with high anti-U1RNP antibodies; with time, however, these patients usually evolve into a more defined CTD.
There is no consensus on how to diagnose unclassified or undifferentiated CTD; such a label may represent the prodrome of lupus; however, some of these patients may remain undifferentiated or incomplete or evolve into a fibromyalgia-like syndrome with ANA positivity.
The first three overlap syndromes are now described in some detail.
Rhupus
Arthralgias and arthritis are rather common in patients with SLE; however, in some patients with SLE, the most prominent clinical manifestation is a symmetric polyarthritis. These patients may or may not have a positive RF. That was the case of our patient whose clinical presentation was a symmetric inflammatory arthritis with radiographic evidence of erosions that resemble RA, yet her serologies were more suggestive of SLE. Patients with RA may present some extra-articular features and a positive ANA test that may suggest the diagnosis of SLE. The term rhupus, however, is reserved for those patients who clearly meet criteria for both SLE and RA, and who present characteristic clinical features of both the disorders. These patients usually have a seropositive, erosive, symmetric polyarthritis, which antedates the onset of unequivocal clinical features of SLE. They also present autoantibodies characteristic of both the disorders; these include IgM-RF, ANA, anti-dsDNA, and in about half the patients, antibodies to Ro. Most recently highly specific antibodies for RA
such as anticyclic citrullinated peptide antibodies have also been described in patients with rhupus (2). Some of the extra-articular features these patients present may be related to the presence of rheumatoid nodules rather than to SLE; this distinction may have therapeutic implications.
such as anticyclic citrullinated peptide antibodies have also been described in patients with rhupus (2). Some of the extra-articular features these patients present may be related to the presence of rheumatoid nodules rather than to SLE; this distinction may have therapeutic implications.
Patient Assessment
Our patient had symmetric polyarthritis in a rheumatoid-like distribution with serologies that were more consistent with SLE rather than with RA.
Hands and feet radiographs demonstrated an erosive arthritis highly suggestive of RA.
There was biopsy-proven polymyositis.
Sclerodactyly and ILD suggested the diagnosis of systemic sclerosis (SSc).
These findings represent the overlap of four rheumatic diseases: RA, SLE, SSc, and polymyositis; however, she lacked anti-U1RNP antibodies, the hallmark of MCTD.
Table 16.2 Overlap Connective Tissue Diseases and Related Syndromes | ||
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In patients with rhupus, RA usually presents first and is not until an average of 15 to 18 years that symptoms and serologies for SLE may ensue (3). Patients with rhupus should be distinguished from those patients with SLE who develop deforming nonerosive arthropathy which resembles that occurring in patients with recurrent rheumatic fever (Jaccoud’s arthropathy). These patients initially present with correctable subluxation of the metacarpophalangeal joints with ulnar deviation, as well as swan-neck and boutonniere fingers and Z-thumb deformities. These abnormalities appear to be the result of ligamentous laxity and compression of hand musculature rather than result from the presence of pannus. The magnitude of the above-described features was the basis for the development of an index to aid in the diagnosis of Jaccoud’s arthropathy. Van Vugt et al. have developed an algorithm to classify the deforming hand arthropathy of patients with lupus; a revision of this algorithm is presented in Figure 16.1.
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