Incomplete lupus syndromes

Definition

Classification criteria for systemic lupus erythematosus (SLE) have been widely utilized in the study of this disease, enabling clinical trials, and new drug approvals. Although not intended to be used as diagnostic criteria, these lists of clinical and laboratory findings are often referred to in clinical practice when trying to determine if a patient has SLE. The starting point for most of these patients is antinuclear antibody (ANA) positivity, because this is in a practical sense a uniform finding in all patients with SLE and a widely used screening test for this and other autoimmune conditions. However, the ANA test has low specificity and a high prevalence. This means that most individuals presenting for ANA evaluation do not have SLE. While many of these ANAs are not of concern, the association with other findings that are suggestive of a lupus diagnosis, such as a characteristic skin rash in a young woman, can be worrisome. Since SLE, like other autoimmune conditions likely has a long preclinical stage during which autoantibodies and immune abnormalities are expressed, it is possible that such a patient may be in an early and evolving disease stage or may have a milder variant of SLE. Several terms have been proposed to describe these patients such as latent lupus, undifferentiated connective tissue disease, incomplete lupus (ILE) and others. Preclinical disease is also used to describe the ILE state, but of course that is a diagnosis that can only firmly be made in retrospect. Since one of the more common associations with ANA positivity seen in rheumatology practice is rheumatoid arthritis (RA), it is also likely that some of these patients are in an early stage of that disease, especially now that it has been shown that accelerating arthralgias may precede the actual diagnosis.

In considering these designations, some distinctions or subsets are possible ( Table 54.1 ). In general, ILE fits most closely those patients who have some of the classification criteria of SLE, such as those in the SLICC set, but in whom four of those criteria have not been documented. These patients may have a stable course as ILE with minimal damage or may differentiate into a classifiable condition, which is most commonly SLE. In contrast, undifferentiated connective tissue disease (UCTD) is a syndrome first proposed in 1980 when it was hypothesized that these were early phases of connective tissue diseases such as scleroderma. More recently, classification criteria for UCTD have been proposed, with the key elements being that the individual has had the findings for several years and does not fit known classification criteria for other diseases. UCTD is a broader designation than ILE, because it includes patients who may differentiate into other conditions such as rheumatoid arthritis, scleroderma or other connective tissue disorders. UCTD is relatively common and it has been estimated that up to 20% of referrals to tertiary rheumatology centers are for this diagnosis. However, not all of these patients are seen in or referred to rheumatology clinics. ANA positivity associated with skin conditions is most likely to be seen in dermatology and cytopenias are seen in hematology. Furthermore, the broad nature of ANA positivity also means that in some patients, the association is with other autoimmune conditions such thyroid disorders, which are relatively common or with neurologic findings.

UCTD patients are distinct from those with other types of intermediate syndromes, such as mixed connective tissue disease (MCTD), which is associated with antibodies to ribonuclear proteins and has a distinct clinical phenotype. Overlap syndromes are generally those in which two classifiable disease states are co-expressed, such as patients who have SLE and rheumatoid arthritis, sometimes described as “rhupus.” A more recently described syndrome related to undifferentiated connective tissue disease is “interstitial pneumonia with autoimmune features” or IPAF. These patients are generally older than those with ILE and due to severe lung manifestations may require treatment with immunosuppressives.

Significance

The ILE designation is significant for two main reasons. The first is that it includes a subset of patients who are in early stages of a classifiable condition, which is usually SLE, but which can include most other autoimmune conditions. In our own clinic, at least one such ILE patient transitioned to myasthenia gravis, for example. Detecting these individuals before any organ damaging manifestations offers the possibility of therapeutic interventions to ameliorate or prevent SLE. The second is that this population of patients can provide insights into early disease manifestations and mechanisms. Studies in these patients have shown increases in autoantibodies, cytokines and expressed genes that offer clues to the earliest immunopathogenic changes leading to disease. Characterization of these early changes is likely to offer clues to the actual cause of SLE.

At this time, it is not possible to reliably determine which individuals in the ILE category are at risk for transition and further disease. Multiplex tests of serum markers have been proposed as one approach. Most algorithms that are available require assessment by a rheumatologist, which is not feasible for the large number of potential patients who are seen in primary care. Further work is needed to develop validated biomarkers that will be useful tests to triage those at highest risk of disease progression or SLE transition for evaluation by a rheumatologist.