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Intermediate nature of ‘incomplete’ lupus shown in large study

By: Bianca Nogrady

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People with incomplete lupus erythematosus exhibit nearly as many disease-related symptoms as do those with systemic lupus erythematosus and often receive many of the same treatments, according to findings reported from a cohort study of 3,837 patients registered with the Lupus Family Registry and Repository.

The study found that while individuals with incomplete lupus erythematosus (ILE) generally have fewer biomarkers of lupus, a subset are at risk of permanent organ damage and may transition to systemic lupus erythematosus (SLE).

“No risk stratification protocols or treatment recommendations for ILE currently exist, and clinical care is largely derived from SLE experience, in part due to the lack of consensus on what constitutes ILE,” wrote Teresa Aberle of the Oklahoma Medical Research Foundation, Oklahoma City, and her coauthors.

The treatments that ILE patients received also ran the gamut from hydroxychloroquine and steroids to immunosuppressants of varying potency.

The investigators classified participants as having ILE if they met three of the 1997 American College of Rheumatology SLE classification criteria, and were classified as having SLE if they met four or more of those criteria. Overall, 440 individuals had ILE and 3,397 had SLE, with ILE patients on average older than SLE patients and less likely to be African American (Arthritis Care Res. 2017 Jan 24. doi: 10.1002/acr.23201).

Among those with ILE, 97.3% were ANA positive, compared with 99.3% of patients with SLE, but fewer ILE patients had ANA titers of 1:1,080 or higher (10.5% vs. 19.5%; odds ratio, 2.03; P less than .0001). ILE patients were also more than three times less likely to show anti-dsDNA antibodies than were SLE patients, but a similar percentage – approximately 42% – of both groups had anti-cardiolipin antibodies.

The researchers also examined plasma levels of B-lymphocyte stimulator, hypothesizing that lower antibody levels and fewer autoantibody specificities in ILE patients might connect with autoantibody production. In a subset of 72 ILE patients, 100 SLE patients, and 172 healthy controls, they observed that median B-lymphocyte stimulator levels were significantly lower in ILE patients, compared with SLE patients, although they were still higher than those in healthy controls. Around one-third of ILE patients had B-lymphocyte stimulator levels that exceeded the positive cutoff value, compared with 54% of SLE patients and 9% of healthy controls.

When it came to symptoms, the researchers found that each lupus classification criterion was seen in at least some ILE patients, although SLE patients were significantly more likely to have protein in urine (65.1% vs. 50%; OR, 1.9; P less than .0001), low blood counts (76.6% vs. 66%; OR, 1.7; P less than .0001), and experience seizures (19.4% vs. 14.4%; OR, 1.4; P = .012). Patients with SLE were also more likely to have pleurisy (58.2% vs. 51.9%; P = .012) and exhibit rapid hair loss (52.2% vs. 47.2%; P = .049) than were those with ILE.

Nearly one in five patients with ILE were affected by at least one clinical criterion of the disease linked to multiple indicators of disease severity, which included criteria such as serositis, renal symptoms, neurologic symptoms, hemolytic anemia, and thrombocytopenia. The investigators also noted that African Americans with ILE showed a higher rate of major clinical manifestations than did European Americans with ILE (25.7% vs. 14.9%).

“Given the association between renal disease and future transition to classified SLE, these observations suggest that patients of non-European American ancestry would likely benefit from careful monitoring and inclusion in future longitudinal studies of early or incomplete lupus,” they wrote.

While ILE patients used fewer medication types and were less likely to have used each type of medication, 65.2% of them had been treated with hydroxychloroquine and 70.7% had been treated with steroids. More than a quarter of ILE patients had used immunosuppressants and 14.8% had used major immunosuppressants, such as mycophenolate mofetil and cyclophosphamide.

“These results show that in clinical practice, ILE is often treated with hydroxychloroquine and/or steroids and occasionally may warrant treatment with potent immunosuppressants,” the authors wrote.

The authors also noted that while some patients with ILE have more severe clinical presentations and require more aggressive treatments, others with less severe disease who are at low risk of transitioning to SLE may be at risk of overtreatment.

“These results reinforce the need for new strategies to personalize disease management in ILE based on individual presentation and risk factors.”

The National Institutes of Health and the U.S. Department of Veterans Affairs supported the study. One author reported grants from pharmaceutical companies outside of the submitted work, and there were no other conflicts of interest declared.


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Improved classification criteria needed for ILE


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<section class="field field-name-field-article-votn-body field-type-text-long field-label-hidden">While having data-driven, universally used, and accepted criteria for classification of disease is essential for interpretation of clinical studies, and most importantly for enrollment and interpretation of clinical trials of potentially toxic agents, classification criteria fall short in clinical care. Even without applying rules from a classification scheme, it is common in clinical practice to see patients with typical manifestations of systemic lupus erythematosus who do not appear to have all of the features of a complete syndrome.


Where the study from Ms. Aberle and her colleagues most advances knowledge of these intermediate phenotype ILE patients is in the more sophisticated interrogation of the immunologic features of ILE vs. SLE patients than has been performed in past studies. These findings are consistent with the conception of ILE as an intermediate state between health and “complete lupus” with similar, but less immune dysregulation than patients classified with SLE.

The results also underscore the need for further classification criteria for ILE patients, with the goal of identifying those who need closer monitoring and have higher risk for severe or progressive disease progression. 

Karen H. Costenbader, MD, is with the division of rheumatology, immunology and allergy at Brigham and Women’s Hospital, Boston, and David I. Daikh, MD, is with the division of rheumatology at the University of California, San Francisco. These comments are adapted from an accompanying editorial (Arthritis Care Res. 2017 Jan 24. doi: 10.1002/acr.23196). No conflicts of interest were declared.


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