Grouping SLE subsets by symptoms may help patients 'proactively manage their disease'
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Grouping patients with systemic lupus erythematosus into subsets based on inflammatory and noninflammatory symptoms may help them better understand their disease and treatment, according to a speaker at the 2020 Congress of Clinical Rheumatology-West.
“I think clinical subsetting of lupus patients — especially thinking about symptoms as they divide into inflammatory or noninflammatory symptoms — may help as we educate our patients better about what medications we are using for what parts of their lupus,” Judith A. James, MD, PhD, of the Oklahoma Medical Research Foundation and the University of Oklahoma Health Sciences Center, told attendees during the virtual meeting. “As most of us know, everybody feels better on prednisone — or at least everyone feels a little bit manic on prednisone — and so many of our lupus patients really, really like prednisone.”
“Unfortunately, if you are taking 20 mg of prednisone just for your fatigue, you are going to end up with a lot more toxicity than any benefit you get,” she added. “I think helping patients understand their inflammatory vs. their noninflammatory symptoms may help them to proactively manage their own disease, and to be better partners with us as we try to help them manage all of their health.”
In addition, James argued that deciphering molecular heterogeneity in SLE could help improve outcomes in lupus clinical trials, as well as aid in better selecting appropriate treatments.
This point was highlighted, she said, in a study authored by herself and colleagues, and published in 2020 in EClinicalMedicine, which found that molecular profiles can distinguish SLE subsets that are not apparent from clinical information.
In that study, James and colleagues analyzed plasma, serum and RNA from 198 adults with SLE from the Oklahoma Lupus Cohort. Researchers scored disease activity using a modified SELENA-SLEDAI and calculated 29 co-expression module scores from microarray gene-expression information. In addition, plasma soluble mediators and autoantibodies were examined using machine learning, combining K-means clustering and random forest analysis of co-expression module scores and soluble mediators.
According to James and colleagues, SLEDAI scores correlated with interferon, plasma cell and select cell cycle modules, as well as with circulating IFN-, IP10 and IL-1 levels. In addition, co-expression modules and soluble mediators differentiated seven clusters of SLE patients with unique molecular phenotypes. Inflammation and interferon modules were elevated moderately in cluster 1 and strongly in cluster 4, with decreased T-cell modules in cluster 4. Meanwhile, monocyte, neutrophil, plasmablast, B-cell and T-cell modules distinguished the remaining clusters.
The researchers also found that active clinical features were similar across clusters. Clinical SLEDAI trended highest in clusters 3 and 4. However, cluster 3 lacked strong interferon and inflammation signatures. Renal activity was more frequent in cluster 4, but rare in clusters 2, 5 and 7. Serology findings were lowest in clusters 2 and 5, and musculoskeletal and mucocutaneous activity were common in all clusters.
“Deciphering lupus molecular heterogeneity may help us improve lupus outcomes, and especially help with lupus clinical trials, as we find homogeneous groups of patients that may be best to try for a certain type of directed immunotherapeutic intervention, and to help us better select, ideally, eventually, appropriate treatments for our patients,” James said.
Lastly, James told attendees this practice of grouping patients into subsets could potentially be the future of medicine in other rheumatic diseases, including rheumatoid arthritis and Sjogren’s syndrome.
“Consider, instead of just thinking about subsetting lupus, we need to be lumpers — put lupus, rheumatoid arthritis, mixed connective tissue disease, Sjogren’s syndrome, undifferentiated connective tissue disease, maybe inflammatory myositis and maybe others, into a big systemic autoimmune rheumatic disease pot,” she said. “And then you use some of the molecular information to divide those groups into ‘interferon-dominant,’ ‘inflammation dominant,’ ‘monocyte-dominant,’ ‘activated B-cell dominant,’ and maybe that is the way we will be practicing medicine in the future.”
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James JA. Can specific SLE phenotypes be defined? Presented at: Congress of Clinical Rheumatology-West annual symposium; October 8-11, 2020 (virtual meeting).
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