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Patients who do not fulfill classification criteria for systemic lupus erythematosus (SLE) can be referred to as having probable SLE (pSLE). These patients can be identified with cell-bound complement activation products (CB-CAPs), according to a recently published study in Arthritis & Rheumatology.1
The findings are relevant because the existing Systemic Lupus Erythematosus International Collaborating Clinics (SLICC)/ACR criteria do not include markers of complement activation. Tests of complement activation are more closely tied to both SLE and pSLE than serum levels of the complement proteins C3 and C4, according to the authors.
“Currently, there are no biomarkers to reliably distinguish who, among the patients with pSLE, will develop SLE by classification criteria,” write Rosalind Ramsey-Goldman, MD, DrPH, Solovy/Arthritis Research Society Research Professor, Feinberg School of Medicine, Northwestern University, Chicago, and Lupus Foundation of America Medical-Scientific Advisory Council member, and co-researchers in their study.
Researchers focused on the frequency of CB-CAPs in pSLE patients enrolled at seven academic institutions. Probable SLE patients were enrolled if they were suspected of having SLE as determined by lupus experts and if they fulfilled only three ACR classification criteria for SLE. Among the 92 pSLE patients, 38% met the SLICC classification at enrollment.
The study also enrolled 53 patients with established SLE per ACR and SLICC criteria. Researchers used the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) to measure disease activity in SLE and pSLE. Anti-dsDNA and complement components were excluded to calculate non-serological SELENA-SLEDAI.
In addition to the 92 patients with pSLE and the 53 with SLE, the study included a group of patients with Sjögren’s syndrome (51 patients) and other rheumatic diseases (an additional 51 patients), both serving as controls, for a total of 246 patients in the study. Patients with pSLE were followed prospectively; 69 patients had a first follow-up at 9–18 months after enrollment.
Researchers measured CB-CAPs using flow cytometry, and positivity rate was compared to that of commonly used biomarkers, including serum complement proteins (C3 and C4), as well as autoantibodies. A multi-analyte assay panel (MAP), including CB-CAPs, was also evaluated.
Study Results
The 92 patients with pSLE were diagnosed more recently than the 53 who had established SLE. Among those with pSLE, the average number of years since diagnosis was lower than for SLE—3.6 vs. 9.6 years, respectively.
The most common ACR clinical criteria among those with SLE and pSLE were arthritis and hematological disorder. The most common SLICC clinical criterion was synovitis. Those with SLE had more mucosal ulceration, serositis, hematological and immunological features than those with pSLE, according to the authors. However, disease activity of both SLE and pSLE was mild at enrollment.
On the day of the enrollment visit, most SLE and pSLE patients were anti-nuclear antibody positive.
More patients with pSLE were positive for CB-CAPs (28%) or MAP (40%) than for low complement (9%) at the enrollment visit.
CB-CAPs positivity was more frequent than low complement in both SLE and pSLE. The difference between low complement and CB-CAPs positivity rate in pSLE was particularly large among the pSLE group that did not fulfill SLICC criteria (2% vs. 18%, respectively). Positive CB-CAPs had higher sensitivity than anti-dsDNA in pSLE. The MAP also had higher sensitivity at enrollment than low complement in SLE and pSLE and was more sensitive and specific than positive CB-CAPs. Positive CB-CAPs were more common among SLE and pSLE patients who were Black than white patients, although the difference was not statistically significant.
Among the 69 pSLE patients with a follow-up visit, 29% met at least one additional ACR criterion, with hematological the one with the highest frequency (50%), followed by oral ulcers (19%), immunological (8%), serositis (8%), arthritis (8%), photosensitivity (4%) and rash (4%).
Fulfillment of SLICC criteria at enrollment did not predict ACR criteria fulfillment 18 months later. On the contrary, a MAP score of greater than 0.8 at enrollment predicted fulfillment of a fourth ACR criterion within 18 months.
The results suggest that CB-CAPs perform well as a potential test to support SLE diagnosis in those with pSLE, the researchers concluded. “In particular, CB-CAPs and MAP performed better than standard testing, including antibodies to dsDNA or low serum complement levels,” they write. In addition, a MAP result of >0.8 was the best predictor of a patient with pSLE acquiring a fourth ACR criterion within 18 months after enrollment.
Activation of complement as measured by CB-CAPs and the MAP—which includes autoantibodies and CB-CAPs—represents better biomarkers for SLE than traditional SLE biomakers, such as C3 and C4, and anti-dsDNA, according to Dr. Ramsey-Goldman and two co-researchers, Exagen CEO Arthur Weinstein, MD, professor emeritus of clinical medicine, Georgetown University, Washington, D.C., and Roberta Vezza Alexander, PhD, of Exagen.
The findings about biomarkers contrast with common findings when using classification criteria, according to the authors. For example, a 2019 study from Mosca et al. found that only 66.1% of newly diagnosed SLE patients were positive by ACR criteria, 83.5% by SLICC criteria, and 23% of patients fulfilled only three ACR criteria.2 This demonstrates that classification of SLE can differ from clinical diagnosis. Identifying patients earlier on and starting treatment as needed could help avoid organ damage.
The study is limited by its small cohort size. However, 29% of patients with a follow-up visit within 18 months fulfilled a fourth ACR criterion within that time frame, confirming researchers’ expectation that this pSLE cohort, coming from academic lupus centers, may be more likely to progress to classifiable SLE than previous studies have suggested.
The results show that CB-CAPs and MAP can help rheumatologists diagnose SLE even in early disease stages. Of course, additional research is needed and is ongoing, according to Dr. Ramsey-Goldman and co-researchers.
Other areas of research include identifying other leukocyte subpopulations that bind CB-CAPs—and whether these subpopulations differ between SLE, pSLE or other rheumatic diseases.
“It would also be of great interest to learn whether our tests for complement activation identify a subset of SLE patients more likely to respond well to some of the newer lupus medications and biologics under study,” the authors tell The Rheumatologist.