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Complement Biomarkers Help Predict Lupus

— Cell-bound complement activation products were more sensitive than traditional biomarkers

MedpageToday
A blue gloved hand holds a vial of blood marked as SLE positive

A commercially available test that measures stable biomarkers of complement activation was helpful in diagnosing systemic lupus erythematosus (SLE) in a real-world setting.

Among 117 patients who had clinical findings suggesting the possibility of SLE but who did not have a confirmed diagnosis at baseline, 65% of those who showed positive results on the had been diagnosed with SLE 2 years later, according to Maureen McMahon, MD, and colleagues from the University of California Los Angeles.

In contrast, among those who had negative results on the test, only 10.3% had developed SLE by 2 years (P<0.0001), the researchers reported online in .

The authors noted that no funding or study input was provided by Exagen, the test developer.

Diagnosing SLE remains challenging despite the availability of classification criteria established by the American College of Rheumatology and the Systemic Lupus International Collaborating Clinics (SLICC), as well as various scoring systems to assess disease activity and damage. Conventional laboratory tests such as complement C3 and C4 have been incorporated into the traditional diagnostic criteria but have low sensitivity.

Yet many of the early manifestations of SLE are nonspecific and overlap with other connective tissue diseases, so interest has been growing in identifying more specific biomarker tests. One such test is AVISE, which measures cell-bound complement activation products such as erythrocyte-bound C4d (EC4d), B-cell-bound C4d (BC4d), and platelet-bound C4d. The test can differentiate SLE from other connective tissue diseases with a reported sensitivity of 56%-72% and a specificity of 80%-98%, and from healthy persons with a sensitivity of 60%-81% and a specificity of 91%-100%.

Aside from EC4d and BC4d, the two-tiered 10-marker test also measures autoantibodies and has panels for rheumatoid arthritis, antiphospholipid syndrome, and thyroid abnormalities. McMahon and colleagues noted that since there have not yet been any studies evaluating the test in a real-world setting, the team decided to conduct a retrospective observational study of patients who underwent testing from 2014 to 2016.

Among the 117 included patients, most were women, and the average age was 53. The presumptive diagnoses at baseline were:

  • Undifferentiated connective tissue disease in 40.2% of the patients
  • Rheumatoid arthritis in 21.4%
  • Other autoimmune diseases in 21.4%
  • Other conditions such as fibromyalgia and osteoarthritis in the remainder

The diagnosis changed between baseline and 2 years in 80% of the patients who had a positive AVISE test compared with 28.9% of those whose baseline test was negative (P<0.0001).

Patients who had a positive baseline test fulfilled more of the SLICC disease criteria both at baseline (3.8 vs 1.9, P=0.001) and at 2 years (4.5 vs 2.1, P<0.0001).

The investigators also compared the accuracy of prediction with the AVISE test and conventional SLE biomarkers. Low C3 and C4 and high levels of double-stranded DNA antibodies had specificities above 90%, but sensitivities were below 20%. In contrast, AVISE positivity for predicting SLE diagnosis at 2 years had a specificity of 93%, sensitivity of 57%, positive predictive value of 65%, and negative predictive value of 90%.

On a logistic regression analysis that compared AVISE and various conventional disease markers, only AVISE positivity at baseline was associated with a confirmed SLE diagnosis at 2 years, with an odds ratio of 10.7 (95% CI 2.6-44.9, P=0.001).

Positive test results also helped predict disease damage at 2 years, with 90% of those who were positive having scores above zero on the SLE damage index compared with 55.7% of those who tested negative (P=0.005).

For the specific components of the AVISE test, the researchers noted that BC4d levels had the strongest association with disease progression. At baseline, patients who already had disease damage had significantly higher levels of BC4d, with mean fluorescence intensities of 34.7 compared with 24.1 for those without damage (P=0.03), while at year 2, mean fluorescence intensities were 32 versus 24, respectively (P=0.04).

The authors noted that have found that the AVISE test can improve the sensitivity and specificity of diagnosing SLE among cases versus controls. But in this study, "we have demonstrated that AVISE positivity can not only predict development of SLE within a 2-year interval, but also with equal or greater specificity and greater sensitivity than traditional biomarkers."

But McMahon and colleagues cautioned that several of their patients who initially had negative test results did ultimately develop SLE. "Thus, while AVISE testing can improve clinical decision-making, it is still important to interpret results in the context of a patient's clinical presentation," the researchers wrote, adding that the study was also limited by its small sample size and retrospective design.

Future work, the team said, will include assessing the ability of the test to predict flares and disease activity, and should include larger cohorts.

Disclosures

The study was funded by a David Geffen School of Medicine Research Grant.

The authors reported no financial conflicts.

Primary Source

Lupus Science & Medicine

Liang E, et al "Utility of the AVISE connective tissue disease test in predicting lupus diagnosis and progression" Lupus Sci Med 2020; DOI: 10.1136/lupus-2019-000345.