No Gold Standard Biomarker for Lupus Flare Prediction

November 7, 2017

A recent systematic review of literature found no validated and widely accepted biomarker.

No validated and widely accepted biomarker for flare prediction in systemic lupus erythematosus (SLE) was found in a recent systematic review of literature, in spite of strong clinical interest in and numerous publications on biomarkers in SLE.

SLE flares are unpredictable in frequency and severity and may lead to substantial organ damage, thus increasing morbidity and mortality and resulting in higher health care costs, researchers noted.

Physicians need to identify patients who are at greater risk for flares, to make early diagnoses, and to initiate rapid treatment or consider preventative therapies, they stated, adding that despite the great clinical necessity, a biomarker with the potential to efficiently predict the occurrence of new SLE flares has not yet been identified.

Two independent investigators, Noémie Gensous and Aurélie Marti, conducted the first systematic review of literature to identify all of the currently available data on biological SLE flare predictors in a study published in Arthritis Research & Therapy.

The study

Using 2 databases (MEDLINE and EMBASE) through April 2015, the researchers aimed to identify the most reliable biomarkers in the literature that could potentially be used as flare predictors in SLE. Congress abstracts from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) from 2010 to 2014 were also reviewed.

Interventional studies (randomized or non-randomized, controlled trials) and observational studies (case-control or cohort studies) were included. The studies considered involved adults with SLE and addressed the relationships between 1 or more defined biological tests and the occurrence of disease exacerbation.

The investigators independently extracted data from each study using a systematic data extraction form. Seven types of biomarkers performed routinely in clinical practice and 9 types of novel biological markers were evaluated. In total, 4668 records were retrieved from both databases, with the addition of 20 studies from reference lists of papers. Of these, 4126 studies did not meet the required criteria and 135 full-text articles across 69 publications were retained for complete screening.

The findings

Anti-double-stranded DNA antibodies (anti-dsDNA ab) were examined in 6 studies with heterogeneous results. Sensitivity ranged from 27.7% to 100%, specificity from 13% to 89.1%, positive predictive value (PPV) from 4.1% to 59%, and negative predictive value (NPV) from 67% to 97.5%.

Complement and complement split products were analyzed in 19 studies. These results were also inconsistent, although some complement split products (C3a, C4d, Ba, Bb, SC5b9) were found to be informative in predicting lupus flares, particularly C3a (1-2 months prior to disease flare, C3a levels increased significantly for all 10 patients studied who experienced flares later), C4d (highest sensitivity, 86.0%), and Bb (highest specificity, 81.0%).
For anti-C1q antibodies, the authors reported very good NPV for lupus nephritis, ranging from 97.0% to 100.0%, though PPV was always unsatisfactory, suggesting that the occurrence of severe nephritis is quite improbable in the absence of anti-C1q antibodies, which may be promising for clearly identifying patients who are at low risk for flares or renal involvement.

Associations between antibodies against extractable nuclear antigens (anti-ENA) and the occurrence of a flare were found in 6 studies, with the important limitation that these results were reported in only 1 study each and none of them have been reproduced. Two reports studied the associations of circulating immune complexes with the occurrence of flares, but these tests are no longer used in clinical practice.

Erythrocyte sedimentation rate was inconsistently associated with flares, and there was no persistent association between C-reactive protein level and SLE flares in multivariate analysis.  The investigators concluded, “The routinely performed and widely accepted biomarkers appeared to be deceiving, with contradictory results.”

Experimental and newly developed biological markers were also considered in the systematic review, including cytokines, chemokines, and their receptors; expression of specific markers by T cells; markers of endothelial activation; urinary markers; and other experimental biomarkers, such as anti-70-kDA, anti-A polypeptides antibodies, plasma adiponectin, plasma cell peaks, and circulating anti-dsDNA ab-secreting cells.

“In this systematic review, none of the newly studied biomarkers stood out,” the investigators determined.

Implications

In summary, the investigators recommended that clinicians be aware that at this time “none of these biological markers is completely reliable in diagnosing exacerbations, and none of them can be considered a serologic gold standard.”

However, these conclusions must also be considered in the presence of possible limitations, such as the high heterogeneity between the study designs. Fourteen studies were retrospective, follow-up frequencies were inconsistent, and flare definitions and disease activity measurements varied considerably.

The concept of an SLE flare is very complex, and although there are many valid and sensitive indices (SLEDAI, SELENA-SLEDAI, BILAG, Physician Global Assessment, SFI, and European Consensus Lupus Activity Measurement [ECLAM]), they do not evaluate the disease in the same manner and thus could prevent comparison of different studies. In addition, concerning the biomarkers themselves, the assay techniques could lead to heterogeneity because of their different performance characteristics.

The investigators recommended that efforts be made to optimize future research and proposed conducting multicenter, longitudinal, prospective, controlled studies, including patients with SLE who fulfill the revised ACR criteria and who are ethnically diverse.

Only 1 SLE flare index score should be used across studies, and the most appropriate index should be chosen among BILAG, SLEDAI,and ECLAM, as encouraged by EULAR recommendations, they noted. Follow-up visits should occur every 3 months over at least 3 years, and thresholds for increases and decreases in each biological marker should be clearly defined.

Biomarkers should be validated with assessments of sensitivity, specificity, and predictive values, whereas candidate biomarkers with promising results in small patient cohorts must be validated in larger populations. Such a standardized pattern for future studies may allow for identification of the most reliable biomarkers that could potentially be used as SLE flare predictors.

References:

Gensous N, Marti A, Barnetche T, et al. “Predictive biological markers of systemic lupus erythematosus flares: a systematic literature review.” Arthritis Res Ther. 2017 Oct 24;19(1):238. doi: 10.1186/s13075-017-1442-1446.