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MADRID—Systemic lupus erythematosus (SLE) experts in North America and Europe are working together to refine the classification system for the disease, with the goal of producing a new set of criteria that is simpler to use and more scientifically rigorous than any classification approach previously published, speakers involved with the process said at the 2017 Annual European Congress on Rheumatology (EULAR).
The system, a joint effort between the ACR and EULAR, is slated to include criteria in clinical and immunological domains, and validation of draft criteria is ongoing. Presentations at the conference pointed to the challenges involved, and showed in detail the lengths to which the experts have gone to produce reliable criteria and how they’ve used technology as a critical tool.1
The nature of SLE makes it a notoriously difficult disease to classify, said Martin Aringer, MD, chief of rheumatology at University Medical Center Carl Gustav Carus in Dresden, Germany, who is helping lead the effort. “Multi-organ, multi-antibody disease is challenging for classification,” he said, speaking at a scientific session.
The 1982 ACR classification criteria, which were updated in 1997, require four of 11 criteria to be met for an SLE classification. These criteria have had great influence in the field over the past two decades. They promote the concept of the disease as multiple antibody and multiple organ, and put all the criteria on equal footing with equal weight, making it easy to use and memorize.
This approach has not been entirely intuitive, Dr. Aringer noted. Dermatologists, for example, have criticized that the criteria could be fulfilled by meeting the four mucocutaneous criteria. And the sensitivity has been considered suboptimal, at just 83% in the cohort of the SLE International Collaborating Clinics (SLICC) and lower in patients earlier in the disease course.
Under the 2012 SLICC criteria, patients have to be positive for anti-nuclear antibodies or antibodies to double-stranded DNA, and lupus nephritis on histology means automatic SLE classification.2 Sensitivity with these criteria is good, but specificity is below that of the ACR criteria. Dr. Aringer said that was likely because the SLICC group chose to keep the classification system structure similar to the previous system.
With this new effort, experts are trying to do better. “The main goals are to have a relatively intuitive set that helps in teaching; increase the sensitivity by comparison to the [current] ACR criteria, but maintain specificity in the same range; improve performance in early SLE; involve the larger SLE community as far as possible; and do this in a strictly scientific way,” Dr. Aringer said.
The Process
Sindhu Johnson, MD, PhD, a clinical researcher at University Health Network in Toronto, who is also helping lead the creation of the new system, described a rigorous, multilayered process of whittling down a list of criteria, literature review and organizing the criteria into seven clinical domains and three immunological domains.
The panel of experts—nine from North America and eight from Europe—chose to use an entry criterion that all cases have to meet even to be considered under the new system. The titer of anti-nuclear antibodies (ANA) must be at least 1–80. The panel also chose not to have any criteria, such as lupus nephritis, that would automatically confer an SLE classification.
The panelists submitted 167 cases, ranging from more likely to be SLE to less likely. The experts scored 20 of the cases using the criteria and ranked them.
Then they met for two days, reviewing the inter-rater reliability of their scoring and refining the definitions of the criteria. The experts entered the multicriteria decision analysis (MCDA) step, in which they each were presented with two criteria under two domains for a pair of cases. They had to choose anonymously which case was more likely to be SLE.
In one example, the panel experts were asked, “Which patient has the higher probability of being classified as SLE?” The choices were a case with malar rash (in the cutaneous domain) and anti-dsDNA (in the highly specific antibodies domain) or a case with oral ulcers and anti-Smith antibodies.
“If there was clear consensus, we knew which patient had the higher rated criteria,” Dr. Johnson said. “However, if there was a lack of consensus, then a discussion ensued.” The experts revoted until a consensus was reached.
The nature of SLE makes it a notoriously difficult disease to classify.
Computer software, called 1000Minds, used these consensus decisions to calculate weights for each of the criteria, then assigned a total score to the other 147 cases and ranked them. The experts then voted on whether each should be classified as SLE.
For criteria that didn’t match expert opinion, the pair-style rankings were done again until the experts reached consensus. The software was used to recalculate the weights and rerank the cases.
The panelists were in complete agreement on the cases with the highest rankings—they were all SLE—until the scores dipped below 84, when some disagreement emerged, Dr. Johnson said. “For this reason, a threshold score of 84 was identified,” she said, meaning that any score above 83 is considered to be SLE and scores of 83 or lower are not.
Through the group discussions, Dr. Johnson said, the definitions for arthritis and pericarditis were modified. Also, cranial neuropathy and Class IV lupus nephritis were removed as criteria, because they weren’t found to be helpful in the classification process.
“We have defined a system of criteria that produces the relative probability that a particular case—that is, a combination of clinical features—has systemic lupus erythematosus,” Dr. Johnson said.
The criteria are still in draft form and in flux, she cautioned. They are now being validated using 1,000 cases and 1,000 controls from 36 international SLE sites, she noted.
Classification criteria are generally used to standardize groups of patients for clinical trials. This can lead to the availability of better therapeutic options, if trials go well and more therapies are approved by the FDA. Thus, Dr. Aringer is hopeful the new system will lead to better care.
“If successful, ANA of at least 1–80 and weighted criteria will lead to better performance, particularly in early disease, and give us a system that is, hopefully, intuitive enough to convey an idea of the disease,” he said.
Thomas R. Collins is a freelance writer living in South Florida.
References
- Tedeschi S, Johnson S, Boumpas D, et al. Multicriteria decision analysis for developing new classification criteria for systemic lupus erythematosus (abstract OP0002). Annual European Congress of Rheumatology. 2017 Jun 15. Madrid, Spain.
- Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012 Aug;64(8):2677–2686.
