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Abstract
Objective To determine the ominosity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) Systemic Lupus Erythematosus Classification Criteria by determining its predictive role for disease severity in the first 5 years following diagnosis.
Methods 867 patients with systemic lupus erythematosus (SLE) from the Toronto Lupus Clinic were included (all first 12 months after SLE diagnosis). The EULAR/ACR criteria score was calculated based on baseline information. To determine disease severity in the first 5 years after diagnosis, adjusted mean SLE Disease Activity Index 2000 (AMS), flares, remission and immunosuppressive treatment were used as outcomes. The Systemic Lupus International Collaborating Clinics (SLICC) registry comprised the validation cohort.
Results Based on receiver operating characteristic analysis, a EULAR/ACR score of 20 was used as a threshold to compare outcomes between groups. In the first 5 years of disease course, patients with a score of ≥20 had higher AMS scores (p<0.001) and were more likely to ever experience a flare (p<0.001). These patients had lower probabilities of achieving remission and higher requirements for immunosuppressives. Results were confirmed in the SLICC validation cohort. Patients with a score of ≥20 had higher AMS during the first 5 years of disease (5.4 vs 3.1% and ≥20 vs <20 respectively, p≤0.001). The score correlated with AMS (r=0.43, p≤0.001) in the same time frame.
Conclusion A EULAR/ACR score of ≥20 is an indicator of ominosity in SLE. Patients with a score of ≥20 were characterised by a more active disease course throughout the first 5 years. These criteria provide prognostic information regarding disease severity in the first 5 years following diagnosis.
- Systemic lupus erythematosus
- classification criteria
- disease severity
- outcomes
- prognosis
Data availability statement
Data are available upon reasonable request.
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Key messages
What is already known about this subject?
Systemic lupus erythematosus (SLE) is a heterogeneous disease characterised by an unpredictable activity course. Persistent disease activity and flares are important predictors of mortality and damage accrual. Prior studies have identified features predictive of disease activity throughout the disease course, such as low education, ethnicity, sex and high double-stranded DNA antibodies at baseline.
What does this study add?
This is the first study that aimed to determine the possible link between the new European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria numerical scores at diagnosis and subsequent disease severity. Our results suggest that the score of the EULAR/ACR criteria could serve to predict ominosity in SLE, that is, to detect patients with a greater likelihood of disease severity over the first 5 years of their disease course.
How might this impact on clinical practice or future developments?
This new set of classification criteria could be helpful not only in classifying SLE cases but could also in providing prognostic information regarding the disease course in the first 5 years following diagnosis.
Introduction
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease in which adverse outcomes remain a major challenge. Over the last five decades, the prognosis of patients with SLE has improved.1 However, they still have a twofold to fivefold increased risk of death compared with the general population,2 and a potential life loss of 23.6 years.1 3 Since the great majority of these patients are younger than 50 years of age,4 5 in addition to mortality, morbidity is also an important outcome. Morbidity in patients with SLE is determined throughout the disease course6 by disease activity, irreversible organ damage and comorbidities.7
SLE is characterised by different patterns of disease activity throughout its course.8 Overall, persistent disease activity and flares appear to be important predictors of both mortality9 and damage accrual.10 11 On the other hand, early and sustained remission predicts a better prognosis.9
Features predictive of disease activity early in the disease course include socioeconomic and demographic characteristics such as ethnicity (non-Caucasians)12–16 and lower education.12 14 In addition, high disease activity and high anti-double-stranded DNA (dsDNA) antibodies at baseline have been described to predict higher disease activity in the SLE course.11 12 15
Recently, a new set of classification criteria for SLE using an additive point system has been introduced,17–19 the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) Classification Criteria.20 21 The EULAR/ACR criteria have been proven to be more sensitive than the 1997 ACR criteria and more specific than the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria.21 In addition, it has been shown to perform well in patients with early disease and in different ethnicities.22 23
Furthermore, in a study including new-onset patients with SLE, EULAR/ACR criteria correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) and Revised Systemic Lupus Activity Measure (SLAM-R) scores, with both disease activity scoring systems indicating a correlation of the EULAR/ACR criteria with disease activity.24 Also, in a separate cohort of patients, higher EULAR/ACR scores were associated with higher rates of organ damage.25
We aimed to determine the ominosity of this classification system by determining its potential predictive role for disease severity in the first 5 years of the disease course.
Methods
Patients and setting
Patients with SLE have been followed up prospectively at the University of Toronto Lupus Clinic since 1970. By November 2019, 870 patients with inception SLE were registered (recruited in the first 12 months after SLE diagnosis). All patients met the revised 1997 ACR classification criteria for SLE26 or three criteria and a supportive biopsy (skin or kidney).
During the first visit, each patient underwent a complete history and physical examination that includes demographic data, past or present organ-specific disease-related symptoms, physical examination findings and laboratory evaluation.
The cohort was followed up at regular intervals (every 2–6 months). At each follow-up visit, clinical and laboratory information is collected according to a standard protocol. For every patient, SLEDAI −2K is calculated and recorded at every visit. All information is stored on a computer database.
EULAR/ACR classification criteria score
For each patient, a score of the EULAR/ACR criteria was calculated based on the baseline clinical, laboratory and renal biopsy information. The baseline information was obtained from the first two visits at the University of Toronto Lupus Clinic, as some of the data and therapies ordered at the first visit were recorded only at the second visit. We confirmed that the clinical and laboratory information fulfilled the proposed definitions of the EULAR/ACR criteria.20 This allowed for the assignment of numerical scores for each of the EULAR/ACR criteria present in each patient.
Outcomes
To determine the ominosity of the EULAR/ACR criteria on the SLE clinical course, we used different outcomes to establish disease severity over the first 5 years after diagnosis.
Adjusted mean SLE Disease Activity Index 2000 (AMS)
The AMS represents the average disease activity over a period of time.27 28
Flares
A flare was defined as an increase in SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥4 from the previous visit.29–31
Remission
Remission was defined according to the definition of remission in systemic lupus erythematosus (DORIS).32
Complete remission off treatment: no clinical and serological disease activity (SLEDAI-2K score=0), no glucocorticoids and no immunosuppressive therapy allowed.
Clinical remission off treatment: serologically active clinical quiescent (SACQ) disease, described as clinical SLEDAI-2K score=0, high anti-dsDNA Abs and/or C3 decrease present, no glucocorticoids and no immunosuppressive therapy allowed.
Complete remission on treatment: SLEDAI-2K score=0, prednisone 1–5 mg/day, immunosuppressive therapy allowed.
Clinical remission on treatment: SACQ disease, prednisone 1–5 mg/day and immunosuppressive therapy allowed.
Antimalarials were allowed in all groups.
Therapy
Glucocorticoid requirement: cumulative doses and average daily dose of glucocorticoids were calculated from the time of entry to the cohort.
Immunosuppressive use: the percentages of patients still on immunosuppressive therapy by the end of the first, third and fifth years.
Antimalarials use: the percentages of patients still on antimalarials by the end of the first, third and fifth year.
Cohort without lupus nephritis (LN)
In order to examine if the EULAR/ACR score was a surrogate for LN, we performed a subgroup analysis excluding patients who had LN at presentation and determined the outcomes for this subgroup, including AMS, flares and remission in the first 5 years following SLE diagnosis.
Validation cohort
To validate our results from the Toronto Lupus Cohort, we used the SLICC registry, a large multiethnic inception cohort followed up for a 10-year period.33 Patients were assessed on an annual basis with laboratory tests to evaluate disease activity parameters. When reviewing the SLICC registry data to determine the feasibility of calculating the EULAR/ACR score at baseline, three issues were detected:
Isolated haemolytic anaemia was not recorded in the database.
Anti-Sm Abs were not reported separately from anti-DNA Abs.
Hypocomplementaemia was reported as normal or low, so we could not separate C3 from C4.
Given that only 1.8% of patients in the lupus clinic cohort had isolated haemolytic anaemia, 11.8% were positive anti-Sm with negative anti-dsDNA Abs and that hypocomplementaemia is in the same section of the EULAR/ACR score with only one point difference between one of them low or both low, we considered that it was feasible to calculate the EULAR/ACR score.
When analysing outcomes, only AMS could be determined, given that the follow-up was annual.
Statistical analysis
Descriptive statistics and bar charts were generated for patients’ baseline characteristics and EULAR/ACR score distributions. P values from unpaired t-tests, χ2 tests and Cochran-Armitage trend test were provided for continuous, binary and multilevel categorical variables. When we examined the linear relationship between EULAR/ACR scores and adjusted mean SLEDAI, although residual diagnostics showed that the square root transformed the AMS fitted the model better, the untransformed data did not depart from the model assumption far. To simplify the clinical interpretation, we reported parameter estimates and p values from the untransformed linear regression model.
Since the flare outcome in our data followed closely to a Poisson distribution, we performed a univariate Poisson regression, the independent variable being the EULAR /ACR score at baseline and the dependent variable being the total number of flares each patient could have over the first 5 years. Overdispersion was corrected by Pearson scaling, relative risk with 95% CIs, and p values were reported.
For the outcome of remission, we described the first remission episode the patients had using the four DORISs as separate outcomes and also performed non-parametric cumulative incidence function curves to look at time to first remission (for each of the four types); Grey’s test was used to detect the differences between patients with a total EULAR/ACR score of ≥20 or below. Multivariable Cox proportional regressions were performed to find the risk (HRs and 95% CIs) of higher EULAR/ACR score on the outcome of remissions; death was considered as competing risk in Fine and Grey’s subdistribution hazard models; baseline age and race were entered as adjusting variables.34 35
We performed receiver operating characteristic (ROC) analysis in order to determine the optimal predictive value for poor outcomes. We chose the best cut-off value for the EULAR/ACR score with the higher Youden Index (equivalent to the point on the ROC closest to the top-left corner). From this ROC analysis, we found the best cut-off for AMS was a score of 22 for year 1, 19 for year 3 and 23 for year 5. The best cut-off for flares was a score of 16. All values were close to 20, which was the median score. We used this as a threshold to compare demographic characteristics, clinical characteristics and outcomes of patients above and below this score.
Patient and public involvement
Patients were involved with data collection and will be involved in choosing results to share, when and in what format to disseminate the study results to the relevant wider patient communities.
Results
Cohort characteristics
A total of 867 inception patients were included; 768 (88.6%) had a follow-up of at least 1 year; 659 (76%) had a follow-up of 3 years; and 568 (65.6%) had a follow-up of 5 years. The majority (87.5%) of the population were woman, with a mean age of 36.2 years at SLE diagnosis. Most patients were Caucasians (66.7%), followed by black (14.2%) and Chinese (8.3%) patients. The mean disease duration, defined as the time between diagnosis and the first visit, was 0.2 years; the median time between the first visit and the second visit was 3.3 months.
At the first visit, the mean±SD SLEDAI-2K score was 9.4±8.0; 56.2% of the patients were treated with glucocorticoids, 17.4% with immunosuppressive therapy and 37% with antimalarials. Data are shown in table 1.
Demographic characteristics of our cohort at first visit
When we applied the EULAR/ACR criteria to our cohort, 16 patients (1.8%) had a score of <10 (online supplemental figure 1 shows the distribution of the 1997 ACR criteria in these patients). In addition, 25 patients (2.8%) had a negative Antinuclear Antibodies; of these patients, only 4 had a score ≤10.
Supplemental material
Overall, the scores had a normal distribution curve, as shown in figure 1.
Histogram distribution of the EULAR/ACR criteria score in our population. ACR, American College of Rheumatology; EULAR, European League Against Rheumatism.
The three most common clinical domains of the EULAR/ACR criteria present in the studied cohort were joint involvement (62.4%), acute cutaneous lupus (48.2%) and non-scarring alopecia (45.5%), as shown in table 2.
Distribution of the EULAR/ACR criteria in our cohort and in the validation SLICC cohort
Based on ROC analysis a EULAR/ACR score of 20 was used as a threshold to compare demographic, clinical characteristics and outcomes between groups.
Associations between the EULAR/ACR score, demographic and clinical characteristics at baseline
The Caucasian population less frequently presented with a score of ≥20 (58.0% vs 76.1% and ≥20 vs <20, respectively; p≤0.001), in comparison to the black population, which most commonly had a score ≥20 (17.9% vs 10.1% and ≥20 vs <20, respectively; p=0.002).
At baseline, patients who presented with a higher score were younger (34.5 vs 38.1 years old and ≥20 vs <20, respectively; p≤0.001), had higher SLEDAI-2K score (12.2 vs 6.3 and ≥20 vs <20, respectively; p≤0.001) and were more likely to receive glucocorticoids (66.8% vs 44.6% and ≥20 vs <20, respectively; p≤0.001) and immunosuppressive therapy (20.6% vs 14.0% and ≥20 vs <20, respectively; p=0.010). The use of antimalarials was the same between the two groups (37.6% vs 36.4%, p=0.709; shown in table 1).
As expected, patients with a score of ≥20 had greater number of organ system involvements, except for autoimmune haemolysis, psychosis, subacute cutaneous and discoid rash, which were evenly distributed between groups. Table 2 shows the distribution of the EULAR/ACR domains in our cohort.
Associations between the EULAR/ACR score and disease severity in the first 5 years after diagnosis
Adjusted mean SLEDAI
Patients with a score of ≥20 were characterised by a more active disease course as determined by higher AMS over the first 1, 3 and 5 years of the disease course, as shown in table 3.
AMS and treatment characteristics in the first 5 years of disease course
The total EULAR/ACR score correlated with the AMS over the first 1, 3 and 5 years (r=0.36, p<0.001; r=0.30, p<0.001; and r=0.28, p<0.001; for 1, 3 and 5 years respectively). In addition, in the first year of the disease course, every increase of 10 points in the score increased the AMS by 2.2 units (univariate linear regression, beta=0.22, p<0.0001).
On multivariable linear regression analysis, the EULAR/ACR score continued to significantly correlate with AMS over the first 1, 3 and 5 years (p=<0.0001); age at baseline also correlated with AMS at 3 and 5 years (p=0.025 and p=0.045, respectively), as shown in online supplemental table 1).
Supplemental material
Flares
Patients with a higher score were more likely to ever present with a flare (69.4% vs 55.8% and ≥20 vs <20, respectively; p<0.001) and more frequently experienced ≥2 flares in the first 5 years of disease course (43.9% vs 34.1% and ≥20 vs <20, respectively; p=0.017), as shown in figure 2.
Graph illustrating the number of flares in the first 5 years of disease course, comparing patients with an European League Against Rheumatism/American College of Rheumatology score of ≥20 vs <20.
Results from the multivariable Poisson regression analysis, adjusting for ethnicity and age at baseline, showed that every 10 point increase in the EULAR/ACR score increased the risk of a flare by 22.5% (RR 1.225, 95% CI 1.110 to 1.352, p<0.001). When comparing organ-specific flares, the group of patients with a score ≥20 more frequently presented renal (31.6% vs 12.8% and ≥20 vs <20, respectively; p≤0.001) and haematological (8% vs 2.2% and ≥20 vs <20, respectively; p=0.007) flares in comparison to patients with a score of <20. There was no difference in the rest of organ-specific flares between groups, as shown in online supplemental table 2.
Supplemental material
Remission
We compared the characteristics of the first remission episode between groups using the four DORISs. The most frequent first remission of patients with a score of ≥20 was clinical remission on treatment (28.46%), in comparison to patients with a score of <20, of whom nearly half (48.73%) achieved a complete remission off treatment as their first remission, as shown in table 4.
First remission episode based on the four DORISs
Individuals with a score of ≥20 had lower probabilities of achieving remission of at least 15% compared with individuals with a low score. The HR with significant p values confirmed this finding (figure 3). The results remained significant in the multivariable Cox proportional regressions adjusting for age and race. Caucasian populations had a higher chance of achieving remission compared with non-Caucasian populations. This information is shown in online supplemental table 3.
Supplemental material
Remission according to the four definitions of remission in systemic lupus erythematosus. Kaplan-Meier survival curves stratified by European League Against Rheumatism/American College of Rheumatology criteria scores of ≥20 and <20. HRs and 95% CIs of higher score group versus low score group on the outcome of four types of remission.
Treatment
Patients with a score of ≥20 were characterised by a greater cumulative and mean daily doses of glucocorticoids during the first 1, 3 and 5 years of disease course. Also, they used more immunosuppressive medications in the same time course compared with patients with a score of <20. The percentage use of antimalarials was similar between groups, as shown in table 3.
Cohort without LN
In order to determine if the EULAR/ACR score was a surrogate for LN, we performed a subgroup analysis excluding 310 patients who had LN at presentation, leaving 557 patients. There was no difference in the outcome AMS as shown in online supplemental table 1. Regarding the remission outcome, the HRs in the subgroup without LN remained significant for all DORISs except clinical remission on treatment, which could be due to the smaller number of patients, as shown in online supplemental table 3. As for the flare outcome, there was a trend towards a higher rate of flares in the group of patients with a higher score, although this was not statistically significant (62.2% vs 53.7% and ≥20 vs <20, respectively; p=0.101).
Validation cohort
A total of 807 patients were included, all of whom completed at least a 5-year follow-up. The mean score was 14; 21.3% had a score of ≥20. table 2 shows the EULAR/ACR clinical and laboratory characteristics of this cohort. Patients with a score of ≥20 had higher AMS during the first 5 years of disease in comparison to patients with a lower score (5.4 vs 3.1% and ≥20 vs <20, respectively; p=<0.001). The EULAR/ACR score correlated with AMS (r=0.43, p≤0.001) in the same time frame.
Discussion
To our knowledge, this is the first study that aimed to determine the possible link between the new EULAR/ACR scores at diagnosis and subsequent disease severity. Our study suggests that this classification criteria score could serve to detect patients with a greater likelihood of disease severity over the first 5 years of their disease course.
Our results revealed that patients with a EULAR/ACR score of ≥20 had higher AMS scores throughout the first 5 years after diagnosis, presented with more flares and were characterised by a less likelihood to achieve any of the four DORISs of remission during the same time frame.
In our cohort, black patients more frequently had a score of ≥20. Also, patients with a higher score tended to be younger. These are known features associated with a more active disease course.12–14 24 36 37 Importantly, after performing multivariable linear regression analysis, the EULAR/ACR score continued to significantly correlate with our studied outcomes throughout the first 5 years. High disease activity at baseline predicts a higher disease activity on subsequent visits.12 14 In our study, patients that scored ≥20 had higher SLEDAI-2K scores at baseline. Interestingly, a recent study by Teng et al on patients with new-onset SLE found an association between EULAR/ACR scores and baseline SLEDAI-2K (r2 0.65, p<0.0001) and SLAM-R (r2 0.37, p<0.0001) scores, in agreement with our findings.24
Individuals with a score of ≥20 experienced more flares in the first 5 years of the disease course. Moreover, this group of patients also had higher numbers of renal and haematological flares. Interestingly, in the study of Carneiro et al, patients with a higher EULAR/ACR score had higher rates of renal damage, which persisted even after they removed the renal domain from the final classification score,25 suggesting that in the setting of renal activity, the presence of a multisystem disease at baseline could predict the risk of subsequent renal flares.
Importantly, patients with a EULAR/ACR score of ≥20 required more aggressive therapy determined by higher cumulative doses of glucocorticoids. By the fifth year, there was a striking difference between groups (close to 4.5 g). They also had higher percentages of immunosuppressive therapy use in the same period of time. These differences in treatment are probably driven by the higher disease activity that characterised this group of patients. These findings are certainly of interest, since glucocorticoid and immunosuppressive therapy are known to increase the risk of infections,38–40 a leading cause of mortality during the first years of the SLE disease course.1 Also, glucocorticoids are known inducers of atherosclerosis, which leads to cardiovascular comorbidities, a major cause of death in patients with SLE older than 40 years.1 41–43
Accumulating knowledge suggests that the use of antimalarials during the early course of the disease is associated with a less severe disease course.14 44 In our results, both groups had similar percentages of antimalarial use throughout the first 5 years of disease course.
In the subgroup of patients without LN, the group with a score of ≥20 had a higher AMS throughout the first 5 years as well as lower probability of achieving remission for all DORISs except clinical remission on treatment. Also, they tended to have a greater number of flares, although this was not statistically significant, which could be attributed to the reduction in sample size.
Our findings were further confirmed in an independent cohort. The SLICC cohort appeared to be milder with a lower EULAR/ACR score in comparison to the Toronto Lupus Clinic cohort. Even with a lower mean score, ≥20 points still correlated with disease activity in the first 5 years of disease course, hence, a predictor of ominosity. It has been well documented that individuals with a more active disease, especially during the first years after diagnosis, have more damage accrual and higher mortality rates.10 11 43
In 1982, Ginzler et al found a correlation between the number of American Rheumatism Association criteria fulfilled at diagnosis and mortality,45 and more recently, a study by Carneiro et al found that patients with higher EULAR/ACR scores at the time of diagnosis tended to have an increased incidence of organ damage.25 We did not find a correlation between EULAR/ACR score at baseline and damage at 5 years after diagnosis (data not shown), although we consider that 5 years is too early to establish damage accrual and mortality, and an independent analysis should be performed after a 10-year follow-up in order to address this question. The strengths of this study are that it was performed in a large prospectively followed inception cohort of patients with SLE who entered the cohort within 0.2 years from diagnosis; a large number were still actively followed up at year 5 at intervals of 3–6 months, allowing for frequent data points affecting the outcomes. Another strength is that the results were validated in the SLICC registry, an independent inception multiethnic cohort.
Overall, a EULAR/ACR score of ≥20 is an indicator of ominosity in the SLE disease course throughout the first 5 years after diagnosis. Patients with SLE with an EULAR/ACR score of ≥20 had higher AMS scores, lower likelihood of achieving remission, a trend towards a greater number of flares and more need for immunosuppressive therapy. Thus, this new set of classification criteria not only could be helpful in classifying SLE cases but also could provide prognostic information regarding the disease course in the first 5 years following diagnosis.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
The study was approved by the University Health Network Research Ethics Board.
Acknowledgments
We would like to thank the Systemic Lupus Cooperating Clinics for allowing us to use the SLICC inception cohort as a validating cohort for our study.
Dr. Whittall Garcia was supported by the Geoff Carr Lupus fellowship provided by Lupus Ontario.
The Toronto Lupus program is supported by donations from Mark and Diana Bozzo and Marissa and Lu Rocca families.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Handling editor Josef S Smolen
Presented at This work was presented at the American College of Rheumatology Convergence Meeting, November 2020. Whittall-Garcia L, Gladman D, Urowitz M, Su J, Johnson S. The New EULAR/ ACR 2019 SLE Classification Criteria: Defining Ominosity in SLE [abstract]. Arthritis Rheumatol 2020; 72 (suppl 10). https://acrabstracts.org/abstract/the-new-eular-acr-2019-sle-classification-criteria-defining-ominosity-in-sle/.
Correction notice This article has been corrected since it published Online First. The provenance and peer review statement has been included.
Contributors All authors contributed to the study design, data collection and/or evaluation and critical review of the final manuscript.
Funding Support for this study came from the Lupus Program, Centre for Prognosis Studies in the Rheumatic Diseases. SRJ is supported by a Canadian Institutes of Health Research Award. ZT is supported by a research salary award from the Department of Medicine, University of Toronto.
Competing interests SRJ reports grants from Bayer, Boehringer Ingelheim, Corbus, GSK, Roche, Merck and personal fees from Boehringer Ingelheim and Ikaria.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.