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Abstract
Aim To identify the shortest duration of remission associated with improved outcomes in systemic lupus erythematosus (SLE).
Methods We studied 293 Caucasian patients with SLE during 7-year follow-up. Disease activity was assessed by SLE Disease Activity Index 2000 and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We defined three remission levels: complete, clinical off-corticosteroids, clinical on-corticosteroids (prednisone 1–5 mg/day). The effect of different durations of remission (1, 2, 3, 4 and ≥5 consecutive years) on damage was evaluated by multivariate logistic regression analysis.
Results Among patients achieving 1-year (27 patients), 2-year (47 patients), 3-year (45 patients), 4-year (26 patients) remission, damage was similar irrespective of the level of remission achieved, whereas, among patients achieving ≥5-year remission (113 patients), damage was higher in those in clinical remission on-corticosteroids (p<0.001).
In multivariate analysis, ≥2 consecutive year remission was protective against damage (OR (95% CI)): 2 years 0.228 (0.061 to 0.850); 3 years 0.116 (0.031 to 0.436); 4 years 0.118 (0.027 to 0.519) and ≥5 years 0.044 (0.012 to 0.159). Predictors of damage were cumulative prednisone dose ≥180 mg/month (3.136 (1.276 to 7.707)), antiphospholipid antibody syndrome (5.517 (2.092 to 14.546)), vasculitis (3.107 (1.030 to 9.307)) and number of flare/year (8.769 (1.692 to 45.449)).
Conclusions Two consecutive years is the shortest duration of remission associated with a decrease in damage progression in Caucasian patients with SLE.
- Systemic Lupus Erythematosus
- Outcomes research
- Disease Activity
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Introduction
An increase in short-term and medium-term survival rates has been observed over the past decades in systemic lupus erythematosus (SLE); nevertheless, patients with SLE are still at risk of morbidity and mortality.1
Disease activity is one of the major determinants of organ damage and death in SLE.2–9 In recent years, remission has emerged as a key concept in the management of autoimmune rheumatic diseases. However, a widely accepted definition of remission in SLE has not been identified yet1 ,10 and the effect of different durations of remission on SLE outcomes has never been evaluated.
In a previous study,11 we demonstrated that patients with 5-year remission accrued less damage than unremitted patients.
The aim of the current study was to assess the effect of different durations of remission on damage accrual, in order to identify the shortest duration of remission associated with a decrease in damage progression in SLE.
Patients and methods
Patients diagnosed with SLE and prospectively followed in Padua Lupus Clinic were considered in our study if they satisfied the following inclusion criteria: (1) fulfilment of SLE American College of Rheumatology (ACR) Classification Criteria;12 (2) Caucasian ethnicity; (3) diagnosis of SLE between January 1990 and December 2008; (4) remission lasting <12 months (in order to exclude patients with long-lasting remission at study entry) or presence of active disease at study entry; (5) at least three visits/year, no more than 5 months apart, during the 7-year follow-up (January 2009–December 2015). An incomplete follow-up due to death did not exclude patients from the study. All patients signed the informed consent for the use of clinical and laboratory data for study purposes.
SLE activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K). SLE flares were defined according to SLE flare index13 and antiphospholipid antibody syndrome (APS) according to the revised Sapporo Criteria. The cumulative prednisone dose (milligram/month) taken by the patients before study entry was calculated.
Three levels of remission were defined:11
complete remission: no clinical and serological activity (SLEDAI-2K=0) in corticosteroid-free and immunosuppressant-free patients (antimalarials allowed);
clinical remission off-corticosteroids: serological activity with clinical quiescent disease according to SLEDAI-2K in corticosteroid-free patients (stable immunosuppressive therapy and antimalarials allowed);
clinical remission on-corticosteroids: clinical quiescent disease according to SLEDAI-2K in patients on prednisone 1–5 mg/day (stable immunosuppressants and antimalarials allowed).
We evaluated the effect on damage of different durations of remission: 1, 2, 3, 4 and ≥5 consecutive years. In patients who experienced a relapsing-remitting disease, only the longest period of remission was considered in the analysis.
We also assessed the effect on damage of the cumulative time spent in remission (calculated as the sum of separate periods of remission during the follow-up).
Organ damage was assessed at study entry and at the end of follow-up using the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI).
Statistical analysis
Comparison of continuous data with parametric and non-parametric distribution was performed using t-test and one-way analysis of variance (ANOVA) with Bonferroni's post-hoc analysis or by the Wilcoxon's test and the Kruskal-Wallis test, respectively. Comparison of categorical variables and correlations were performed using χ2 test (Fisher's exact test) and Spearman's test, respectively. Logistic regression was used to assess the association between organ damage accrual and the different levels or durations of remission. Factors with a p<0.2 in univariate analysis were entered into the multivariate model. Backward stepwise multivariate logistic regression was performed with damage accrual considered as a dichotomous dependent variable (ie, SDI increased or not increased during the follow-up), with significance set at 5%. Analyses were performed by the SPSS software for Windows V.22.0 (SPSS, Chicago, Illinois, USA).
Results
Among the 462 consecutive patients who were evaluated, 293 patients (63.1%) fulfilled inclusion criteria.
During the 7-year follow-up, 27 patients (9.2%) achieved 1-consecutive-year remission, 47 patients (16.0%) achieved 2-consecutive-year remission, 45 patients (15.4%) achieved 3-consecutive-year remission, 26 patients (8.9%) achieved 4-consecutive-year remission and 113 patients (38.6%) achieved ≥5-consecutive-year remission. Conversely, 35 patients (11.9%) had never been in remission.
Reasons for exclusion, clinical features and treatment according to the durations of remission are reported in online supplementary text, tables S1 and S2. Demographic characteristics and damage are summarised in table 1.
supplementary text
supplementary table 1
supplementary table 2
Demographic characteristics and damage in total study cohort and in subgroups of patients according to the durations of remission (irrespective of the level of remission) achieved during the follow-up (upper part); damage accrual according to the levels of remission for each duration of remission (lower part)
SDI significantly increased during the 7-year follow-up in the study cohort (p<0.001): the median SDI increase was higher in unremitted patients compared with patients in remission for 2 (p=0.005), 3 (p<0.001), 4 (p=0.001) and ≥5 consecutive years (p<0.001). Conversely, median change in SDI was similar in 1 year remitted and unremitted patients. An inverse correlation between the duration of remission and damage accrual was observed (figure 1A).
Graphs showing the correlation between different durations of remission and damage accrual (A), regression analysis of the impact of different levels of remission on damage accrual (B) and prevalence of the levels of remission according to the duration of remission (C). (A) Correlation between the duration of remission (irrespective of the level of remission) and damage accrual in the study cohort is shown. Damage accrual (y axis) is expressed as mean±SEM. Points stand for mean SDI increase in patients with different durations of remission. (B) Linear regression analysis exploring the relationship between different levels of remission and damage accrual in the study cohort. Damage accrual (y axis) is expressed as mean±SEM. Points stand for mean SDI increase in patients with different levels of remission. (C) Proportion of patients achieving different levels of remission according to the duration of remission is shown. Numbers in brackets represent the number of patients. SDI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index.
The proportion of remitted patients achieving one of the three levels of remission according to the duration of remission is reported in figure 1C and the distribution of different durations and levels of remission in the entire cohort (remitted plus unremitted patients) is reported in online supplementary figure S1. Notably, the longer the duration of remission, the higher the proportion of patients in clinical remission off-corticosteroids or in complete remission (figure 1C).
supplementary figure
Among patients achieving 1, 2, 3 and 4 consecutive years’ remission, damage accrual was similar in patients with complete remission, clinical remission off-corticosteroids or clinical remission on-corticosteroids (table 1). Among patients achieving ≥5-year remission, patients in clinical remission off-corticosteroids or in complete remission accrued less damage (p<0.001) than patients in clinical remission on-corticosteroids. However, when analysed altogether, no difference among the three levels of remission in terms of damage progression was found (figure 1B).
In multivariate analysis, a remission lasting ≥2 consecutive years was protective against damage (table 2); conversely, a cumulative prednisone dose ≥180 mg/month, APS, vasculitis, number of flare/patient/year, disease duration and age were independent predictors of new damage (table 2).
Multivariate analysis: independent risk factors and protective factors for damage accrual over the follow-up
Data on the effect on damage of the cumulative time spent in remission during the follow-up are reported in online supplementary table S3: in multivariate analysis, three cumulative years was the shortest length of remission which was protective against damage.
supplementary table 3
Discussion
One of the major challenges in the management of SLE is to control disease activity and to prevent irreversible organ damage, which impacts on patient quality of life and mortality.14
Several studies showed that disease activity, flares and disease severity are predictors of poor outcomes.2 ,4–9 ,11 By contrast, few data on the beneficial effect of remission on damage are available.2 ,11 ,15
In a previous study,11 we demonstrated that a remission lasting five consecutive years was associated with lower damage accrual in Caucasian patients. However, how long the remission should last to yield significant benefits on patients' outcome has not been evaluated yet.
In this study we showed that a remission of at least two consecutive years had a protective effect on damage accrual. No difference in damage accrual was observed among patients with different levels of remission lasting 1, 2, 3 or 4 years, meaning that the effect on damage of the absence of disease activity is more relevant than the treatment taken by the patient in the short term. By contrast, patients with ≥5-year remission on corticosteroids accrued more damage than other ≥5-year remitted patients who were corticosteroid free which is in keeping with our previous data.11
Thus, the levels of remission seem to have a smaller impact on damage than the duration of remission in the short term, which might be due to the low daily dose of prednisone allowed in our definition of remission on-corticosteroids leading to a low increase in corticosteroid cumulative dose over the follow-up. However, corticosteroids, even at low dose, can contribute to damage progression in the long term (≥5 years).
When looking at the cumulative time spent in remission, we found that a remission lasting at least three cumulative years was needed to protect against damage, which means that a continuous period of remission is more beneficial than the sum of short periods interspersed with flares.
In our cohort, remission was not rare, since only 35 out of 293 patients had never been in remission over the 7-year follow-up. This observation is in keeping with some recent studies which reported a remission rate ranging between 32.5% and 74.4%.16–19 Moroni et al20 found a complete renal remission lasting at least 1 year in 73 of 161 patients (45.3%) with lupus nephritis. Of these, 32 patients (20%) completely withdrew treatment and maintained complete prolonged remission for a median time of 8.5 years.
In keeping with previous studies,5–9 age, disease duration, disease flares and high cumulative corticosteroid dose were independent risk factors for damage accrual in our cohort; in addition, we found that APS was independently associated with damage.
Our study has number of strengths: we studied a large cohort of recently diagnosed patients, prospectively and regularly followed for a 7-year period by the same team; we used a validated definition of remission11 and we evaluated a range of durations of disease remission.
Our study has also some limitations: it is a retrospective analysis carried out in Caucasian patients (thus, our findings cannot be generalised to other ethnic groups) and non-SLE related risk factors for organ damage were not assessed.
In conclusion, a remission of two consecutive years could be considered as a clinically meaningful treat-to-target goal in the management of SLE. Notably, the absence of SLE activity is more relevant than low-dose corticosteroid intake in hindering damage progression in the short term, while in the long term even low-dose corticosteroids can contribute to organ damage.
References
Footnotes
Handling editor Tore K Kvien
Contributors MZ contributed to the conception and design of the work, the follow-up of patients, acquisition, analysis and interpretation of data and drafted the work; LI and MG followed up patients and gave their contribution in drafting the work; SB and FS contributed to the follow-up of patients and helped in the acquisition of data; AG helped in the analysis of data; LP critically revised the final work and AD led the team who followed up patients, designed the work, interpreted the data, drafted and revised the manuscript for important intellectual content. All the authors approved the final version of the manuscript and gave their agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Competing interests None declared.
Patient consent Obtained.
Ethics approval The study was approved by the Ethics Committee of the ‘Azienda Ospedaliera-Università degli Studi di Padova’, Padova, Italy. Participants gave informed consent before taking part to the study.
Provenance and peer review Not commissioned; externally peer reviewed.
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