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Abstract
Objectives To study the prevalence of remission and its effect on damage and quality of life (QOL) in Chinese patients with systemic lupus erythematosus (SLE).
Methods Patients who fulfilled ≥4 American College of Rheumatology criteria for SLE were identified. Their remission status at last clinic visits was determined by the European consensus criteria (complete/clinical remission ± immunosuppressive drugs). The increase in SLE damage index (SDI) in the preceding 5 years was compared between patients who were and were not in remission for ≥5 years. QOL of patients as assessed by the validated Chinese version of the Medical Outcomes Study Short-Form-36 (SF36) and the LupusPRO was also compared between the remission and non-remission groups by statistical analysis.
Results 769 SLE patients were studied (92% women; age: 46.4±14.6 years; SLE duration: 12.6±8.1 years). At last visit, clinical remission was present in 259 (33.7%) patients and complete remission was present in 280 (36.4%) patients. Clinical and complete remissions for ≥5 years were achieved in 64 (8.3%) and 129 (16.8%) of the patients, respectively. Patients remitted for ≥5 years were older, and had significantly lower prevalence of renal involvement, leucopenia or thrombocytopaenia. Fifty-three (6.9%) patients in remission ≥5 years were taken off all medications, including hydroxychloroquine (HCQ) (drug-free). Patients who remitted for ≥5 years but off-therapy (except HCQ) had significantly less SDI increment than those who did not remit (0.17±0.53 vs 0.67±1.10; p<0.001). Among 453 patients who had QOL assessment, remission for ≥5 years was associated with significantly higher SF36 and the total health-related scores of the LupusPRO.
Conclusions Durable remission can be achieved in a quarter of patients with SLE. Patients with remission for ≥5 years have significantly less damage accrual and better QOL. Prolonged remission is an appropriate criterion for outcome assessment in SLE.
- remission
- damage
- quality of life
- lupus
- Chinese
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Introduction
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease of unclear aetiology. The disease course of SLE is largely unpredictable, with periods of remission and flares, which may affect organs in various combinations.1 2 The consequence of this fluctuating disease course is accrual of organ damage, as a result of disease activity or treatment-related complications. Organ damage in SLE is a major risk factor for further organ damage accrual, deterioration of quality of life (QOL) as well as mortality.3 4
Despite the improvement in survival of SLE patients in the past few decades, the death rate of SLE is still 4–5 times higher than the general population matched for age and gender.5 Early mortality of SLE is often due to infective complications and persistent disease activity (refractory manifestations), whereas late mortality is usually contributed by cardiovascular complications and other comorbidities.6
Treatment of SLE should target at improving long-term survival, preventing organ damage, optimising health-related QOL (HRQOL) by adequate control of disease activity, and reducing treatment-related morbidities and disease-related complications.1 7 Remission of systemic symptoms and organ manifestations is the main treatment target; when remission cannot be reached, the lowest possible disease activity state should be achieved.7
There is still no universal consensus on the definition of clinical remission and low disease activity (LDA) state. Different criteria were used in different studies.8–12 Nevertheless, what is in common in these studies is that remission refers to the lack of clinical activity that warrants change in treatment, regardless of the presence of serological activity and maintenance immunosuppression. Recent cohort studies among Caucasians have demonstrated that long-lasting clinical and serological remission without treatment other than the antimalarials is uncommon in SLE, with figures ranging from 1.7% to 7% for 5 years or more.10 11 13 Non-remission of SLE was associated with more organ damage accrual.8 10 As there are still no data on clinical remission of SLE in Chinese, this study was carried out to evaluate the prevalence of disease remission and its effect on organ damage and QOL in a large cohort of Chinese SLE patients.
Patients and methods
Study design and population
This is a retrospective study of longitudinally collected data from our database. Adult patients (≥18 years of age at entry) who fulfilled the 1997 revised American College of Rheumatology classification criteria for SLE14 were identified from our cohort registry. Patients who were lost to follow-up were excluded. The remission status of these patients during their last clinic visits was defined according to the European consensus criteria (see below).9 The duration of the latest remission status was verified by medical record review. For patients who had an incident flare at the last clinic visit, data were censored at the second last visit. The usual follow-up interval of our patients was 4 months, but more frequent clinic visits would be arranged for those with recent flare, refractory manifestations or complications.
The increase in SLE organ damage index from 5 years prior to the last clinic visits was compared between patients who were and were not in remission for at least 5 years. Data regarding QOL of patients within 6 months of their last visits were also retrieved and compared between the remission and non-remission groups. This study was approved by the ethics committee of our hospital.
Assessment of SLE activity and damage
Disease activity of SLE was assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLE disease activity index (SLEDAI), a validated instrument that was employed in the SELENA trials.15 SELENA-SLEDAI includes the physician’s global assessment (PGA) of disease activity (score 0–3).
Organ damage was assessed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).16 Damage (after SLE diagnosis) has to be present for 6 months or more before it is scored, irrespective of the cause, and be irreversible.
Definition of SLE remission
The definitions of SLE remission were adapted from the European consensus criteria.9 In brief, clinical remission was defined as a clinical SELENA-SLEDAI score equal to 0 and PGA score of <0.5. Complete remission was defined as clinical remission together with inactive lupus serology (anti-dsDNA and complements). These two categories of SLE remission were further divided into those who required ongoing immunosuppressive treatment (prednisolone ≤5 mg/day or equivalent and/or other immunosuppressive agents) and who did not (except hydroxychloroquine (HCQ)).
Anti-dsDNA in our study was measured by a commercially available ELISA kit (Euro Diagnostica). Serum complement levels were assayed by immunoturbidimetry (Abbott Architect).
QOL assessment
The QOL of our patients were assessed by the validated Chinese version of the Medical Outcomes Study Short-Form-36 (SF36)17 and the LupusPRO questionnaires.18
The SF36 is a validated generic self-administrated patient-reported outcome (PRO) instrument.19 It consists of 36 questions that measure patient’s HRQOL in eight domains: physical functioning (PF), role-physical (RP), bodily pain and general health, which represent the physical HRQOL; and vitality, social functioning, role-emotional and mental health (MH), which represent the mental HRQOL. Each domain is scored from 0 (worst health status) to 100 (best health status), and this is linearly transformed into norm-based score using the US general population as a reference (each 10 points from 50 is the SD from the mean). The scores of these domains are summarised into the physical component score (PCS) and mental component score (MCS).
The LupusPRO is an SLE-targeted PRO measure that was developed and validated in the USA.20 It consists of eight health-related domains) and four non-health-related domains to enable an understanding of the broader burden of the disease. The HRQOL domains are SLE symptoms, cognition, SLE medications, physical health (PF and RP), pain vitality (fatigue, sleep), body image, emotional health (emotional function and role-emotional) and procreation (sexual health and reproduction). The non-HRQOL domains are desires/goals, relationship/social support, coping and satisfaction with medical care. The LupusPRO questionnaire has 43 items (30 for HRQOL construct, 13 for non-HRQOL construct). Each item has five options, ranging from ‘none of the time’ to ‘all of the time.’ Individual domains, total HRQOL and non-HRQOL score 0–100, where higher score denotes better QOL.
Statistical analyses
Unless otherwise stated, values in this study were expressed as mean±SD. Comparison of continuous data between the two groups was performed by independent Student's t-test. Categorical variables were compared by the χ2 test, and when the frequency of any cell in the contingency table was ≤5, the Fisher exact test was used. Logistic regression was used to study the OR of having new damage in patients with remission for ≥5 years as compared with the remaining patients, adjusted for age, sex, SLE duration, damage score 5 years prior to the latest visit and the daily maintenance dose of prednisolone at the last visit. Statistical significance was defined as a p value of <0.05, two-tailed. Statistical analyses were performed using SPSS V.16.0 for Windows 8.
Results
Study population and remission status
A total of 840 patients with SLE were identified from our cohort database. Excluding 71 patients who were lost to follow-up, 769 patients were studied (92% women; age: 46.4±14.6 years, SLE duration: 12.6±8.1 years). All were ethnic Chinese. At the last clinic visit, clinical remission (serologically active) was present in 259 (33.7%) patients (median duration: 43 months), and complete remission (clinically and serologically inactive) was present in 280 (36.4%) patients (median duration: 51 months). Clinical and complete remissions for ≥5 years were achieved in 64 (8.3%) and 129 (16.8%) of the patients, respectively. Fifty-three (6.9%) patients in clinical or complete remission ≥5 years were taken off all medications, including HCQ (drug-free remission). Table 1 shows the frequency of the remission status of the patients studied and the duration. In patients with SLE duration of ≥5 years, the frequencies of clinical and complete remission for ≥5 years were 10.4% and 21.0%, respectively. On the other hand, in those with disease duration of ≥7 years, clinical and complete remissions (≥5 years) occurred in 11.7% and 23.6% of the patients, respectively.
Frequency and duration of remission in the studied patients with SLE (n=769)
Clinical manifestations and medications
Table 2 shows the cumulative clinical manifestations of the patients studied according to their remission status. Compared with patients who did not remit at their last clinic visits, those with complete or clinical remission for ≥5 years were older, and had significantly lower prevalence of renal involvement, leucopenia or thrombocytopaenia. The prevalence rates of certain autoantibodies (Ro, La, nRNP) were also significantly lower in the remission (≥5 years) group. At the last visits, significantly fewer patients who remitted for ≥5 years were maintained on prednisolone when compared with the remaining patients (31% vs 68%; p<0.001). For those maintained on prednisolone, the daily dose was also significantly lower in patients who remitted for ≥5 years than all other patients (3.8±2.4 vs 7.7±9.4 mg; p<0.001). Moreover, the use of mycophenolate mofetil, tacrolimus and HCQ, but not azathioprine or ciclosporin, was significantly less frequent in the group with remission ≥5 years than the remaining patients (data not shown).
Organ damage accrual
Cumulative clinical manifestations according to remission status
The increase in SDI scores over the preceding 5 years was 0.17±0.53 in patients who had complete or clinical remission off-therapy (except HCQ) for ≥5 years (n=88), 0.25±0.51 in those remitted for ≥5 years but maintained on immunosuppressive medications (n=105), 0.41±0.84 in those remitted for <5 years (n=346) and 0.67±1.10 in those who did not remit (n=230). The increase in SDI score was significantly lower in patients who remitted for ≥5 years than those who remitted for <5 years (p=0.007) or who did not remit (p<0.001). However, among those who had remission for ≥5 years, the increase in damage accrual was not significantly higher in those who were maintained on immunosuppressive medications than those off-therapy (except HCQ) (0.25±0.51 vs 0.17±0.53; p=0.89). There was also no significant difference in the SDI increase between those with complete remission (n=129) and clinical remission (n=64) for ≥5 years (0.20±0.47 vs 0.23±0.61; p=0.71).
Table 3 shows the logistic regression results of the effect of SLE remission (≥5 years) on the occurrence of new damage score over the preceding 5 years, with adjustment for age, sex, SLE duration, damage score 5 years prior to the last visit and the daily maintenance dose of prednisolone at last visit. Patients with remission (clinical or complete) for <5 years or who did not remit had a 1.42-fold increase in the risk of new damage accrual as compared with those with remission for ≥5 years (OR: 2.42 (1.50–3.89); p<0.001).
Health-related and non-health-related QOL
Effect of SLE remission on new organ damage accrual in 5 years (logistic regression model)
Data regarding QOL of the patients within 6 months of their latest clinic visits were available in 112 patients with remission ≥5 years, 216 patients with remission <5 years and 125 patients with non-remission.
Table 4 shows the results of SF36 assessment in the three groups of patients. Patients with remission (complete or clinical) of 5 years or more had a significantly better QOL than those not in remission, as reflected by significantly higher PCS (59.7±21.8 vs 51.5±22.6; p=0.005) and MCS (59.9±21.4 vs 52.6±21.8; p=0.01) of the SF36. All domains of the SF36, except PF and MH, showed significantly higher scores in patients who remitted for ≥5 years than those without remission.
Quality of life (SF36) in the patients studied according to remission status (complete or clinical) from last clinic assessment
Table 5 shows the results of the LupusPRO assessment in the patients studied. Patients with remission for 5 years or more had significantly higher scores in the health-related domains of the questionnaire than those who did not remit (80.4±14.9 vs 71.7±17.5; p<0.001). All domains, except cognition, showed significantly higher scores in the remission (≥5 years) than non-remission group of patients (figure 1). However, the scores of the non-health-related domains were not significantly different between these two groups of patients.
Quality of life (LupusPRO) in the patients studied according to remission status (complete or clinical) from last clinic assessment
LupusPRO scores in patients who had remission (complete or clinical) for ≥5 years compared with those who did not remit at last clinic assessment.
Discussion
The management of SLE should aim at adequate control of disease activity and minimisation of disease or treatment-related comorbidities and complications. These treatment targets are essential for the minimisation of organ damage, improvement in QOL and ultimately reduction in mortality.1 Consensus statements from Europe and Asia emphasise that remission of systemic symptoms and organ disease activity is the main target of treatment of SLE, or when remission cannot be reached the lowest possible disease activity state should be achieved.7 8 Regular monitoring of SLE disease activity by a validated scale and/or organ-specific parameters and maintenance therapy to prevent disease flare is an important part of the management.
Although disease remission is the main target of SLE treatment, universal agreement on its definition is lacking. An editorial summarised 12 studies regarding SLE remission in the past two decades and concluded that the definitions for disease remission varied substantially, partly contributed by the unavailability of disease activity indices when some of these studies were published.21 Urowitz et al defined SLE remission when the SLEDAI score was 0 and patients were not using immunosuppressive drugs except antimalarials.11 Using this definition, only 1.7% of their 703 patients achieved sustained remission for more than 5 years. An Italian study reported that 7.1% of their 224 SLE patients achieved sustained remission for 5 years or more, which was defined as a SLEDAI score of 0 and the absence of immunosuppressive therapy except HCQ.10 More recently, a study from UK defined complete SLE remission as clinical inactivity (British Isles Lupus Assessment Group scores of C, D and E only), absence of laboratory evidence of serological activity (normal complement and negative anti-dsDNA) and being off treatment except the antimalarial drugs.12 Of 532 patients, 14.5% achieved complete remission for ≥3 years and 4.3% did so for ≥10 years.
Recently, a group of European SLE experts agreed on a set of criteria for defining remission of SLE.9 Essentially, clinical remission refers to the lack of clinical activity that warrants a change in immunosuppressive therapies, as evidenced by a 0 score in the clinical SLEDAI and a PGA score of ≤0.5. When clinical remission is coupled with inactive SLE serology (anti-dsDNA, complements), this is regarded as complete remission. Remission of SLE can be achieved with (remission on treatment) (prednisolone ≤5 mg/day or other immunosuppressive drugs) or without immunosuppressive medications (except HCQ). Using this definition, 11.5% of a cohort of 2745 SLE patients had remission on treatment for at least 1 year and 0.6% had sustained remission for 5 years or more.13 Another multicentre lupus registry cohort reported that 7.6% and 5.4%, respectively, of their 1228 patients had remission on therapy and off therapy for 1 year or more.22 In our study which adopted a similar definition of remission, 25% of SLE patients had remission for ≥5 years, but only 6.9% could achieve this in the absence of immunosuppressive drugs (including HCQ). The rate of remission off-therapy in our patients was similar to that reported by the Italian group10 but appeared to be higher than those reported in the USA. Although the cause for the interstudy discrepancy in SLE remission rates is multifactorial, case-mix of the cohorts with variation in disease severity may contribute. African-American and Hispanic patients generally have more serious SLE manifestations,23 24 and this may lead to the lower remission rates observed in the US cohorts.
An Asian panel defined an LDA state of SLE when the following five criteria were fulfilled: (1) SLEDAI ≤4, with no activity in major organ systems; (2) no new lupus disease activity compared with the previous assessment; (3) PGA ≤1; (4) a current prednisolone (or equivalent) dose of ≤7.5 mg daily; and (5) well-tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents.8 This LDA state encompasses the definitions of clinical or complete remission with and without immunosuppressive drug maintenance by the European group.9 A validation study of 191 SLE patients (52% Caucasians, 36% Asians) showed that 89% achieved LDA for at least one occasion, and the median cumulative duration of LDA among all patients was 1.6 years.8
Disease remission of SLE has been associated with better prognosis in terms of organ damage. In the study by Zen et al 10 unremitted disease and high-dose glucocorticoid therapy were reported to be independent risk factors for damage accrual. Franklyn et al 8 also demonstrated in their study that patients with SLE who had 50% of their follow-up time in LDA had significantly fewer flares and less organ damage accrual. Our finding that patients with remission for less than 5 years were 1.42-fold more likely to accrue organ damage in 5 years’ time was consistent with these two previous reports.
Although the effect of SLE activity on QOL has been reported in the past,25–28 studies had used the SF36 tool, which was not SLE-specific. Moreover, SLE remission was not defined to facilitate evaluation for its contribution to organ damage or QOL. Our study is the first that demonstrated that patients with SLE in remission had better HRQOL, as documented by the LupusPRO questionnaire, which is a validated lupus-specific QOL measurement tool.18 20 This is probably related to less SLE activity and fewer medications (particularly prednisolone, mycophenolate mofetil and tacrolimus) required for disease control, which resulted in a lower likelihood of having disease or treatment-related complications and hence organ damage. Despite HCQ having been shown to be associated with less organ damage and mortality in SLE cohorts,29 30 fewer patients with durable remission in our study were maintained on HCQ. This is probably related to the practice of tapering of medications and request of patients when the disease became quiescent for a long time. Another observation from our study is that damage accrual over time did not differ significantly between patients with complete or clinical remission. This is consistent with the common practice that treatment of SLE should not be targeted at serological activity alone.
The strength of our study is the large sample size and the application of the same criteria for the determination of the remission status of our patients without bias. However, there are some limitations. Our study is retrospective in nature and QOL data were not available in all the patients studied. As we only looked at the duration of remission assessed during the last or second last clinic visits, there existed some patients who had been in remission for quite some time but had incident flares shortly before assessment. These patients were classified as not having durable remission. Furthermore, patients with disease duration of <5 years were included and regarded as not having durable remission. These two factors might have led to an underestimation of the SDI accrual in the groups of patients without durable remission. However, this effect was likely to be modest as the difference in SDI increment between patients with and without durable remission remained highly significant. After all, because of the wax-and-wane nature of SLE disease activity, there are no ideal ways of evaluating the effect of the duration of remission on organ damage and QOL. Summating the total periods of remission during the course of SLE since diagnosis is one suggestion, but patients with multiple scattered periods of remission are clearly different from those with continuous remission for the same duration of time. Our study focused on the characteristics and outcome of patients with durable remission, which is non-ambiguous according to the definition. Thus, the impact of the above methodological issues on the overall results is likely minimal.
We concluded that in southern Chinese patients with SLE, durable disease remission was present in a quarter of patients, the majority of whom required maintenance immunosuppressive medications. Drug-free remission for ≥5 years was uncommon. SLE patients with renal and haematological disease were less likely to have durable remission. Patients who remitted for ≥5 years had less organ damage accrual over time and enjoyed better HRQOL. Prolonged remission is an appropriate criterion for assessing the outcome of SLE in cohort studies and clinical trials. Further prospective studies are valuable in evaluating the effect of disease remission on mortality and organ-specific morbidities.
References
Footnotes
Contributor CCM: design, data collection and interpretation, and statistical analyses; LYH: data collection and interpretation; SMT: data collection and interpretation; KLC: data collection and interpretation.
Competing interests None declared.
Ethics approval Ethics Committee of Tuen Mun Hospital, HK.
Provenance and peer review Not commissioned; externally peer reviewed.