You are here

  • Home
  • Archive
  • Volume 5, Issue 2
  • Glucocorticoid withdrawal in systemic lupus erythematosus: are remission and low disease activity reliable starting points for stopping treatment? A real-life experience

Article Text

Article menu

Download PDFPDF

Lupus
Original article
Glucocorticoid withdrawal in systemic lupus erythematosus: are remission and low disease activity reliable starting points for stopping treatment? A real-life experience
  1. Chiara Tani1,
  2. Elena Elefante1,
  3. Viola Signorini1,
  4. Dina Zucchi1,
  5. Valentina Lorenzoni2,
  6. Linda Carli1,
  7. Chiara Stagnaro1,
  8. Francesco Ferro1 and
  9. Marta Mosca1
  1. 1Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
  2. 2Institute of Management, Scuola Superiore Sant'Anna, Pisa, Italy
  1. Correspondence to Marta Mosca; marta.mosca{at}med.unipi.it

Abstract

Objectives To evaluate the proportion of patients who have successfully withdrawn glucocorticoids (GCs) in a longitudinal cohort of patients with systemic lupus erythematosus (SLE) over a period of 6 years; to evaluate patient characteristics during GC withdrawal in relation to existing definitions of remission and Lupus Low Disease Activity State (LLDAS); and to evaluate the occurrence of flares after GC withdrawal.

Methods Patients who attempted GC withdrawal were identified for the cohort, and the following information was assessed during withdrawal attempts: date of last disease flare, disease activity and damage and ongoing treatment. Information regarding the occurrence of disease flares after GC withdrawal was also recorded for patients who successfully stopped treatment.

Definitions of remission were applied to GC withdrawal in line with European consensus criteria (Definitions of remission in SLE [DORIS]) and LLDAS in line with the Asian Pacific Lupus Consortium definition.

Results 148 patients were involved in the study; GC withdrawal was attempted in 91 patients (61.5%) with 77 patients (84.6%) successfully stopping GCs. At the beginning of the GC reduction, the majority of patients were in complete or clinical remission (48.9% and 39.6%, respectively). Disease activity was significantly lower in patients who successfully stopped GCs, and the proportion of patients in complete remission was higher (54.2%) with respect to patients who failed in their attempt. Among patients who stopped GCs, 18 flares were recorded after a median of 1 year. The time period since the last flare was shorter in patients who experienced flares with respect to patients who did not flare (mean 0.93 years vs 6.0, p<0.001).

Conclusions GC withdrawal is an achievable goal in SLE and may be attempted after a long-term remission or LLDAS to protect the patient from disease flares.

  • glucocorticoids
  • remission
  • low disease activity state

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2019-000916

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Key messages

    What is already known about this subject?

    • At present, the decision to withdraw glucocorticoids (GCs) in systemic lupus erythematosus (SLE) is left to the judgement and experience of the treating physician who is required to weigh up the individual risk of disease flares against GC-related damage.

    • A significant proportion of patients are kept on GCs by their treating physician despite clinical remission, particularly if there is a history of severe organ involvement.

    What does this study add?

    • We demonstrated that GCs tapering and complete withdrawal is an achievable goal in patients with SLE.

    How might this impact on clinical practice?

    • Long-term remission or Lupus Low Disease Activity State can be considered a reliable starting point for GCs tapering.

    • Disease flares after GCs withdrawal are not common, and they can occur both early and a long time after stopping GCs.

    Introduction

    Glucocorticoids (GCs) have been used in systemic lupus erythematosus (SLE) treatment since the late 1940s1 and still remain a cornerstone of SLE treatment despite advances in immunosuppressive therapies.

    While pulse GCs are able to rapidly control disease activity, their effect is not maintained in the long term. Therefore, a chronic low-dose treatment is continued for many years,2 particularly in patients with a relapsing–remitting course who experience several disease flares.

    Observations of SLE cohorts demonstrate that up to 88% of patients are treated with GCs, and between 57% and 86% of patients undergo long-term treatment.1 3 4

    In a recent survey of existing practice patterns in the treatment of patients with SLE by Canadian rheumatologists, approximately one-quarter of responders stated that they prescribed low-dose prednisone indefinitely to approximately 6%–10% of their patients.5

    Chronic GC therapy is, however, associated with many side effects, in particular an increased risk of osteoporosis and avascular osteonecrosis, infections, diabetes, cardiovascular disease, cataract and glaucoma and also neuropsychiatric disorders, such as depression, hypomania and overt psychosis.6–11

    Thus, treat-to-target recommendations suggest GC withdrawal where possible, or alternatively dosage reduction to ≤5 mg prednisone equivalent/day as an important target of the treatment plan.12

    Strategies aimed to reduce GC use through the universal prescription of hydroxychloroquine, the early use of immunosuppressive drugs together with the use of pulses of GCs and maintenance therapy with ≤5 mg/day have demonstrated success in reducing GC-related damage without increasing damage due to SLE.13

    Some studies have reported complete GC withdrawal, especially in lupus nephritis (LN).14–19 There is, however, a lack of data available in terms of which patients may represent ideal candidates for GC withdrawal and how to carry out a GC withdrawal programme.

    At present, in the majority of cases, the decision to withdraw GCs is left to the judgement and experience of the treating physician who is required to weigh up the individual risk of disease flares against GC-related damage.

    For LN, European Renal Association–European Dialysis and Transplant Association (EULAR-ERA/EDTA) recommendations suggest that a gradual withdrawal of GCs is attempted in patients who have been in remission for at least 3 years after induction therapy.20

    According to a recent internet-based survey of 130 clinicians from 30 countries, a longer duration of clinical remission (>5 years) with normal serology is associated with approximately a 35% likelihood of GC withdrawal; however, a significant proportion of patients are kept on GCs by their treating physician despite clinical remission, particularly if there is a history of severe organ involvement. From the same survey, serology emerged as the main influencer for the physician’s decision to withdraw GCs.21

    Definitions of remission and low disease activity have recently been developed in SLE.22 23 This study’s hypothesis is that such conditions might also represent the optimal moment to begin steroid withdrawal in clinical practice.

    This study aims to: evaluate the proportion of patients who successfully withdraw GCs in a prospective cohort of SLE patients over a period of 6 years; evaluate the main characteristics of patients at GC withdrawal in terms of existing definitions of remission and low disease activity (Lupus Low Disease Activity State (LLDAS)); and evaluate the occurrence of flares after GC withdrawal.

    Methods

    This study is a retrospective analysis of prospectively collected data from a monocentric longitudinal cohort of patients with SLE that began in 2012. Patients fulfilling the 1997 revised ACR criteria for SLE were enrolled in this cohort. Patients were considered eligible according to the following criteria:

    • Undergoing ongoing GC therapy at study baseline (2012).

    • Having at least two assessments/year from 2012 to 2017.

    • Completing clinical and serological data (anti-dsDNA, C3 and C4) at each specialist appointment.

    Ethical approval for this study was obtained from the Institutional Review Board and a local ethics committee approved the study; each patient signed the informed consent for the use of clinical and laboratory data for study purposes.

    Definitions and outcomes

    Patients who attempted GC withdrawal have been categorised into two groups: successful withdrawal and unsuccessful withdrawal. Withdrawal was defined successful when a patient was able to reduce the dosage of GC until complete stopping without having disease flares during the dose reduction.

    Last disease flare, disease activity and damage and ongoing treatment were assessed for these patients; the occurrence of disease flares after GC withdrawal was recorded for the patients who successfully stopped treatment.

    Disease activity was assessed at each visit using the Safety of Estrogens in Lupus Erythematosus National Assessment -systemic lupus erythematosus disease activity index (SELENA-SLEDAI), while organ damage was assessed annually with the American College of Rheumatology/Systemic Lupus International Collaborating Clinics Damage Index (ACR-SLICC/DI); remission has been defined according to European consensus criteria (DORIS) and low disease activity (LLDAS) defined according to Asian Pacific Lupus Consortium criteria.22 23 Considering the overlapping between the LLDAS and remission definitions, in the cohort description, patients fulfilling LLDAS but not remission criteria (LLDAS not remission) and patients fulfilling both criteria were indicated separately.

    Disease flares have been defined according to the SELENA-SLEDAI flare index as mild/moderate flares or severe flares.

    The treating physician decided when and how to stop GC in agreement with the patient, and there was not a predefined protocol for GC tapering.

    Statistical analysis

    Variables were described in terms of mean and SD or median and 25th–75th percentiles depending on variable distribution. T-test and the non-parametric Wilcoxon test have been used to investigate differences between groups of patients. Cross-tabulated data have been analysed by χ2 test or Fisher’s test when the expected cell count was less than 5.

    The association between successful GC withdrawal and the occurrence of flares and different types of disease status, disease activity, organ damage and duration from last flare has been evaluated by logistic regression analysis. The following variables were included in the univariate analysis: age, disease duration, complete remission on treatment (yes/no), clinical remission on treatment (yes/no), SLEDAI at the physician’s decision to stop GC, baseline SLICC, duration from last flare, type of organ involvement (cumulative) and ongoing therapy at the physician’s decision to stop GC.

    The same variables were considered for the derivation of a propensity score used to estimate the adjusted probability of experiencing a flare between the subgroup of GC-free patients versus the rest of the cohort.

    Factors with a p<0.1 at univariate analysis were considered for inclusion into multivariate models.

    Statistics were performed using the STATA software. P values less than 0.05 were considered statistically significant.

    Results

    From the whole cohort (n=310), GC-free patients at the cohort entry (n=47), patients with incomplete follow-up (n=53) and patients with incomplete data (n=30) have been excluded from this analysis. A total of 148 patients have been included. Their epidemiological and clinical characteristics at study entry are summarised in table 1. In short, patients were predominantly Caucasians (98.6%), at study entry the mean age was 42.2±12.5 and disease duration was 13.9±9.1 years; as expected, musculoskeletal manifestations (76.3%) were the most prevalent manifestations during the disease course and approximately half the patients had a history of haematological, cutaneous or renal manifestations (57.5%, 56.2% and 53.4%, respectively).

    View this table:
    Table 1

    Characteristics of the cohort

    Clinical characteristics at GC withdrawal

    GC withdrawal was attempted in 91 patients (61.5%) during the 6 years of follow-up; the median daily dosage of GC in use when GC tapering was started was 5 mg/prednisone equivalent (IQR 2.5–5), and the median time required to completely withdrawn GC resulted 11 months (IQR 6–15).

    GCs were successfully stopped in 77 patients (84.6%), while 14 (15.4%) patients were not able to discontinue treatment due to symptom flares during the period of reduction (mainly arthralgias and fatigue). The mean yearly rate of GC discontinuation therefore resulted in 8.7%.

    Table 2 reports the characteristics of patients for whom GC withdrawal was attempted at the time of the physician’s decision. Patients who attempted GC withdrawal were slightly younger (mean 40.7±12 years vs 44.6±13, p=0.06) with less organ damage (mean SLICC 0 0–1) vs 1 0–2), p=0.033), while disease duration was similar to the group who had never attempted GC withdrawal.

    View this table:
    Table 2

    Characteristics of patients at the physician’s decision to stop GCs

    When physicians opted to begin GC reduction, disease activity was generally low (median SLEDAI 2 (0–2)), and only a few patients (6.6%) had SLEDAI >4. The majority of patients were in LLDAS (97%); among those, complete remission or clinical remission were fulfilled in 48.9% and 39.6%, respectively, while only a minority were in LLDAS but not in remission (9.9%).

    When comparing patients who successfully stopped GCs with patients who failed in their attempt, disease activity when the physician decided to begin GC reduction was significantly lower in the first group (mean SLEDAI 1.31±1.1 vs 2.57±2.1, p=0.01); indeed, the proportion of patients in complete remission was higher (54.2%) in patients who successfully stopped GCs, while fewer patients were on clinical remission (37.3%) or in LLDAS (6.8%). By logistic regression, the state of being in complete remission and the SLEDAI score were associated with an increased likelihood of successfully stopping GCs (OR 4.29, p=0.035; OR 0.7, p=0.023 4.4, respectively); however, at the multivariate analysis, this significance is lost (table 3).

    View this table:
    Table 3

    Univariate and multivariate analysis for predictors of successful GC stopping and flares after GC withdrawal

    Moreover, in patients who successfully stopped GCs, the time period since the last flare was longer (5.21±0.64 vs 4.57±1.45 years), even though this difference was not statistically significant (table 2).

    Flares after GC withdrawal

    For those patients who successfully stopped GCs, over a median follow-up period of about 2 years a total of 18 flares were recorded involving 23% of patients.

    In the subgroup of patients who had never attempted GC withdrawal during the 6-year period of follow-up, about 69.8% of patients experiences at least one flare; in particular, a total of 46 flares were recorded and four patients were chronically active.

    Attempting to compare the probability of experiencing a flare in the GC-free subgroup versus patients who had never attempted GC withdrawal over the whole 6-year follow-up period and using a propensity score adjustment, probabilities were significantly different with a mean difference of about −19.9 (95% CI −36.4 to −0.03).

    For patients who successfully stopped GCs, in 13 cases (72.2%) flares were mild, while in five cases (27.7%), a major flare occurred. Moreover, the reintroduction of GCs was necessary in almost all patients (94.4%). Flares were articular in six cases (33.3%), cutaneous in three cases (16.6%), renal in four cases (22.2%), haematological in three cases (16.6%), serositis in one case (5.5%) and neurological in one case (5.5%). Flares occurred after a median of 1 (0–2) year after GC withdrawal and after a maximum of 5 years.

    Table 2 reports characteristics of patients at the physician’s decision to stop GCs who experienced flares in comparison with the whole group. In short, patients who experienced a disease flare after GC withdrawal presented a higher disease activity (as expressed by the mean SLEDAI and the percentage of patients with SLEDAI >4) when the physician decided to start GC withdrawal.

    The time period since the last flare was shorter in patients who flared (median 21–4 vs median 42–9 years, p<0.001); lower SLEDAI scores and longer time period from the last flare were associated with lower likelihood of flare after GC withdrawal (OR 1.43, p=0.031 and OR 0.78, p=0.033 respectively); no differences were observed in terms of disease status or ongoing treatments at the time of GC withdrawal.

    In the multivariate analysis, only the time period since the last flare remained the most important determiner of disease flare (table 3).

    Discussion

    GC tapering and withdrawal are considered one of the main targets of SLE management. While GC tapering is a well-consolidated practice in SLE management, there is little guidance in terms of how and when to stop GCs; thus, the decision to begin GC withdrawal is determined principally by the physician’s experience.

    A recent survey showed that clinicians’ preferences in withdrawing GCs in patients with SLE in clinical remission are highly variable: serological abnormalities, previous disease severity and duration of remission are the most recurrent variables that influence this decision.21

    Definitions for disease remission and LLDAS have recently been proposed and validated as meaningful targets to be pursued in SLE management; indeed, sustained remission and LLDAS have been associated with less organ damage accrual and better quality of life.15 24–30 This study’s hypothesis is therefore that such conditions might also be considered an effective starting point for GC withdrawal in clinical practice.

    The aim of this study is to describe GC withdrawal rate in a real-life setting of patients with SLE as well as the variables that most likely influenced the decision to stop GCs and the occurrence of flares after GC withdrawal; this study also aims to assess the possible role of LLDAS and remission definitions to start GC withdrawal.

    This study found that GC withdrawal was attempted in the majority of patients in this cohort during the observation period (61.5%), and in many cases (85.7%), GC withdrawal was successful, thus demonstrating that GC-free remission is an achievable goal in SLE; indeed, only 15.4% of patients failed to stop GCs due to the emergence of subjective complaints (fatigue and arthralgia) or a disease flare during reduction.

    Overall, the patients at study entry were young, with a long disease duration and a full-blown disease history making this cohort well representative of the disease in Caucasian patients.

    Data on the frequency of GC withdrawal in SLE are scarce and extremely heterogeneous; the main literature is summarised in table 4.14–17 24 31–34 The prevalence of GC-free patients in SLE cohorts is highly variable in the literature; one of the lowest frequencies is reported by Steiman et al, who described prolonged remission lasting for ≥5 years while taking no medications in less than 3% of the cohort;15 similarly, Zen et al31 and Urowitz et al32 reported a frequency of GC-free patients of less than 10%.

    View this table:
    Table 4

    Frequency of GCs-free patients in the cohorts reported in the literature

    In 2013, Zahr et al reported that the dose of prednisone was reduced to <5 mg/day in 11% of the visits of the Hopkins Lupus cohort and 55% of patients successfully remained below 5 mg for at least 1 year; ongoing cutaneous or arthritis activity were associated with unsuccessful reduction, while lack of disease activity was the only major clinical variable that significantly predicted successful reduction.35

    A greater experience can be found in LN, where GC withdrawal seems to be more common; the first successful experience of GC withdrawal in LN was reported by Ponticelli et al in 198836; thereafter, the same group confirmed the results in a larger study with long-term follow-up where 32% of patients were able to completely withdraw GCs and immunosuppressive drugs. Interestingly, Moroni et al did not find significant differences in the clinical presentation, histological characteristics or the type of induction therapy between patients who were able to stop treatment and those who were not, with the exception of a higher activity index in the latter.16

    In this cohort, we observed a higher percentage of patients in whom GC withdrawal is attempted, which may reflect the increasing knowledge of the long-term harm of even low-dose chronic GC use; this is in line with observations by Zahr et al on the increase of the successful tapering of GCs since the year 2000.35

    These data could be reinforced by the observation that in the majority of our cases GC tapering has been successful and that disease flares after GC withdrawal have been rare and in the majority of the cases mild.

    By analysing the physician’s triggers for GC withdrawal, this study found that remission (particularly complete remission) is the main driver for attempting GC tapering, while only a minority of patients were presenting some degree of clinical manifestations. At the physician’s decision to stop GCs, about one-third of the patients was on immunosuppressants and/or biologicals, thus demonstrating that GC withdrawal can be considered a priority compared with immunosuppressants. Moreover, 76% of patients were on hydroxychloroquine (HCQ), and no differences were observed in term of successful GC withdrawal and risk of flare between HCQ users or not. Considering the importance of HCQ for the disease activity control, one could argue that even more successful GC withdrawal would be expected by increasing the percentage of patients taking this drug.

    Data concerning disease flares also confirmed the importance of conducting a disease activity assessment before GC withdrawal; indeed, the risk of flare was significantly influenced by disease activity at the time of the decision to stop GCs.

    The time period since the last flare represented another significant factor in the risk of flaring after GC withdrawal. The importance of remission duration as a fundamental driver for a successful outcome is well documented in the literature.24 25 27 32

    Interestingly, the state of being in clinical remission, in complete remission or in LLDAS at the time of the physician’s decision to stop GCs does not constitute a different risk in terms of disease flare; this is a crucial point demonstrating that all such conditions might be similarly considered a valid starting point for treatment tapering and withdrawal.

    Important information for a successful GC withdrawal in clinical practice can be drawn from the above data: the ideal situation to start GC withdrawal is a patient with low disease activity and who has not experienced a recent disease flare; therefore, sustained disease remission or LLDAS constitutes optimal conditions for considering to start treatment tapering.

    The limitations of this study are as follows: first, the follow-up after GC withdrawal is variable and short on average (1–5 years), thus late flares might be missed by the analysis. Moreover, our data are derived from a real-life practice from a tertiary referral centre enrolling mainly Caucasian patients; thus, their direct applicability could be limited to this setting. Lastly, we have to acknowledge that the relatively small sample size (especially in subgroups analysis) could be a limitation by inflating the risk of a type I error.

    Despite such limitations, we hope that these data might be useful to treating physicians as an initial input on when the right moment could be to attempt GC withdrawal.

    In conclusion, GC tapering and complete withdrawal can be achievable and sustainable in patients with SLE and might be attempted after a long-term remission or LLDAS to protect the patient as much as possible from disease flares. Disease flares are not common in this subset of patients and can occur both early and a long time after stopping GCs, thus, close disease monitoring after GC withdrawal is necessary.

    Acknowledgments

    We would like to thank all the clinicians and the nurses of the Rheumatology Unit of Pisa who cared for the patients enrolled in this study. Data from this study were presented in part at the 2018 American college of Rheumatology/Association of Rheumatology Professionals

    (ACR/ARHP) annual meeting: Signorini V, Tani C, Elefante E, Stagnaro C, Carli L, Mosca M. Glucocorticoid Withdrawal in Systemic Lupus Erythematosus: Are Remission and Low Disease Activity Reliable Starting Points for Stopping Therapy? a Real-Life Experience. Arthritis Rheumatol 2018; 70 (suppl 10).

    References

    1. 1.↵
      1. Mosca M,
      2. Tani C,
      3. Carli L, et al
      . Glucocorticoids in systemic lupus erythematosus. Clin Exp Rheumatol2011;29(5 Suppl 68):S126–9.
      OpenUrlPubMed
    2. 2.↵
      1. Little J,
      2. Parker B,
      3. Lunt M, et al
      . Glucocorticoid use and factors associated with variability in this use in the systemic lupus international collaborating clinics inception cohort. Rheumatology2018;57:677–87.doi:10.1093/rheumatology/kex444
      OpenUrl
    3. 3.↵
      1. Gladman DD,
      2. Urowitz MB,
      3. Rahman P, et al
      . Accrual of organ damage over time in patients with systemic lupus erythematosus. J Rheumatol2003;30:1955–9.
      OpenUrlAbstract/FREE Full Text
    4. 4.↵
      1. Zonana-Nacach A,
      2. Barr SG,
      3. Magder LS, et al
      . Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum2000;43:1801–8.doi:10.1002/1529-0131(200008)43:8<1801::AID-ANR16>3.0.CO;2-O
      OpenUrlCrossRefPubMedWeb of Science
    5. 5.↵
      1. Keeling SO,
      2. Bissonauth A,
      3. Bernatsky S, et al
      . Practice variations in the diagnosis, monitoring, and treatment of systemic lupus erythematosus in Canada. J Rheumatol2018;45:1440–7.doi:10.3899/jrheum.171307
      OpenUrlAbstract/FREE Full Text
    6. 6.↵
      1. van Staa TP,
      2. Leufkens HGM,
      3. Cooper C, et al
      . The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int2002;13:777–87.doi:10.1007/s001980200108
      OpenUrlCrossRefPubMedWeb of Science
    7. 7.↵
      1. Dixon WG,
      2. Abrahamowicz M,
      3. Beauchamp M-E, et al
      . Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested case-control analysis. Ann Rheum Dis2012;71:1128–33.doi:10.1136/annrheumdis-2011-200702
      OpenUrlAbstract/FREE Full Text
    8. 8.↵
      1. Raúl Ariza-Andraca C,
      2. Barile-Fabris LA,
      3. Frati-Munari AC, et al
      . Risk factors for steroid diabetes in rheumatic patients. Arch Med Res1998;29:259–62.
      OpenUrlPubMedWeb of Science
    9. 9.↵
      1. Bruce IN
      . 'Not only… but also': factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus erythematosus. Rheumatology2005;44:1492–502.doi:10.1093/rheumatology/kei142
      OpenUrlCrossRefPubMedWeb of Science
    10. 10.↵
      1. Bhangle SD,
      2. Kramer N,
      3. Rosenstein ED
      . Corticosteroid-induced neuropsychiatric disorders: review and contrast with neuropsychiatric lupus. Rheumatol Int2013;33:1923–32.doi:10.1007/s00296-013-2750-z
      OpenUrlCrossRefPubMed
    11. 11.↵
      1. Alderaan K,
      2. Sekicki V,
      3. Magder LS, et al
      . Risk factors for cataracts in systemic lupus erythematosus (SLE). Rheumatol Int2015;35:701–8.doi:10.1007/s00296-014-3129-5
      OpenUrl
    12. 12.↵
      1. van Vollenhoven RF,
      2. Mosca M,
      3. Bertsias G, et al
      . Treat-to-target in systemic lupus erythematosus: recommendations from an international Task Force. Ann Rheum Dis2014;73:958–67.doi:10.1136/annrheumdis-2013-205139
      OpenUrlAbstract/FREE Full Text
    13. 13.↵
      1. Ruiz-Arruza I,
      2. Lozano J,
      3. Cabezas-Rodriguez I, et al
      . Restrictive use of oral glucocorticoids in systemic lupus erythematosus and prevention of damage without worsening long-term disease control: an observational study. Arthritis Care Res2018;70:582–91.doi:10.1002/acr.23322
      OpenUrl
    14. 14.↵
      1. Drenkard C,
      2. Villa AR,
      3. García-Padilla C, et al
      . Remission of systematic lupus erythematosus. Medicine1996;75:88–98.doi:10.1097/00005792-199603000-00005
      OpenUrlCrossRefPubMedWeb of Science
    15. 15.↵
      1. Steiman AJ,
      2. Urowitz MB,
      3. Ibañez D, et al
      . Prolonged clinical remission in patients with systemic lupus erythematosus. J Rheumatol2014;41:1808–16.doi:10.3899/jrheum.131137
      OpenUrlAbstract/FREE Full Text
    16. 16.↵
      1. Moroni G,
      2. Longhi S,
      3. Giglio E, et al
      . What happens after complete withdrawal of therapy in patients with lupus nephritis. Clin Exp Rheumatol2013;31:S75–81.
      OpenUrl
    17. 17.↵
      1. Moroni G,
      2. Gallelli B,
      3. Quaglini S, et al
      . Withdrawal of therapy in patients with proliferative lupus nephritis: long-term follow-up. Nephrol Dial Transplant2006;21:1541–8.doi:10.1093/ndt/gfk073
      OpenUrlCrossRefPubMedWeb of Science
    18. 18.↵
      1. Moroni G,
      2. Gatto M,
      3. Raffiotta F, et al
      . Can we withdraw immunosuppressants in patients with lupus nephritis in remission? an expert debate. Autoimmun Rev2018;17:11–18.doi:10.1016/j.autrev.2017.11.003
      OpenUrl
    19. 19.↵
      1. Mosca M,
      2. Tani C,
      3. Aringer M
      . Withdrawal of therapy in non-renal systemic lupus erythematosus: is this an achievable goal?Clin Exp Rheumatol2013;31(4 Suppl 78):S71–4.
      OpenUrlPubMed
    20. 20.↵
      1. Bertsias GK,
      2. Tektonidou M,
      3. Amoura Z, et al
      . Joint European League against rheumatism and European renal Association–European dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis2012;71:1771–82.doi:10.1136/annrheumdis-2012-201940
      OpenUrlAbstract/FREE Full Text
    21. 21.↵
      1. Ngamjanyaporn P,
      2. McCarthy EM,
      3. Sergeant JC, et al
      . Clinicians approaches to management of background treatment in patients with SLE in clinical remission: results of an international observational survey. Lupus Sci Med2017;4:e000173.doi:10.1136/lupus-2016-000173
    22. 22.↵
      1. van Vollenhoven R,
      2. Voskuyl A,
      3. Bertsias G, et al
      . A framework for remission in SLE: consensus findings from a large international Task Force on definitions of remission in SLE (DORIS). Ann Rheum Dis2017;76:554–61.doi:10.1136/annrheumdis-2016-209519
      OpenUrlAbstract/FREE Full Text
    23. 23.↵
      1. Franklyn K,
      2. Lau CS,
      3. Navarra SV, et al
      . Definition and initial validation of a lupus low disease activity state (LLDAS). Ann Rheum Dis2016;75:1615–21.doi:10.1136/annrheumdis-2015-207726
      OpenUrlAbstract/FREE Full Text
    24. 24.↵
      1. Petri M,
      2. Magder LS
      . Comparison of remission and lupus low disease activity state in damage prevention in a United States systemic lupus erythematosus cohort. Arthritis Rheumatol2018;70:1790–5.doi:10.1002/art.40571
      OpenUrl
    25. 25.↵
      1. Tsang-A-Sjoe MWP,
      2. Bultink IEM,
      3. Heslinga M, et al
      . Both prolonged remission and lupus low disease activity state are associated with reduced damage accrual in systemic lupus erythematosus. Rheumatology2017;56:121–8.doi:10.1093/rheumatology/kew377
      OpenUrlCrossRefPubMed
    26. 26.↵
      1. Zen M,
      2. Iaccarino L,
      3. Gatto M, et al
      . Lupus low disease activity state is associated with a decrease in damage progression in Caucasian patients with SLE, but overlaps with remission. Ann Rheum Dis2018;77:104–10.doi:10.1136/annrheumdis-2017-211613
      OpenUrlAbstract/FREE Full Text
    27. 27.↵
      1. Zen M,
      2. Iaccarino L,
      3. Gatto M, et al
      . The effect of different durations of remission on damage accrual: results from a prospective monocentric cohort of Caucasian patients. Ann Rheum Dis2017;76:562–5.doi:10.1136/annrheumdis-2016-210154
      OpenUrlAbstract/FREE Full Text
    28. 28.↵
      1. Tselios K,
      2. Gladman DD,
      3. Touma Z, et al
      . Clinical remission and low disease activity outcomes over 10 years in systemic lupus erythematosus. Arthritis Care Res2018. doi:doi:10.1002/acr.23720
    29. 29.↵
      1. Mok CC,
      2. Ho LY,
      3. Tse SM, et al
      . Prevalence of remission and its effect on damage and quality of life in Chinese patients with systemic lupus erythematosus. Ann Rheum Dis2017;76:1420–5.doi:10.1136/annrheumdis-2016-210382
      OpenUrlAbstract/FREE Full Text
    30. 30.↵
      1. Golder V,
      2. Kandane-Rathnayake R,
      3. Hoi AY-B, et al
      . Association of the lupus low disease activity state (LLDAS) with health-related quality of life in a multinational prospective study. Arthritis Res Ther2017;19.doi:10.1186/s13075-017-1256-6
    31. 31.↵
      1. Zen M,
      2. Iaccarino L,
      3. Gatto M, et al
      . Prolonged remission in Caucasian patients with SLE: prevalence and outcomes. Ann Rheum Dis2015;74:2117–22.doi:10.1136/annrheumdis-2015-207347
      OpenUrlAbstract/FREE Full Text
    32. 32.↵
      1. Urowitz MB,
      2. Feletar M,
      3. Bruce IN, et al
      . Prolonged remission in systemic lupus erythematosus. J Rheumatol2005;32:1467–72.
      OpenUrlAbstract/FREE Full Text
    33. 33.↵
      1. Formiga F,
      2. Moga I,
      3. Pac M, et al
      . High disease activity at baseline does not prevent a remission in patients with systemic lupus erythematosus. Rheumatology1999;38:724–7.doi:10.1093/rheumatology/38.8.724
      OpenUrlCrossRefPubMedWeb of Science
    34. 34.↵
      1. Pons-Estel BA,
      2. Catoggio LJ,
      3. Cardiel MH, et al
      . The GLADEL multinational Latin American prospective inception cohort of 1,214 patients with systemic lupus erythematosus: ethnic and disease heterogeneity among "Hispanics". Medicine2004;83:1–17.doi:10.1097/01.md.0000104742.42401.e2
      OpenUrlCrossRefPubMedWeb of Science
    35. 35.↵
      1. Zahr ZA,
      2. Fang H,
      3. Magder LS, et al
      . Predictors of corticosteroid tapering in SLE patients: the Hopkins lupus cohort. Lupus2013;22:697–701.doi:10.1177/0961203313490434
      OpenUrlCrossRefPubMedWeb of Science
    36. 36.↵
      1. Ponticelli C,
      2. Moroni G,
      3. Banfi G
      . Discontinuation of therapy in diffuse proliferative lupus nephritis. Am J Med1988;85.doi:10.1016/S0002-9343(88)80366-8

    Footnotes

    • Contributors All authors substantially contributed to the planning and carrying out of the study. VL performed the statistical analysis. The manuscript was written by CT, DZ and MM and subsequently revised critically by all the remaining coauthors (VS, EE, LC and CS).

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval Comitato Etico Area Vasta Nord Ovest.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All data relevant to the study are included in the article or uploaded as supplementary information.