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Available online at
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Editorial
Is it possible to stop glucocorticoids in systemic lupus?
Since their first use in inflammatory diseases in 1948, gluco-
corticoids (GCs) have remained a cornerstone of the treatment
of systemic lupus erythematosus (SLE). Nowadays, the optimal
management of GCs is one of the most important contemporary
challenges in SLE, as identified by our team from the national ref-
erence center for auto-immune diseases (CRMR RESO/PACIFIC) of
Strasbourg [1]. Our capacity to improve the quality of life of patients
will certainly result from our success in meeting this goal.
As a reminder of the importance of stopping GCs or giving the
lowest possible dose, we can recall the side effects of GCs on car-
diovascular risk, infections or osteoporosis, in particular:
• Early mortality in SLE remains mostly related to disease activ-
ity, but the frequency of late cardiovascular morbi-mortality is
increasing in line with prolonged overall patient survival [2].
Multiple risk factors contribute to this, such as the classical car-
diovascular risk factors, the disease activity, complications and
treatments with GCs as primary contributors [3];
• Infections remain one of the major causes of morbidity and mor-
tality in SLE. Despite the use of immunosuppressive agents, the
use of GCs is still statistically associated with the occurrence of
serious infections in SLE [4];
• Osteoporosis is a source of chronic pain in case of fractures and
disability, which contributes to morbidity. SLE is significantly
associated with lower bone mineral density (BMD) levels and
with an increased fracture risk at all sites [1,5]. It is also important
to remember that the adverse effects of GCs on bone resorption
occur already at a dose of 5 mg/day of prednisone-equivalent [6].
GCs are still broadly used in SLE. In a recent study by the SLICC
group, 81.3% of patients received oral GCs and 26.3% received par-
enteral GCs [7]. In a multicenter study performed in 5 European
countries, 93% of SLE patients with active disease received GCs. In a
recent multicenter Italian inception study, the median cumulative
dose of prednisone was 1 g at baseline, 2.9 g after 1 year, and 5.4 g
after 3 years [8]. Importantly, the initial GC dose is a strong pre-
dictor of the overall GC exposure independently of initial disease
activity.
The use of GCs is strongly associated with treatment centre, age,
ethnicity, sex, disease duration and disease activity [7] and has
been reported as an independent predictor of fatigue in SLE [9].
Importantly, numerous studies have emphasized the risk of dam-
age accrual in SLE patient treated with GC, including with doses “as
low as” 5 mg/day day of prednisone-equivalent. In this context, the
previous treat-to-target recommendations in SLE advocated that
https://doi.org/10.1016/j.jbspin.2020.03.008
1297-319X/© 2020 Published by Elsevier Masson SAS on behalf of Société française de rhumatologie.
Please cite this article in press as: Felten R, Arnaud L. Is it possible to stop glucocorticoids in systemic lupus? Joint Bone Spine (2020),
https://doi.org/10.1016/j.jbspin.2020.03.008
lupus maintenance treatment should aim at the lowest GC dosage
needed to control disease activity, and that, if possible, GCs should
be withdrawn completely. Special tools such as the Glucocorticoid
Toxicity Index have been developed to monitor GC-toxicity in tri-
als. The recent EULAR guidelines for SLE [10] recommend the use of
long-term doses of less than 7.5 mg/day of prednisone-equivalent,
the exact same threshold as what was believed to be a “low-dose”
of GC almost 15 years ago. This strongly questions the validity of
these recommendations.
Some authors have suggested that the use of methylpred-
nisolone infusions could trigger non-genomic effects of GCs and
eventually allow the subsequent use of reduced doses of GC but
there has been not comparative trial to demonstrate the validity
of this strategy. The action of GCs is mediated by genomic effects
dependent on the positive or negative regulation of gene tran-
scription by glucocorticoid receptors (GR) and by non-genomic
effects, depending on the dose used [11]. The non-genomic action
of glucocorticoids is mediated by their binding to glucocorticoid
receptors, in particular membrane receptors, but is also medi-
ated by protein-protein interactions, in particular with calcium
and sodium channels responsible for cell activation. Membrane
and cytosolic receptors are capable of inducing a intracellular sig-
nalling pathway involving various kinases, such as PI-3-kinase,
AKT and MAP Kinases, which are responsible for these effects. A
crucial element is the involvement of non-genomic effects from
30 mg/day of prednisone-equivalent and in particular for dosages
above 100 mg/day, making this mechanism the main mode of
action of corticosteroid pulses [11] (Fig. 1).
A GC-sparing effect has been demonstrated for several immuno-
suppressive agents and biologics [12], with a variable level of
evidence. Unfortunately, several studies have shown that remission
is difficult to achieve in SLE [13,14] despite the availability of those
immunosuppressive agents [15], and up to one third of patients
never discontinue GCs [7]. In an Italian study, damage was higher in
those in clinical remission on versus off GCs (P < 0.001). Low-disease
activity [16] has therefore been suggested as a potential alterna-
tive target when remission [17,18] cannot be achieved, and the
most commonly accepted definition, the lupus low-disease activity
state (LLDAS) incorporates a threshold of 7.5 mg/day of prednisone-
equivalent. It is interesting to note that the definitions of the stages
of disease activity take into account whether or not corticosteroid
therapy is used. The strictest stages of remission correspond to the
total absence of glucocorticoids (Fig. 2).
In a preliminary prospective observational study of 50 patients
(44% of whom had pure class V lupus nephritis) using the
RITUXILUP Trial regimen (intravenous rituximab, intravenous
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Fig. 1. Genomic and non-genomic effects of glucocorticoids.

Fig. 2. Current definitions for remission and low-disease activity in systemic lupus.

methylprednisolone without oral GCs, and mycophenolate), 52%
and 34% of patients attained complete and partial remissions after
1 year, respectively [19]. This demonstrates the feasibility of use
of a limited dose of GCs. Unfortunately, the subsequent and larger
international study by the same group has been terminated early
because of insufficient inclusion. Similarly, we have shown that
some patients with proliferative lupus nephritis could be treated
successfully without any GC at all [20].
More recently a French group showed that patients with qui-
escent SLE who discontinued low-dose prednisone (5 mg/day)
experienced significantly more flares than those who maintained
this treatment [21]. In this monocentric study, SLE patients who
had clinically inactive disease and a stable SLE treatment includ-
ing 5 mg/day prednisone during the year preceding the inclusion
were randomized to go on with prednisone 5 mg/day (n = 61) or
discontinue the treatment (n = 63). The primary endpoint was the
proportion of patient experiencing a flare defined with the SELENA-
SLEDAI flare index (SFI) at 52 weeks. The proportion of patients
experiencing a flare was significantly lower in the maintenance
group as compared with the withdrawal group (4 patients vs. 17;
RR: 0.2 [95% CI: 0.1 to 0.7], P = 0.003) [21]. The interpretation of
the study is difficult and raises several questions including the
risk of potential underestimation of disease activity in apparently
quiescent patients. The identification of patients most at risk of
relapse in whom corticosteroid therapy should not be stopped
shall probably also takes into account the history of the disease
and the occurrence of severe relapses in the past. Further, it is dif-
ficult to conclude whether patients with a history of severe SLE
would benefit from using long-term low-dose GCs. Finally, most
rheumatologists slowly taper GCs before discontinuation and do
not abruptly stop the treatment as proposed in this trial. In a
recent twitter survey (@lupusreference), half of the international
respondants confirmed that, according to them, the maintenance of
low-dose GCs (eg. 5 mg/day of prednisone) was an acceptable alter-
native to the discontinuation of GCs in patients with a history of
severe lupus. Altogether, GCs have an undeniable efficacy in SLE and

Please cite this article in press as: Felten R, Arnaud L. Is it possible to stop glucocorticoids in systemic lupus? Joint Bone Spine (2020),
https://doi.org/10.1016/j.jbspin.2020.03.008
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therefore remain a cornerstone of the treatment of SLE flares. Given
their side effects and their major role in the SLE morbi-mortality,
corticosteroid-sparing strategies should therefore be implemented
to enable the use of the minimal possible dose of GCs for the shortest
duration. Future trials should assess cumulative doses of GCs, use
GC-toxicity index, and incorporate GC-sparing among their main
objectives.
Fundings
None.
Disclosure of interest
Laurent Arnaud is a consultant for Alexion, Amgen, Astra-
Zeneca, GSK, Janssen-Cilag, LFB, Lilly, Menarini France, Medac,
Novartis, Pfizer, Roche-Chugaï, UCB.
The other author declares that he has no competing interest.
Acknowledgements
The authors wish to thank Ms Sylvie Thuong for her invaluable
assistance in the preparation of the manuscript.
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Renaud Felten
Laurent Arnaud ∗
Service de rhumatologie, centre national de référence
des maladies auto-immunes et systémiques rares
Est/Sud-Ouest (RESO), centre hospitalier universitaire
de Strasbourg, 1, avenue Molière, 67098 Strasbourg,
France
∗ Corresponding
author.
E-mail address: Laurent.arnaud@chru-strasbourg.fr
(L. Arnaud)
Accepted 18 March 2020
Available online xxx