Glucocorticoids in Systemic Lupus Erythematosus. Ten Questions and Some Issues
Glucocorticoids in Systemic Lupus Erythematosus. Ten Questions and Some Issues
Glucocorticoids in Systemic Lupus Erythematosus. Ten Questions and Some Issues
Clinical Medicine
Review
Glucocorticoids in Systemic Lupus Erythematosus.
Ten Questions and Some Issues
Sabrina Porta 1 , Alvaro Danza 2 , Maira Arias Saavedra 1 , Adriana Carlomagno 2 ,
María Cecilia Goizueta 3 , Florencia Vivero 4 and Guillermo Ruiz-Irastorza 5,6, *
1 Rheumatology Department, Hospital JM Ramos Mejía, Buenos Aires 1221, Argentina;
[email protected] (S.P.); [email protected] (M.A.S.)
2 Department of Internal Medicine, Faculty of Medicine, Universidad de la República,
Montevideo 11000, Uruguay; [email protected] (A.D.); [email protected] (A.C.)
3 Autoimmune Disease Unit, Sanatorio 9 de Julio, Tucumán T4000, Argentina; [email protected]
4 Autoimmune Disease Unit, Hospital Privado de Comunidad, Mar del Plata B7600, Argentina;
[email protected]
5 Autoimmune Diseases Research Unit, BioCruces Bizkaia Health Research Institute, Cruces Univeristy
Hospital, 48903 Bizkaia, Spain
6 University of the Basque Country, 48940 Leioa, Spain
* Correspondence: [email protected]
Received: 9 July 2020; Accepted: 17 August 2020; Published: 21 August 2020
Abstract: Since the discovery of glucocorticoids (GCs), their important anti-inflammatory effect,
rapid mechanism of action, low cost, and accessibility have made them one of the mainstays of
treatment for Systemic lupus erythematosus (SLE). Although their use has allowed controlling the
disease and reducing acute mortality in severe conditions, the implementation of a scheme based on
high doses for long periods has inevitably been accompanied by an increase in adverse effects and
infections, including long-term damage. The objective of this review is to answer some important
questions that may arise from its use in daily clinical practice, and to propose a paradigm based on the
use of methylprednisolone pulses followed by medium-low doses and a rapid decrease of prednisone.
1. Introduction
Systemic lupus erythematosus (SLE) is a complex disease characterized by autoimmunity,
inflammation, and a variable degree of organ damage, which depends on the number and severity of
flares but also on the treatments received. The management of SLE is often challenging. Most guidelines
refer to “standard of care” as a combination of hydroxychloroquine, glucocorticoids (GCs), and,
sometimes, an immunosuppressive agent. Such therapy often achieves disease remission, but too
many times at the cost of a large degree of damage accrual.
Irreversible organ damage is not only very frequent in SLE, but also particularly relevant
considering that most patients are young or middle-aged women. According to a growing amount
of scientific evidence, irreversible damage, as well as other serious side effects, such as infections,
are strongly associated with the use of GCs [1–3]. Indeed, the recently updated EULAR guidelines
highlight the need to prevent organ damage and to optimize pharmacological strategies in order to
improve health-related quality of life and to achieve long-term patient survival [4].
The purpose of this review is to answer ten daily clinical practice questions by updating the
current evidence about the optimal doses of GCs in several scenarios, based on pharmacological and
clinical evidence, as well as to offer our point of view regarding the “standard of care” of GC use.
1.2. What Is the Non-Genomic Way and How Does It Get Activated?
A second mechanism of action of GCs, the non-genomic pathway, acts by modulating inflammatory
and immune cells by three molecular mechanisms independent from nuclear interactions. First,
the GC-cGR complex directly blocks the activation of phospholipase A2 and thus the production
of arachidonic acid by a transcription-independent mechanism. Second, the activation of the
membrane-bound GR (mGR) leads to the reduction of lymphocyte activity via the p38 MAP kinase.
Third, nonspecific interactions with the cellular membranes of immune cells result in the inhibition of
ATP production and thus decrease cell activity [13]. In addition, mGR activation also modifies gene
expression, so priming the immune cells for the upcoming genomic effects [13]. These non-genomic
mechanisms are characterized by a rapid onset of action (less than 15 min) because they do not need
time for translation to the nucleus and modulation of gene transcription.
The activation of the non-genomic pathway starts at doses >100 mg/day of prednisone or
equivalent. This pathway is especially sensitive to methylprednisolone (MP) and dexamethasone,
which have non-genomic effects up to five times more potent than genomic ones [8].
Non-genomic effects are responsible for the efficacy of pulse therapy with GCs at doses over
125 mg of MP [14]. Work by the group of Buttgeterit et al. has shown the relative anti-inflammatory
potency of different GCs by the non-genomic method, based on the effects on respiration, protein
synthesis, and Na+−K+-ATPase and Ca2+−ATPase in concanavalin A-stimulated rat thymocytes [15].
MP and dexamethasone show the highest non-genomic-mediated potency (Table 1). The potency of
treatment with MP also allows a faster tapering of oral prednisone and therefore, a reduction in the
cumulative dose of GC [14,16,17]. A summary of the genomic and non-genomic GC effects is shown
in Table 2.
J. Clin. Med. 2020, 9, 2709 3 of 13
1.3. Should High Doses of Prednisonse Be Still Considered the Standard Starting Dose?
The “classical” standard 1 mg/kg/day prednisone dose is not supported by either basic
pharmacology or clinical evidence (Figure 1) [19,20]. It is unlikely that anti-inflammatory effects
increase significantly after prednisone doses have reached 30–40 mg/day, since such doses already
result in a saturation of almost 100% of the genomic pathway [12,19]. Recent data suggest that higher
initial doses of prednisone are associated with higher cumulative doses [21] with the well proven result
of increasing damage accrual [1,22–25].
Instead, the combination of MP pulses followed by doses of prednisone up to 30 mg/day, depending
on severity, is more effective, more rapid, and safer than the use of the “classical” 1 mg/kg/day (Figure 2).
Several studies support this view. A European multicenter randomized, controlled study compared
standard dose (1 mg/kg/day, n = 42) and reduced dose prednisone groups (0.5 mg/kg/day; n = 39),
both associated with mycophenolic acid, during the induction phase of class III-IV lupus nephritis
(LN). The complete remission rates at week 24 were similar for both groups, with fewer infections in
the reduced prednisone dose group [26].
J. Clin. Med. 2020, 9, 2709 4 of 13
J. Clin. Med. 2020, 9, x 4 of 14
Figure 1. The “classical paradigm” in SLE therapy. Note: PDN: prednisone; MP: methylprednisolone
pulses; proportions showed in “clinical picture” are merely illustrative.
Figure
Figure 2.
2. The
The“new
“new paradigm”
paradigm” in
in SLE
SLE therapy.
therapy. Note:
Note: PDN:
PDN: prednisone;
prednisone; MP:
MP: methylprednisolone
methylprednisolone
pulses;
pulses;proportions
proportionsshowed
showedinin“clinical
“clinical picture”
picture” are
are merely
merely illustrative.
illustrative.
In
Inan
an observational study of
observational study ofpatients
patientswith
withclass
classIII-IV-V
III-IV-VLNLN from
from thethe Lupus-Cruces
Lupus-Cruces (CC; n = n29)
(CC; = and
29)
and the Lupus-Bordeaux
the Lupus-Bordeaux cohorts
cohorts n = 44),
(BC; (BC; n =the
44),number
the number of pulses
of pulses of MPof perMP per patient
patient (9.3 vs.(9.3
2.3),vs.
but2.3),
notbut
the
not the cumulative
cumulative dose,
dose, and theand the proportion
proportion of patientsof patients on hydroxychloroquine
on hydroxychloroquine (100% vs.(100%
63%) vs.
were 63%) were
higher in
higher
the CC.inThe
the maximum
CC. The maximum doses of prednisone
doses of prednisone (21 vs. 42(21 vs. 42 mg/day),
mg/day), the number theof
number
weeks of weeks
until until
5 mg/day
(12 vs. 22), and the mean doses at six months (8.3 vs. 21 mg/day) were all lower in the CC. Complete
renal remission rates were significantly higher in the CC at six (69% vs. 30) and 12 months (86% vs.
43%)Figure
[27]. Of note,“new
2. The the number (notinthe
paradigm” SLEtotal dose)Note:
therapy. of MPPDN:pulses was the only
prednisone; MP: independent therapeutic
methylprednisolone
predictor
pulses;ofproportions
achieving showed
complete remission
in “clinical and ofare
picture” reducing GCs-related side effects [27].
merely illustrative.
The AURA–LV was a 48-week randomized clinical trial comparing the efficacy in the treatment of
LN ofIn two
an observational study ofor
doses of voclosporin patients
placebowith class
added to III-IV-V LN frommofetil.
mycophenolate the Lupus-Cruces
All patients (CC; n = 29)a
received
and
maximum initial dose of 25 mg/day of prednisone with tapering to 5 mg in 8 weeks and to 2.5but
the Lupus-Bordeaux cohorts (BC; n = 44), the number of pulses of MP per patient (9.3 vs. 2.3), mg
not the cumulative dose, and the proportion of patients on hydroxychloroquine (100% vs. 63%) were
higher in the CC. The maximum doses of prednisone (21 vs. 42 mg/day), the number of weeks until
J. Clin. Med. 2020, 9, 2709 5 of 13
in 12 weeks. Remission rates at 48 weeks were 49.45% and 39.8% in both voclosporin groups [28].
Even patients in the control arm of the AURA trial had remission rates higher than those in previous
studies such as ALMS [29] and LUNAR [30,31].
The “Rituxilup” schedule, which consisted of rituximab and MP, followed by maintenance
treatment with mycophenolate mofetil and no oral steroids, resulted in 72% of patients with LN class III,
IV, or V eventually achieving complete remission within a median period of 36 weeks [32].
In patients presenting with an SLEDAI score ≥6 (those with severe LN excluded), initial therapy
with doses of prednisone ≤30 mg/day resulted in a similar decrease in SLEDAI scores at one year and
reduced damage at five years compared with initial doses >30 mg/day. It must be noted that, in order
to reduce prednisone doses, hydroxychloroquine was used in 100% vs. 33% of patients and MP pulses
in 34% vs. 10%, respectively [1].
Thus, current evidence, based on large observational cohorts and a few clinical trials, supports the
idea that low-medium initial doses of prednisone (i.e., ≤30 mg/day) are at least as effective as high-dose
schemes and with a better safety profile [31,33]. MP pulses offer additional potency and allow the use
of lower doses of prednisone. Of note, no studies of similar quality have ever shown the superiority of
high-dose prednisone regimes.
a retrospective, new-user study including 3030 SLE patients found that the rate of severe infections
in patients on prednisone >15 mg/day was high and not influenced by antimalarials use [22]. Thus,
the use of maintenance doses of prednisone not exceeding 5 mg/day with pulses of 500 mg of MP
instead of 1000 mg is probably a good way to reduce the infectious complications in lupus patients.
Dose of Prednisone
Guideline Methodology Clinical Setting Pulses Recommended? Tapering Scheme? Maintenance Dose?
Recommended?
YES. 500–1000 mg/day YES. 0.5–1 mg/kg/day or
LN III–IV methyl-prednisolone for 1 mg/kg/day if NO. Only “a few weeks” NO
Opinions of highly-qualified 1–3 days crescents seen Only “to lowest
ACR (2012) [54] effective dose”
experts.
NO. Maintain initial dose by for
LN V NO YES. 0.5 mg/kg/day
6 months
YES. 500–750 mg/day
A modified Delphi method was LN III–IV methyl-prednisolone for YES. 0.5 mg/kg/day YES. Maintain initial dose by 4 weeks,
EULAR/ERA-EDTA used to compile questions, 1–3 days reducing to ≤10 mg/day by 4–6 months. YES. ≤10 mg/day
(2012) [55] elicit expert opinions and reach
YES. If proteinuria >1 g/
consensus LN II NO
24 h: 0.25–0.5 mg/kg/day
NO. Only maintain initial dose by
Mild activity flare NO YES. ≤20 mg/day YES. ≤7.5 mg/day
1–2 weeks
YES. ≤250 mg/day
Evidence-based guidelines,
Moderate activity flare methyl-prednisolone for YES. ≤0.5 mg/kg/day NO YES. ≤7.5 mg/day
supplemented as necessary
BSR (2018) [51] 1–3 days
with expert opinion and
consensus agreement. YES
YES. ≤0.75–1 mg/kg/day
500 mg/day
Severe activity flare: or ≤0.5 mg/kg/day with NO YES. ≤7.5 mg/day
methyl-prednisolone for
pulses
1–3 days
Mild-moderate flare NO YES. ≤0.5 mg/kg/day NO. Only gradual tapering YES. ≤7.5 mg/day
Delphi method, to form
EULAR (2019) [4] questions, elicit expert YES. “Consider”
opinions and reach consensus. Severe/organ-threatening 250–1000 mg/day
YES. 0.5–0.7 mg/kg/day NO. Only “gradual tapering” YES. ≤7.5 mg/day.
disease: methyl-prednisolone for
1–3 days
YES. 1–2 mg/kg/ NO. “Regardless of manifestations of
LN NO
GLADEL/PANLAR maximum 60 mg/day disease, should prescribed at the lowest
GRADE YES. ≤7.5 mg/day.
(2019) [52] doses and for the shortest period
Diffuse alveolar
YES NO
haemorrhage of weather”
YES. 0.3–0.5 mg/kg/day for up to
4 weeks. Tapered to ≤7.5 mg/day by 3 to
EULAR/ERA-EDTA Delphi methodology. LN III-IV YES. Total dose 500–2500 mg, YES. 0.3–0.5 mg/kg/day 6 months. Gradual withdrawal of YES. ≤7.5 mg/day
(2020) [56] Task Force voted on their level depending on disease treatment (glucocorticoids first, then
of agreement with the formed severity. immunosuppressive)
statements.
LN V YES. 20 mg/day YES. Tapered to ≤5 mg/day by 3 months YES. ≤5 mg/day
ACR: American College of Rheumatology. EULAR: European League Against Rheumatism. ERA-EDTA: European Renal Association-European Dialysis and Transplant Association.
BSR: British Society of Rheumatology. LN: Lupus nephritis. GLADEL: Grupo Latino-Americano de Estudio del Lupus. PANLAR: Liga Panamericana de Asociaciones de Reumatología.
J. Clin. Med. 2020, 9, x 10 of 14
J. Clin. Med. 2020, 9, 2709 9 of 13
Figure 3. The Lupus-Cruces protocol for the treatment of SLE according to severity. Note: HCQ:
Figure 3. The Lupus-Cruces protocol for the treatment of SLE according to severity. Note: HCQ:
hydroxychloroquine; PDN: prednisone; MP: methylprednisolone pulses; ¶ Polyarthralgia, small joint
hydroxychloroquine; PDN: prednisone; MP: methylprednisolone pulses; ¶ Polyarthralgia, small
monooligoarthritis, limited skin lesions; Polyarthritis, moderate thrombocytopenia (20,000–
joint monooligoarthritis, limited skin lesions; ¶¶ Polyarthritis, moderate thrombocytopenia
50,000/mm3), haemolytic anaemia with a low rate of haemolysis, widespread skin lupus lesions, non-
(20,000–50,000/mm3 ), haemolytic anaemia with a low rate of haemolysis, widespread skin lupus
severe pericardial effusion/pericarditis, pleural effusion; Lupus nephritis, pneumonitis, severe
lesions, non-severe pericardial effusion/pericarditis, pleural effusion; ¶¶¶ Lupus nephritis, pneumonitis,
thrombocytopenia (<20,000/mm3), haemolytic anaemia with a high rate of haemolysis, severe
severe thrombocytopenia (<20,000/mm3 ), haemolytic anaemia with a high rate of haemolysis, severe
pericardial effusion, refractory pleural effusion, severe neuropsychiatric manifestations; * depending
pericardial effusion, refractory pleural effusion, severe neuropsychiatric manifestations; * depending
on specific
on specific organ
organ involvement.
involvement.
2. Conclusions
•• Glucocorticoids may act
Glucocorticoids act by
by genomic
genomic and
and non-genomic
non-genomic pathways.
pathways. The second way is faster and
non-related to
non-related to chronic
chronic damage.
damage.
•• The classic
The classic glucocorticoid
glucocorticoid dose
dose of 1 mg/kg/day
mg/kg/day is is not
not evidence-supported
evidence-supported and and has a well-known
range of serious adverse effects
range of serious adverse effects
•• Recruiting the
Recruiting the non-genomic
non-genomic pathway
pathway by
by methylprednisolone
methylprednisolone pulsespulses followed
followed byby aa reduced
reduced dose
dose
scheme of prednisone may avoid adverse effect and chronic
scheme of prednisone may avoid adverse effect and chronic damage damage
•• Immunosuppressive agents
Immunosuppressive agents should
should be
be early
early introduced
introduced in in the
the treatment
treatment ofof moderate-severe
moderate-severe SLE
SLE
to spare glucocorticoids
to spare glucocorticoids
J. Clin. Med. 2020, 9, 2709 10 of 13
• Prednisone maintenance doses ≤5 mg/day should be ideally achieved in no more than 12 weeks.
• Hydroxychloroquine is mandatory in SLE treatment, except in the exceptional cases with
contraindications.
Author Contributions: Conceptualization, S.P., A.D., and G.R.-I.; comprehensive literature review, S.P., A.D.,
M.A.S., A.C., M.C.G., F.V., and G.R.-I.; writing—original draft preparation, S.P., A.D., M.A.S., A.C., M.C.G., and
F.V.; writing—review and editing, S.P., A.D., and G.R.-I.; supervision, G.R.-I. All authors have read and agreed to
the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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