Journal of

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;
psachu@gmail.com (S.P.); mairaariassaavedra@gmail.com (M.A.S.)
2 Department of Internal Medicine, Faculty of Medicine, Universidad de la República,
Montevideo 11000, Uruguay; alvarodanza@gmail.com (A.D.); adrianacarlomagno@gmail.com (A.C.)
3 Autoimmune Disease Unit, Sanatorio 9 de Julio, Tucumán T4000, Argentina; cecigoizueta@yahoo.com.ar
4 Autoimmune Disease Unit, Hospital Privado de Comunidad, Mar del Plata B7600, Argentina;
florenciavivero82@gmail.com
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: r.irastorza@outlook.es




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.

Keywords: systemic lupus erythematosus; SLE; prednisone; methylprednisolone; glucocorticoids;

mortality; prognosis; damage

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.

J. Clin. Med. 2020, 9, 2709; doi:10.3390/jcm9092709 www.mdpi.com/journal/jcm

J. Clin. Med. 2020, 9, 2709 2 of 13

1.1. What Is the Main Mechanism of Action of GCs?

The first mechanism of action of GCs is to interfere with the genomic transcription of inflammatory
molecules. This process starts by means of GCs binding the cytosolic-GC receptor (cGR). The GC-cGR
complex is translocated into the nucleus where it modulates gene expression. This is called the
genomic pathway [5,6]. The first effect generated by the GC-cGR complex within the nucleus is
transrepression, consisting of the inhibition of those genes which promote cytokine and other protein
synthesis involved in the inflammatory process, with the resulting anti-inflammatory effect. As the
intranuclear concentration of GCs increases, a second process named transactivation starts. Although
this mechanism stimulates the transcription of some inhibitory genes, it mainly mediates the activation
of gluconeogenesis, insulin resistance, skin atrophy, and the inhibition of bone formation, all well-known
adverse effects of GCs [7–9].
The use of low doses of prednisone (≤7.5 mg/day) is associated with a progressive saturation up
to 50% of the cGR. At medium doses (>7.5 mg/day to 30 mg/day of prednisone), the receptor becomes
progressively saturated from 50 to close to 100%, keeping a less lineal relation with the daily dose.
It is estimated that the almost complete saturation of cGR occurs at approximately 30–40 mg/day of
prednisone. At higher doses, up to 100 mg/day, the predominant effect is transactivation, and therefore
the occurrence of unwanted effects with no major increase in anti-inflammatory actions [10–12].
This pharmacodynamic behavior is the basis of the new GC dosage schemes [12].

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

Table 1. Anti-inflammatory potency exerted by genomic/non-genomic ways of the different

glucocorticoids [15,18].

Anti-Inflammatory Effect Anti-Inflammatory Effect

Glucocorticoid
(Genomic Way) (Non-Genomic Way)
Cortisol/hydrocortisone 1 Low
Prednisone/prednisolone 4 4
Methylprednisolone 5 10–15
Dexamethasone 20–30 20
Betamethasone 20–30 <4

Table 2. Summary of the mechanisms of action of glucocorticoids.

Genomic Pathway Non-Genomic Pathway

Cells targeted All the organism Inflammatory cells
Membrane receptor and intracellular
Mechanism of action Genomic modulation
inflammatory pathways
Start of action ~4 to 6 h ~15 min
Saturation dose of the
~100% at 30 to 40 mg/day of
immunosuppressive – Unknown
prednisone-equivalent
anti-inflammatory effects
2.5 to 5 mg/day of
Minimum effective dose Over 100 mg of prednisone-equivalent
prednisone-equivalent
30 to 40 mg/day of
Maximum effective doses that
prednisone-equivalent (for 500/day mg of methylprednisolone
minimize adverse effects
trans-repression)
Damage accrual with
Proven Not proven
cumulative doses
Glucocorticoids acting by Mainly methylprednisolone and
All
this way dexamethasone

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.

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 Figure
fewer infections
Figure1.
1.The in the
The“classical
“classical reducedinprednisone
paradigm”
paradigm” inSLE dose
SLEtherapy.
therapy. group
Note:
Note: [26].
PDN:
PDN: prednisone;MP:
prednisone; MP:methylprednisolone
methylprednisolone
pulses;proportions
pulses; proportionsshowed
showedin
in“clinical
“clinical picture”
picture” are
are merely
merely illustrative.
illustrative.

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].

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.

1.4. Are 1000 mg MP Pulses More Effective than Lower Doses?

In a study from 1987 including 21 patients with active SLE with severe manifestations refractory
to other treatments, patients were either treated with intravenous MP 100 mg/day or 1000 mg/day for
three days. The study did not find significant differences between the two groups [34]. In addition,
a retrospective study by Badsha et al., 2002 reported that 1500 mg of MP given throughout three days
were equally effective in controlling the disease and associated with fewer serious infections than 3000
to 5000 mg in the same period [35]. The same authors carried out a prospective study comparing the
use of 500 mg/day of methylprednisolone for three days with a historical cohort given higher doses
and obtained the same results [36].
In the Lupus-Cruces cohort, the use of intravenous MP pulses, in all cases between 125 and
500 mg/day for three consecutive days, were not associated with long-term damage accrual [17]. In the
previously mentioned study of patients with class III-IV-V LN from the CC and the BC, the number of
intravenous MP pulses, rather than the total dose, was an independent predictor of complete response
and of reduced GC-related toxicity. CC patients were treated with three consecutive 250–500 mg
intravenous pulses and then with additional 125 mg pulses every two weeks before each intravenous
dose of cyclophosphamide [27].
In 2018, Danza et al. compared the efficacy and rates of infections among patients with several
autoimmune conditions, including SLE, treated with MP pulses, for a total dose over three days
≤1500 mg, <1500 to ≤3000 mg and >3000 mg [19]. No differences among the different doses were seen
in patients achieving complete response, partial response, or no response. No patients in the ≤1500 mg
group suffered infections, vs. 9.1% in the high dose group.

1.5. Should Pulses of MP Be Reserved for Life Threatening Flares?

It is well assumed that MP pulses, due to their higher potency and faster mechanism of action
compared to oral prednisone, are indicated in those patients with severe manifestations of SLE in
whom a rapid effect is necessary [4,14]. However, they might not be limited to this clinical scenario.
The rapidity and potency of action make MP pulses at doses 125–250 mg/day for three days is ideal to
deal with many moderate lupus flares, like arthritis, skin rashes, and pericarditis, and also for recurrent
or non-responding mild flares. Thus, MP pulses may contribute to avoid high-dose prednisone and to
promote a faster tapering, reducing the cumulative GC dose and thus the short and long-term side
effects of oral prednisone [4,33].
J. Clin. Med. 2020, 9, 2709 6 of 13

1.6. Can GC-Related Damage Be Avoided without Reducing Efficacy?

There are several factors that contribute to organ damage accrual in patients with SLE. Among them,
the role of GCs has proven fundamental. In 2003, Gladman et al. categorized damage as definite,
probable and not related to GCs [3] and found that the latter increased over disease course, being the
most frequent in latter stages of SLE. Joo et al. have also found that patients with LN have more
damage associated than non-associated to GCs [37]. In the Hopkins cohort, GC-related irreversible
damage has been shown to depend on the cumulative dose of prednisone [38]. Compared to patients
who did not receive prednisone, the risk of accruing damage increased 1.2 times if they had received a
cumulative dose of 180 mg per month, and twice for a cumulative dose >540 mg per month [23]. On the
other hand, the use of MP pulses has not been associated with damage accrual in large series [17,38].
A possible reason explaining this is the different toxicity associated with the activation of
the genomic (increasing toxicity in parallel with activation) and the non-genomic ways (free of
genomic transactivation-related toxicity). Therefore, the use of MP pulses (activating non-genomic
mechanisms), rather than prednisone doses >30 mg/day (fully activating the genomic way), for inducing
rapid remission, followed by maintenance doses of prednisone ≤5 mg/day (activating less than 25%
of the genomic way) may be a good approach to minimize GC-related side effects. In addition,
hydroxychloroquine helps spare prednisone and, by itself, also prevents damage accrual [39].
Ruiz-Arruza et al found that the use of this treatment scheme achieved the same efficacy, with no
increase in SLE-related damage and less global, cardiovascular and GC-related damage [33].
Whilst the eventual discontinuation of GC is the ultimate goal, a recent monocentric, 12-month,
superiority, open label, randomized controlled trial compared the efficacy to prevent flares of
maintenance versus withdrawal of 5 mg/day prednisone in patients with clinically quiescent SLE.
The study found that maintenance therapy with 5 mg/day of prednisone prevents relapses, with
no worsening of damage and no GC toxicity observed during the follow-up period [40]. Therefore,
long-term therapy with low-dose GC may be necessary in a number of patients with SLE. This could
contrast with the results of the aforementioned Rituxilup study [32], in which no oral GCs were
used during the induction phase in patients with LN. However, the clinical setting (maintenance and
induction) is different, and no data were given regarding how many patients in this study eventually
needed GCs for other manifestations of SLE.

1.7. How Can the Risk of Infections Be Reduced during GC Treatment?

Infections represent one of the most important causes of morbidity and mortality in patients
with SLE [41]. The factors predisposing lupus patients to infection are not only disease activity and
the malfunction of the immune system, but also the use of immunosuppressive drugs, particularly
GCs [41,42]. GCs suppress the production of inflammatory cytokines, the microbicidal activity of
activated macrophages, the adhesion of neutrophils to endothelial cells, the release of lysosomal
enzymes, the respiratory burst, and the chemotaxis. In addition, they cause marked lymphopenia in
all lymphocyte subpopulations, inhibit the activation of T cells and have immunosuppressive effects
on the maturation and function of dendritic cells, responsible for triggering the adaptive immune
response [43]. Although these effects increase with the dose and the duration of treatment, the risk of
infection is already high at maintained doses of 7.5 mg/day. Indeed, the chance of suffering a severe
infection increases by 12% for each mg/day of prednisone [2].
According to the data obtained from the Spanish Registry of Systemic Lupus Erythematosus (RELES),
6.4% of patients had a documented episode of major infection during the first year of follow-up and
5.67% during the second. Mean prednisone doses >30 mg/day during the first month and >7.5 mg/day
during the first year independently predicted major infections within the first and the second year of
follow-up, respectively [44]. Regarding MP pulses, the use of 1000 mg/day for three days has been
associated with an increase in infections compared with 500 mg/day [35].
A number of prophylactic measures, such as the administration of vaccines, can be recommended
in SLE, and the use of hydroxychloroquine is also protective against infections [45]. However,
J. Clin. Med. 2020, 9, 2709 7 of 13

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.

1.8. How Should GC Therapy Be Managed during Pregnancy?

Since the therapeutic possibilities are lower in pregnant women, GCs are one of main therapeutic
resources during gestation in case of lupus flares [46]. Indeed, their potent anti-inflammatory effect
seems not to be accompanied by any significant teratogenicity.
The choice of GC will depend on whether our goal is to treat the mother or the fetus. According
to the most recent EULAR and BSR guidelines, in the first case, the use of non-fluorinated GCs such as
prednisone or MP will be of choice, while in the second case, the treatment will be with fluorinated GCs,
such as betamethasone or dexamethasone [46,47]. This is due to the presence of the placental 11-beta
dehydrogenase enzyme that converts non-fluorinated GCs into relatively inactive forms, with less
than 10% of the drug reaching the fetal circulation [48].
The adverse effects observed are similar to those occurring outside pregnancy, however,
hypertension, preeclampsia, insulin resistance, infections and premature rupture of membranes
represent additional serious problems during gestation. For this reason, prednisone is recommended at
doses not exceeding 20 mg/day for the treatment of severe manifestations of the disease, and 7.5 mg/day
for minor manifestations, with rapid tapering in both cases to maintenance doses ≤5 mg/day. If necessary,
in moderate-severe flares, intravenous pulses of MP 125–500 mg can be safely used [49].
During the lactation, the amount of prednisone found in breast milk is very low, although it is
advisable to delay breastfeeding until four hours after taking doses greater than 50 mg/day (which are
not recommended, anyhow) [46].
In women undergoing corticotherapy during pregnancy or lactation, adequate supplementation
with calcium 1000 mg/day and vitamin D 800 IU/day is recommended for the prevention of GC-induced
osteoporosis [50].

1.9. What Are the Current Recommendations?

The current recommendations are, once a SLE flare is diagnosed, to achieve remission or low
disease activity as soon as possible, and then prevent new flares [4,51,52]. An intensification of
the immunosuppressive regimen is universally recommended for this purpose. Although there is
no universal agreement regarding the definition of low dose of GCs, most authors accept doses
≤7.5–5 mg/day of prednisone or equivalent [52,53]. Since no consensus about tapering has been
established, such doses can be reached within variable periods ranging from four weeks to up to
12 months.
Table 3 shows how starting doses of GCs vary among the different guidelines, from 0.3 to
2 mg/kg/day for patients with severe, renal or extra-renal involvement [51,52,54–56], or whenever the
administration of MP pulses during induction therapy is not possible [54]. Even though the recent
2019 EULAR recommendations do not provide a specific tapering scheme, they recommend avoiding
an initial dose of 1 mg/kg/day of prednisone and highlight the importance of using early MP pulses
and immunosuppressants in order to spare oral GCs [4], with some significant recommendations:
in cases of mild to moderate disease, start with prednisone doses ≤0.5 mg/kg/day, with “gradual
tapering”; in cases of severe or organ-threatening disease, MP pulses (250–1000 mg/day) for 1–3 days
are suggested, followed by prednisone 0.5–0.7 mg/kg/day “with tapering” [4]. Recommended MP
doses vary from 250 mg/day to 1000 mg/day for 3 days when a flare is diagnosed [54]. Again, there is
no agreement on its use during induction, often being reserved for severely active patients who do not
achieve a sufficient response after initial high doses of prednisone [54,55].
J. Clin. Med. 2020, 9, 2709 8 of 13

Table 3. Recommended doses of glucocorticoids in recent lupus guidelines.

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

1.10. What Is our Proposed “Standard of Care” for GC Use?

1.10. What Is our Proposed “Standard of Care” for GC Use?
We advocate for a new paradigm in the use of GCs in SLE. The old, vague expression “the
We advocate for a new paradigm in the use of GCs in SLE. The old, vague expression “the shortest
shortest time and at the lowest dose possible” is not enough, since many doctors feel that a rapid
time and at the lowest dose possible” is not enough, since many doctors feel that a rapid decrease in the
decrease in the dose of prednisone can precipitate a flare or a situation of adrenal insufficiency (Figure
dose of prednisone can precipitate a flare or a situation of adrenal insufficiency (Figure 1). Nowadays,
1). Nowadays, there is enough evidence to support the use of doses of prednisone ≤30 mg/day in
there is enough evidence to support the use of doses of prednisone ≤30 mg/day in most severe flares,
most severe flares, equally effective than higher doses, with a much better safety profile, both in the
equally effective than higher doses, with a much better safety profile, both in the short and in the long
short and in the long term. MP pulses should not be limited life-threatening situations since they
term. MP pulses should not be limited life-threatening situations since they contribute to rapid disease
contribute to rapid disease control while sparing oral GCs. Pulses can be used in a wide range of
control while sparing oral GCs. Pulses can be used in a wide range of doses, from 125 mg to 500 mg,
doses, from 125 mg to 500 mg, depending on the severity of flares (Figures 2 and 3). Using this
depending on the severity of flares (Figures 2 and 3). Using this scheme, along with hydroxychloroquine
scheme, along with hydroxychloroquine and early immunosuppressive therapy, it is possible to
and early immunosuppressive therapy, it is possible to accomplish a quick tapering of prednisone,
accomplish a quick tapering of prednisone, and therefore to achieve maintenance doses ≤5 mg/day
and therefore to achieve maintenance doses ≤5 mg/day within a maximum period of 12 weeks [57,58].
within a maximum period of 12 weeks [57,58].

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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