The Use of Glucocorticoids in Lupus Nephritis: New Pathways for an Old Drug

REVIEW

published: 16 February 2021

doi: 10.3389/fmed.2021.622225

Frontiers in Medicine | www.frontiersin.org 1 February 2021 | Volume 8 | Article 622225

Edited by:

Savino Sciascia,

University of Turin, Italy

Reviewed by:

Claudio Ponticelli,

Retired, Italy

Jose Inciarte-Mundo,

Hospital Clínic de Barcelona, Spain

*Correspondence:

Isabelle Ayoub

[email protected]

Specialty section:

This article was submitted to

Rheumatology,

a section of the journal

Frontiers in Medicine

Received: 28 October 2020

Accepted: 20 January 2021

Published: 16 February 2021

Citation:

Mejía-Vilet JM and Ayoub I (2021) The

Use of Glucocorticoids in Lupus

Nephritis: New Pathways for an Old

Drug. Front. Med. 8:622225.

doi: 10.3389/fmed.2021.622225

The Use of Glucocorticoids in Lupus

Nephritis: New Pathways for an Old

Drug

Juan M. Mejía-Vilet

and Isabelle Ayoub

Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán,

Mexico, Mexico,

Division of Nephrology, Department of Internal Medicine, The Ohio State University Wexner Medical Center,

Columbus, OH, United States

Glucocorticoids therapy has greatly improved the outcome of lupus nephritis patients.

Since their discovery, their adverse effects have counterbalanced their beneﬁcial

anti-inﬂammatory effects. Glucocorticoids exert their effects through both genomic

and non-genomic pathways. Differential activation of these pathways is clinicall y

relevant in terms of beneﬁt and adverse effects. Ongoing aims in lupus nephritis

treatment development focus on a better use of glucocorticoids combined with

immunosuppressant drugs and biologics. Newer regimens aim to decrease the peak

glucocorticoid dose, allow a rapid glucocorticoid tapering, and intend to control disease

activity with a lower cumulative glucocorticoid exposure. In this review we discuss the

mechanisms, adverse effects and recent strategies to limit glucocorticoid exposure

without compromising treatment efﬁcacy.

Keywords: glucocorticoids, lupus nephritis, systemic lupus erythematosus, prednisone, methylpredisolone,

steroids, adverse effect

INTRODUCTION

Cortisone (“compound E” or 17-hydroxy-11-dehydrocorticosterone) was identiﬁed in the 1930’s

by Edward Kendall and Tadeusz Reichstein, and later puriﬁed and synthesized in the 1940’s.

Compound E had strong anti-inﬂammatory eﬀects but also potent mineralocorticoid eﬀects which

manifested as ﬂuid retention, hypertension, and hypokalemia. Compound E was ﬁrst applied

for treatment in 1948 by Philip Hench. At that time, a young woman with severe rheumatoid

arthritis would become the ﬁrst pat ient treated with cortisone. The anti-inﬂammatory eﬀects of

the cortisone were remarkable but so were the adverse eﬀects (

1, 2).

Subsequently, other glucocorticoid (GC) preparations were developed for treating autoimmune

diseases, including systemic lupus eryt hematosus (SLE) (3). The use of these anti-inﬂammatory

steroids in lupus nephritis (LN) dramatically improved survival. For example, survival was 17%

at 5 years in the pre-glucocorticoid era, but 55% at 5 years after introduction of glucocorticoids

(

4, 5). The addition of immunosuppressive drugs to GC, and later on, the development of biologic

drugs, have transitioned LN management to one focused on improving kidney outcomes while

minimizing adverse events. In this review, we discuss the use of GCs from mechanisms, adverse

events to management of lupus nephritis, and current strategies to limit toxicity of these drugs.

Mejía-Vilet and Ayoub The Use of Glucocorticoids in Lupus Nephritis

MECHANISM OF ACTION: THE CLINICAL

RELEVANCE OF THE GENOMIC AND

NON-GENOMIC MECHANISMS

Glucocorticoids are involved in regulatory processes throughout

the body, such as energy and lipid metabolism, and adaptation

to stress. Two of their most important eﬀects are their strong

anti-inﬂammatory and immunosuppressive eﬀects, evident at

concentrations above the physiological glucocorticoid levels (6).

Glucocorticoids and synthetic glucocorticoids have two

mechanisms of action: the genomic and non-genomic

mechanisms (Figure 1) (7). Genomic mechanisms are activated

after GC, as lipophilic molecules, cross the cell membranes

and bind to the multiprotein complex of chaperones (e.g.,

Hsp40, Hsp56, Hsp70, and Hsp90), immunophilins that act as

co-chaperones (e.g., p23, FKBP51, FKBP52), and the intracellular

cytoplasmic glucocorticoid receptor (cGR). After binding and

subsequent dissociation from these proteins, the complex

GC-cGR translocates to the nucleus and binds to DNA binding

sites known as glucocorticoid response elements. The ﬁnal result

is a decreased transcription of genes encoding inﬂammatory

cytokines (e.g., interleukin-6, i nterleukin-8, tumor necrosis

factor-a), a process known as transrepression; and an increased

transcription of anti-inﬂammatory genes (e.g., interleukin-10,

IκB, annexin A1), known as transactivation (

8).

Genomic me chanisms are generally evident 30 min after

GC administration. By contrast, a second type of non-

genomic mechanisms produce eﬀects within minutes after the

administration. These non-genomic eﬀects are mediated through

changes in cellular membranes, inactivation of the phospholipase

A2 enzyme, and interaction with membrane glucocorticoid

receptors (mGR). Second messengers include kinases, such as the

p38 MAP kinase. The ﬁnal eﬀect is decreased lymphocyte activity

and proliferation (

9).

Identiﬁcation of genomic and non-genomic mechanisms

is clinically important due to the diﬀerential adverse eﬀect

proﬁle and diﬀerential activation exerted by currently used

glucocorticoid dosages and preparations (Figure 1). Genomic

eﬀects are activated with low (<7.5 mg prednisone equivalent

per day) to moderate (7.5–30 mg prednisone equivalent per

day) GC doses, and cGRs a re progressively saturated wit h

high-doses above 30 to 50 mg per day (10). From this

pharmacologic concept, prednisone doses above 50 mg per

day approach the ceiling of cGR saturation, with limited

additional anti-inﬂammatory beneﬁt, yet increasing th e risk

for adverse eﬀect s. As will be further discussed, some adverse

eﬀects, such as avascular bone necrosis, are dependent on the

peak GC dose and duration of high-dose exposure (tapering

speed) (Figure 2).

Non-genomic mechanisms are activated with very-high GC

dosages, such as those reached with methylprednisolone pulses.

This activation starts at prednisone dosages of 100 mg, and

reaching its maximum around 250 to 500 mg. In contrast

to eﬀects mediated by genomic mechanisms, non-genomic

mechanisms are thought to be associated with less adverse eﬀects,

at le ast in part due to the short duration of administration (

11).

The relative activation of these genomic and non-genomic

pathways diﬀers among diﬀerent GC preparations. For example,

dexamethasone and methylprednisolone activate the non-

genomic pathway at a 3-fold greater rate than prednisone (

12).

Diﬀerent GC preparations also diﬀer in potency (expressed

relative to hydrocortisone), mineralocorticoid eﬀects, and

duration of suppression of the hypothalamic-pituitary-adrenal

axis (

13). Other factors, such as time of administration (less

suppression when administered in the morning) and their

chronopharmacology, contribute to the degree of GC-axis

suppression and in consequence to the severity of adverse eﬀects,

but are beyond the scope of this review (14).

Understanding these mechanisms is important to de ve lop

strategies to limit GC toxicity. As shown in Figure 2, GC

administration strategies used in recent clinical trials have

included intravenous methylprednisolone pulses, which activate

non-genomic pathways, followed by lower peak oral GC dosages

and a faster tapering of oral GCs. This strategy aims to maintain

treatment eﬃcacy while limiting GC-related adverse eﬀects.

GLUCOCORTICOID-RELATED ADVERSE

EVENTS

Both disease activity and glucocorticoid exposure have been

associated with organ damage in SLE (

15, 16). As patients

with higher degree of disease activity are usually treated with

higher GC doses, many of the reported studies suﬀer of

confounding by indication (i.e., patients with more severe activity

are administered higher GC doses). Also, as damage is frequently

measured through indices that group several manifestations

[e.g., the SLIC C/ACR damage index (SDI)], it is diﬃcult to

distinguish organ damage caused by prednisone from that

caused by disease activity or concomitant immunosuppressive

medications (17). Finally, many studies also suﬀer from time

bias, as the contribution of disease activity to da mage is usually

higher at earlier stages, while GC-related damage is greater at

later stages (

17).

Organ damage occurs in 50% of patients with SLE within 5-

years of SLE diagnosis (18), with reported increased risk of 2.8%

for each 1 mg prednisone per day (19). Organ da mage has been

reported to be minimized by achieving disease remission (15, 20),

and by using maintenance doses of prednisone lower than 6.0 to

7.5 mg per day (21–23).

GC-related adverse eﬀects have also been classiﬁed into

those related to high dosing over a short period of time, and

those related to cumulative GC doses. Table 1 summarizes t he

reported GC adverse eﬀects according to the use of intravenous

methylprednisolone pulses, the peak oral-GC dose, the duration

of exposure to high-GC doses, and the GC cumulative dose.

INFECTIONS

Infections have been frequently associated with the peak dose of

GC and the duration of exposure to high GC doses. Infections

continue to be a major cause of hospitalizat ion and mortality in

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Mejía-Vilet and Ayoub The Use of Glucocorticoids in Lupus Nephritis

FIGURE 1 | Genomic and non-genomic mechanisms of glucocorticoids. Glucocorticoid genomic pathway is mediated through the cytoplasmic glucocorticoid

receptor (cGR) leading to the mechanisms of gene transactivation and transrepression. The non-genomic pathway is mediated through the membrane glucocorticoid

receptor (mGR), inhibition of the phospholipase A2, and changes in cell membranes. The arrow in the left depicts the dose of prednisone required to activate these

pathways. The upper and lower gray zones represent the doses were genomic (lower gray zone) and non-genomic (upper gray zone) are fully saturated without added

beneﬁt and with higher incidence of adverse effects. mGR, membrane glucocorticoid receptor; PLA2, phospholipase A2; cGR, cytoplasmic glucocorticoid receptor;

GRE, glucocorticoid response element; Hsp70·HOP·Hsp90, multiprotein complex including chaperones such as heat shock proteins and the glucocorticoid receptor;

Hsp90·FKBP52·p23, multiprotein complex including chaperones, co-chaperones, and the glucocorticoid receptor.

FIGURE 2 | Glucocorticoid dosing in induction of remission schemes. High-dose oral glucocorticoid schemes (blue) apply starting doses of oral glucocorticoids at

0.8–1.0 mg/kg/day, with slow tapering, reaching low glucocorticoid doses by 24 weeks of therapy. Recent schemes (green) apply methylprednisolone pulses followed

by medium starting doses of oral glucocorticoids (<0.5 mg/kg/day) with a faster tapering, reaching low glucocorticoid doses by 12 weeks of therapy.

SLE (24–26). An increased incidence of these infections occurs in

patients with kidney disease (

27). Although bacterial infections in

lungs, skin, and urinary tract are far more frequent (25, 28, 29),

the risk for both bacterial and opportunistic infections increases

progressively with the use of medium- to high-dose of GC

(

30–33). The risk of infections associated with high-dose GC

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Mejía-Vilet and Ayoub The Use of Glucocorticoids in Lupus Nephritis

TABLE 1 | Reported associations between glucocorticoid (GC) administration and adverse effects.

Methylprednisolone pulses High GC doses Longer time under high GC doses Cumulative GC dose

Acute cardiovascular events Cardiovascular events Cardiovascular events Cardiovascular events

Acute cerebrovascular event Cerebrovascular events Bacterial and opportunistic infection Hypertension

Uncontrolled glucose Insulin resistance Insulin resistance Insulin resistance

Uncontrolled hypertension Cushingoid features Cushingoid features Skin thinning, bruising

Peptic ulcer disease Weight gain Hypertension

Myopathy Dyslipidemia Osteoporosis and vertebral fractures

Mood disorders Glaucoma Sleep disorders

Psychiatric Osteoporosis Avascular necrosis

Sleep disorders

Avascular necrosis

administration seems to be independent of the use of other

immunosuppressive medications (21).

Studies of infections with administration of

methylprednisolone pulses have also been confounded by

indication, due to the traditional administration of this treatment

in combination wit h other aggressive immunosuppressive

regimens to sicker patients (32, 34). Some studies suggest that

the risk of infe c tion is lower with the use of methylprednisolone

pulses of less than 1.5 g in total (35, 36). It has also been

hypothesized that the shorter duration of pulse therapy (3–5

days) may limit the prolonged suppression of T-cell responses,

which usually peaks after 21 days of GC administration (37).

Therefore, methylprednisolone pulses of less than 1.5 g in total

followed by reduced oral GC may potentially decrease the

incidence of steroid induced infections. Additional preventive

measures include vaccination and the use of prophylactic

antibiotics and antivirals when indicated (38, 39).

BONE DISEASE

Avascular bone necrosis occurs in 5–15% of patients with SLE.

It is most commonly found in the femoral head, but may occur

in other weight-bearing joints, and may occur bilaterally (

40–

42). The pathophysiology of avascular bone necrosis is not fully

understood and suggested mechanisms are reviewed elsewhere

(

43). As for infections, avascular bone necrosis has been reported

to occur more frequently in association with lupus nephritis

(44, 45). Also, it has been associated with GC pulse therapy (46),

the peak initial GC dose (47, 48), and the high cumulative GC

doses in the ﬁrst months of treatment (40, 49).

The prevalence of osteoporosis in SLE is 10 to 20%, with

up to 20% of patients experiencing vertebral fractures (50).

Glucocorticoids increase bone resorption and reduce bone

formation. The former is more pronounced in the ﬁrst months

of steroid use while the latter becomes predominant with

chronic GC use (51). Osteoporosis and vertebral fractures have

been associated with higher GC doses, cumulative doses, and

prolonged administration (

52). The risk of osteoporotic fractures

has been estimated to increase 4.2% for each 1 mg per day

of prednisone (

19). As bone loss develops over a long-time,

many studies with short follow-up fail to assess the impact of

GC therapy on bone density. Assessment of risk for fractures

and of the need for concomitant preventive therapies including

calcium, vitamin D, and bisphosphonates are recommended for

all patients on GC therapy and are reviewed elsewhere (

53, 54).

Metabolic Disease

Long-term and high-dose GC therapy are associated with

pro-atherogenic disturbances that characterize the metabolic

syndrome (

55). This syndrome occurs in 30 to 40% of patients

with SLE and has been associated with higher disease activity,

past or present history of LN, and higher oral doses of GCs.

Its prevalence varies according to age and ethnicity as expected

(56, 57).

Insulin resistance increases in patients with SLE on oral GC

above 7.5 mg per day (58). Furthermore, the risk of diabetes

increases 2- to 4-fold in non-diabetic patients with SLE, especially

with increasing years of chronic GC use (

59–61). In patients with

pre-existing diabetes, exacerbation of the disease is particularly

severe i n patients with poor glycemic control at baseline (62, 63).

Hypertension is common in SLE and LN patients, with a

prevalence up to 70% when assessed by 24-h blood pressure

monitoring (64). Acute exacerbation of hypertension is frequent

during pulse GC therapy. Although hypertension during an

active LN is mediated by salt-sensitive mechanisms (65), the risk

of hypertension has been also reported to be higher in patients

exposed to GC, and has been associated with the duration of

exposure and the daily dosage of GCs (61, 66, 67).

Glucocorticoids contribute to weight gain by increasing the

appetite for high caloric, high fat food intake (

68, 69). The weight

gain is characterized by central hypertrophy of adipose tissue

with concomitant thinning of peripheral subcutaneous adiposity,

providing a lipodystrophic appearance (Cushingoid phenotype)

(70). Up to 60–70% of patients prescribed long-term GCs report

weight gain (52), and thi s eﬀect has been associated with doses of

GC above 5 mg per day (52, 61).

CARDIOVASCULAR DISEASE

It is known that the incidence of cardiovascular events is

increased in SLE, particularly, in patients with lupus nephritis

and chronic kidney disease (23). Although it is diﬃcult to

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Mejía-Vilet and Ayoub The Use of Glucocorticoids in Lupus Nephritis

diﬀerentiate the eﬀect of dise ase activity, traditional risk factors,

and tre atment-related factors; the use of medium- to high-

dose GCs has been associated with increased cardiovascular

events, subclinical atherosclerosis such as carotid intima-media

thickening, severity of coronary calciﬁcations, and severity of

arterial stiﬀness (

71, 72). The risk of cardiovascular events is

estimated to increase 5-fold in SLE patients taking >20 mg

per day of prednisone (23), and 3-fold in those who develop

cushingoid features (73). Cardiovascular events may be reduced

by administering lower peak GC doses, faster GC tapering, and by

limiting cumulative dose. In fact, reductions in cumulative oral

GC were associated with lower incidence of cardiovascular events

in a reported cohort study (74).

STRATEGIES TO MINIMIZE

GLUCOCORTICOID EXPOSURE DURING

THE INDUCTION PHASE OF TREATMENT

The treatment of lupus nephritis has been traditionally divided

into an induction phase of intense immunosuppression, aimed

to quickly suppress inﬂammation, followed by a prolonged

maintenance phase, directed to consolidate response and to

prevent disease ﬂares (75). For the induction phase, current

guidelines recommend the use of medium to high-dose GCs,

combined with an immunosuppressant such as mycophenolate

mofetil, cyclophosphamide, and more recently, calcineurin

inhibitors (38, 39). Next, we describe strategies aimed to reduce

exposure while keeping treatment eﬃcacy. These strategies

have 3 main objectives: (1) reducing the peak GC dose, (2)

reducing t h e duration of exposure to high-dose GC via a

faster GC tapering, and (3) limiting the cumulative dose from

prolonged administration.

THE USE OF INTRAVENOUS

METHYLPREDNISOLONE PULSES TO

LIMIT GLUCOCORTICOID EXPOSURE

Administration of methylprednisolone pulses may allow the

use of lower initial oral GC doses (lower peak GC dose)

with a faster tapering schedule (lower exposure to high

GC doses). Several clinical studies in lupus nephritis have

included methylprednisolone pulses, followed by moderate (≤0.5

mg/kg/day) doses of oral GCs (Figure 3) (76–78). The Euro

Lupus Nephritis Trial (ELNT) scheme (77) included three

750 mg methylprednisolone pulses, followed by 0.5 mg/kg/day

prednisone slowly tapered to 10 mg/day by 6 months. This

trial reported renal response rates (complete and partial) around

20 and 50% at 6- and 12-months, respectively, and long-term

preser vation of kidney function (77, 79).

The MYLUPUS trial (80) is the only randomized clinical trial

that compared the eﬃcacy of medium-dose oral GC therapy

to high-dose GC. In this trial, all patients received three 0.5 g

methylprednisolone pulses plus extended-release mycophenolate

acid. Subjects were randomized to either high-dose oral GC

scheme (starting dose 1 mg/kg/day) or to a reduced-dose oral

GC scheme (starting dose ≈0.5 mg/kg/day). Complete and tot a l

FIGURE 3 | Induction of remission schemes in several studies. (A) Euro Lupus

Nephritis Trial low-dose cyclophosphamide arm; (B) MYLUPUS reduced-dose

glucocorticoid arm; (C) Lupus-Cruces protocol; (D) RITUXILUP protocol; (E)

AURA-LV study voclosporin-treated arm; (F) NOBILITY study

obinutuzumab-treated arm.

response rates were similar at 6 months, 19 vs. 21% and 67 vs.

56%, respecti vely, in both groups.

In a trial evaluating a combination of calcineurin

inhibitor, mycophenolate mofetil and GCs vs. intravenous

cyclophosphamide, all patients received three 0.5 g/day

methylprednisolone pulses followed by 0.6 mg/kg oral

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Mejía-Vilet and Ayoub The Use of Glucocorticoids in Lupus Nephritis

prednisone slowly tapered to 10 mg/d a y by week 16. Response

rates of 84 and 63% at 6-months, were documented in the multi-

targeted therapy and cyclophosphamide groups, respectively,

and of 78% in both groups by 2 years of therapy (81–83).

More recent clinical trials have used lower doses of

methylprednisolone pulses combined with a lower and faster

oral GC tapering. In the AURA-LV (

84) and AURORA

(NCT03021499) trials evaluating combination therapy of

voclosporin (a novel calcineurin inhibitor) with mycophenolate

mofetil and oral GC, patients were treated with two 0.25–0.5 g

methylprednisolone pulses, followed by a ﬁxed 20–25 mg/d

starting oral prednisone rapidly tapered to 5 mg by 12 weeks.

Among clinical trials in LN, these two trials used the lowest peak

oral GC doses and the faster tapering (Table 2). At 12 months,

complete and total renal response rates of 49 vs. 24%, and 67 vs.

48%, respectively, were observed in the multi-targeted treatment

and control groups in the AURA-LV trial (

84).

Uncontrolled single center experiences also suggest that

treatment with methylprednisolone pulses allows a safe

administration of lower starting oral GCs, and a faster tapering

without compromising response and possibly reducing adverse

eﬀects. For example, the “Lupus Cruces” protocol for class III or

IV LN includes the administration of three methylprednisolone

pulses between 0.25–0.50 g, and an extra pulse of 0.1 g along with

each cyclophosphamide bolus, following t he ELNT scheme. The

starting oral GC in this protocol was below 30 mg per day. In two

reports, including 15 and 29 patients, response rates of 60 and

80%, and 86 and 87%, have been achieved at 6- and 12-months,

respectively, with relapse rates below 15%. More importantly,

the incidence of GC-related adverse eﬀects was reduced to

7%, a signiﬁcantly lower percentage when compared to that of

historical or concurrent cohorts treated with higher doses of oral

GC (48, 90).

Therefore, as evidenced in clinical trials and single-center

experiences, the use of methylprednisolone pulses may allow

reducing the starting oral GC doses and the duration of the

exposure to high GC doses by allowing a faster tapering.

THE USE OF “REDUCED-DOSE”

INTRAVENOUS METHYLPREDNISOLONE

PULSES

There are no speciﬁc reports evaluating the dose of

methylprednisolone in lupus nephritis. Although the use of

methylprednisolone pulses has been associated with higher

risk of infection in some cohort studies (

32), these studies

do not control for methylprednisolone dose. A small clinical

trial including 21 patients with SLE (6 of them with nephritis)

suggested that clinic a l outcomes are similar when using three

daily 100 mg vs. 1 g methylprednisolone pulses. However, this

trial did not control for other important variables such as

concomitant treatment (91). While quality evidence is still

low to support lower doses of meth ylprednisolone pulses,

pharmacologic studies suggest that pulse doses above 0.5 g

provide little additional anti-inﬂammatory beneﬁt, and as

mentioned earlier, may be associated with a higher incidence of

adverse eﬀects.

MEDIUM-DOSE GLUCOCORTICOID IN

COMBINATION WITH NEW

IMMUNOSUPPRESSANT DRUGS AND

BIOLOGICS

Combination therapy of mycophenolate mofetil, calcineurin

inhibitors, and glucocorticoids may facilitate the use of lower

GC doses. As previously mentioned, the AURA-LV trial used

a forced reduced steroid taper along with mycophenolate ±

voclosporin. The multi-targeted group showed 67% response rate

by 12 months of treat ment (

84).

A recent trial evaluated the combination t herapy of

obinutuzumab, a novel B-cell depleting t herapy , with

mycophenolic acid analogs. All patients received a starting

oral prednisone dose of 0.5 mg/kg with a fast taper to 7.5 mg by

week 12, and optional methylprednisolone pulses. This trial has

reported 52-week CR rates of 35%, maintained at 40 and 41% by

76 and 104 weeks, respectively (89).

Other immunosuppressants such as Janus kinase inhibitors,

spleen tyrosine kinase inhibitors and biologics such as

anifrolumab and ustekinumab, are being tested in patients

with LN. Their addition might also facilitate the use of lower

dose glucocorticoids in the future.

SCHEMES FREE OF ORAL

GLUCOCORTICOIDS

After initial reports describing the potentia l use of rituximab

without increasing GC dose in renal (

92) and non-renal lupus

(93), the UK group from the Imperial College in London

reported their ﬁrst 50 patient experience with the RITUXILUP

scheme (86). This regimen consists of 2 doses of rituximab

1 g administered with 0.5 g met h ylprednisolone followed by

mycophenolate mofetil and no oral glucocorticoids. The initial

report, which included class III, IV, and V LN patients, showed

6-month complete and total response rates of 32 and 62%,

respectively. During follow-up, kidney function was preserved

in most patients, with 22% of patients experiencing nephrotic

relapses. Importantly, unlike the LUNAR tria l (94) that failed

to demonstrate a beneﬁt of added rituximab to the standard of

care therapy, depletion of B-cells to <5 B lymphocytes/mL was

achieved in 93% of patients. The importance of B-cell depletion is

supported by a sub-analysis from the LUNAR trial showing that

complete response was more frequent in t h ose subjects with B

cell depletion (95). Therefore, although not yet demonstrated in

a clinical trial, the RITUXILUP scheme supports the concept that

the use of biologic drugs may facilitate the administration of GC

free regimen in some patients with LN.

Targeting the activated complement system with complement

inhibitors may also promote GC-reduced or GC-free regimens.

Although complement inhibition in lupus nephritis has been

used in a few case reports (

96, 97), particularly in the context

of concomitant thrombotic microangiopathy, the CLEAR (

98)

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Mejía-Vilet and Ayoub The Use of Glucocorticoids in Lupus Nephritis

TABLE 2 | Estimated cumulative glucocorticoid doses in a 24-week period for a 60 kg patient in different induction to remission schemes.

Regimen Methylprednisolone

total cumulative

dose (g)

Oral prednisone

total cumulative

dose (g)

Oral prednisone

average dose

(mg/day)

Total GC dose (g)

Modiﬁed NIH, 2001 (76) 9.00 2.84 16.9 11.8

ELNT, 2002 (

77) 2.25 3.12 18.5 5.37

ALMS, 2009 (

85) – 4.27 25.4 4.27

MYLUPUS, 2011 (

80) 1.50 2.14 12.7 3.64

RITUXILUP, 2013 (

86) 1.00 – – 1.00

LupusCRUCES, 2014 (

48) 1.50-3.00 1.30-1.50 8.0-9.0 2.80–4.50

Chinese multitarget, 2015 (

81) 1.5 3.25 16.2 4.75

4+2 Rituximab, 2015 (

87) 2.70 2.52 15.0 5.22

AURA-LV, 2019 (

84) 1.00 1.33 7.9 2.33

BLISS-LN, 2020 (

88) 0.50–3.00* 3.12–4.27 18.5–25.4 3.12–4.27

NOBILITY, 2020 (

89) 0.75–3.00* 1.79–1.93 10.6–11.5 1.79–1.93

Methylprednisolone pulses elective at discretion of the investigator.

and ADVOCATE (

99) studies in ANCA-associated vasculitis

suggest this may be an approach worth investigating in lupus

nephritis. In these studies, administration of avacopan (an oral

complement C5aR inhibitor) along with cyclophosphamide or

rituximab, allowed the administration of a GC-free re gimen with

higher remission rates at 52 weeks of follow-up in patients with

ANCA-associated vasculitis (99).

CONCOMITANT USE OF ANTIMALARIALS

The use of anti malarial in all patients with SLE and lupus

nephritis is recommended in recent guidelines (

38, 39). Although

unexplored in controlled trials, combination schemes with

antimalarial may add to the use of lower doses of GC by an

enhanced eﬀect for remission (

100–102). O ther demonstrated

beneﬁts from antimalarial, as the protective eﬀe ct for damage

accrual (103, 104), infections (33), and mortality (105), may add

to th e potential beneﬁt of GC-reduced regimens.

GLUCOCORTICOIDS DURING THE

MAINTENANCE PHASE OF TREATMENT

Maintenance therapy in lupus nephritis a ims to consolidate

the response obtained after the induction phase of t h erapy,

and to prevent systemic and renal relapses. Current guidelines

suggest tapering glucocorticoids to “the lowest possible dose”

and to consider discontinuation after 1 2 months of complete

remission (

39).

Although there is no solid evidence in lupus nephritis, t h e

CORTICOLUP trial (106) evaluated discontinuation of steroid

in stable SLE patients (34–41% had history of LN). In this trial,

patients receiving 5 mg of prednisone who have been stable for

1 year (the median quiescence duration was ≈5 yea rs) were

randomized to suspend or continue prednisone at the same

dose. Disease ﬂares were observed in 27% of patients who

suspended prednisone vs. 7% in those who continued prednisone

at 5 mg per day (RR 0.2, 0.01–0.7, p = 0 .003) . Only 3 patients

had renal ﬂares and the study was underpowered to evaluate

the subgroup of patients with LN. Noteworthy, there were no

diﬀerences in adverse events or damage accrual in both groups

measured using t h e glucocorticoid toxicity index (

107) and the

SDI, respe ctively .

This study suggests that a low-dose of glucocorticoids at

5 mg per day may be safe and keeps patients free from disease

ﬂares. In other studies, the longer duration of the GC therapy

before suspension has also been associated with less disease

ﬂares (108). A recent EULAR expert consensus suggested

that at ≤5 mg/day, there is a low level of harm related to

GC’s main adverse eﬀects (109), however, acknowledges that

the actual risk of harm is patient-speciﬁc. Therefore, long-

term glucocorticoid therapy must be balanced individually

considering individual risk factors for ﬂares (e.g., partial instead

of complete response, persistently low C3), against individual

risk factors for GC related adverse eﬀects (e.g., age, cumulative

GC dose, cardiovascular risk factors, presence of metabolic

disease, etc.).

STRATEGIES TO MINIMIZE

CORTICOSTEROIDS DURING THE

MAINTENANCE PHASE

Antimalarial Treatment

Antimalarials have been associated with lower incidence of

disease ﬂares in several observational cohort studies (

110,

111). Moreover, reports of successful with drawal of therapy

in SLE patients have repeatedly found antimalarial treatment

and duration of remission as the main factors associated

with decreased odds of ﬂares (

112, 113). Also, as pre viously

mentioned, antimalarials may reduce long-term damage from the

disease activity (

114).

Frontiers in Medicine | www.frontiersin.org 7 February 2021 | Volume 8 | Article 622225

Mejía-Vilet and Ayoub The Use of Glucocorticoids in Lupus Nephritis

BIOLOGICS FOR MAINTENANCE

THERAPY

Although evidence is still scarce, there is growing data suggesting

that the use of cert a in biologics during the maintenance phase

may aid in achieving sustained remission. For patients already

on glucocorticoids, the RITUXIRESCUE regimen includes the

administration of rituximab and methylprednisolone without

increasing oral GC dose. This regimen showed a response rate

of 78% in LN relapses, furthermore it allowed reduction or

discontinuation of oral GC in more than 50% of patients during

follow up (

92).

An Italian strategy consisting of four 375 g/m

rituximab

doses reinforced by two additional doses at 1 and 2 months after

(the 4+2 rituximab scheme), showed no ﬂares during follow-

up without the need for additional maintenance therapy beyond

5 mg of prednisone per day (87). Other small reports have

highlighted the potential role of rituximab as a maintenance drug

allowing glucocorticoid suspension (115). Therefore, although

rituximab has not been tested for maintenance in a clinical trial,

its use may aid in preventing ﬂares during GC withdrawal.

In the BLISS-LN trial, the addition of belimumab to standard

of care therapy (MMF or cyclophosphamide plus GC) showed

a better response and a stable glomerular ﬁltration rate beyond

the induction phase, for up to 2 years of follow up (

88).

Furthermore, t here have been small reports (116–118) suggesting

that belimumab therapy may allow reduction or suspension of

maintenance GCs, but this remains to be further st udied.

Likewise, the NOBILITY trial has reported that the addition

of obinutuzumab to standard of care therapy favored a sustained

response, better glomerular ﬁltration rate, and better serological

proﬁle at 76 weeks and onwards (

89). This suggests that B cell

targeted therapy may potentially facilitate GC withdrawal or at

least a safe reduction to <5 mg/d of prednisone.

FUTURE STEPS AND A WORD OF

CAUTION

Although recent advances in drug development in lupus nephritis

promote the use of lower glucocorticoid doses, we must

acknowledge that “one size does not ﬁt all” patients. For example,

patients with severe lupus nephritis presenting with a glomerular

ﬁltration rate below 30 mL/min/1.73 m

have been excluded

from most clinical trials, and there are no data to support the

eﬀectiveness of reduced glucocorticoid doses in this group of

patients. Moreover, many of the published studies are single-

center and observational reports subject to bias. Therefore,

caution and case-by-case evaluation is recommended in selecting

an appropriate glucocorticoid therapy.

Future studies in lupus nephritis will likely aim at using

the lowest eﬀective dose of glucocorticoids or glucocorticoid-

free regimens. Studying the safety and eﬃcacy of calcineurin

inhibitors, biologic drugs or perhaps complement inhibitors

in combination with standard of care therapy might lead

successfully to this aim.

CONCLUSIONS

The anti-inﬂammatory properties of GC have always been

counterbalanced by their side eﬀects. Adverse eﬀects may be

associated with peak doses, time under high doses, or cumulative

doses. An objective for current and future management of lupus

nephritis is to develop strate gies that increase response to t h erapy

with the least glucocorticoid exposure.

AUTHOR CONTRIBUTIONS

JM-V and IA designed the concept, planned, and performed

this work.

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Conﬂict of Interest: The authors declare that the research was conducted in the

absence of any commercial or ﬁnancial relationships that could be construed as a

potential conﬂict of interest.

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Frontiers in Medicine | www.frontiersin.org 11 February 2021 | Volume 8 | Article 622225