Autoimmunity Reviews 12 (2013) 617–628

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Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

Review

The use of glucocorticoids in Systemic Lupus Erythematosus. After 60 years still more
an art than science
Remco K.M.A.C. Luijten ⁎, Ruth D. Fritsch-Stork, Johannes W.J. Bijlsma, Ronald H.W.M. Derksen
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Systemic Lupus Erythematosus (SLE) is a clinically diverse, chronic autoimmune disease with inflammation in
Received 15 November 2012 several organ systems. Its pathogenesis is complex, but includes many factors that can be influenced by glucocor-
Accepted 2 December 2012 ticoids (GCs). Indeed, GCs constitute the corner-stone in SLE-treatment. However, guidelines for GC-treatment of
Available online 8 December 2012
the different disease manifestations are lacking and not every patient responds (sufficiently). The focus of this
systematic review is to evaluate the differential glucocorticoid treatment of various SLE manifestations. In
addition, some relevant mechanisms of glucocorticoid action as well as resistance are discussed.
© 2013 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
2. SLE pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
2.1. Adaptive immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
2.2. Innate immune system: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
3. Glucocorticoid mechanisms of action: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
3.1. Glucocorticoid-resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
3.2. Literature search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
4. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
4.1. General features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
4.2. Cutaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
4.3. Nephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
4.4. Cardiac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
4.5. Pulmonary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
4.6. Gastrointestinal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
4.7. Musculoskeletal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
4.8. Neurologic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
4.9. Ophthalmologic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
4.10. Hematologic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
4.11. Lupus cystitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
5. Intravenous pulse treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
6. Tapering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
7. Conclusions and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624

⁎ Corresponding author at: Department of Rheumatology & Clinical Immunology,
University Medical Center Utrecht, Box 85500, 3508 GA Utrecht, The Netherlands.
Tel.: + 31 88 755 7357; fax: + 31 30 252 3741.
E-mail address: r.luijten@umcutrecht.nl (R.K.M.A.C. Luijten).
1. Introduction
Systemic Lupus Erythematosus (SLE) is a clinically diverse, chronic
autoimmune disease, brought about by multiple abnormalities in

1568-9972/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.autrev.2012.12.001
618 R.K.M.A.C. Luijten et al. / Autoimmunity Reviews 12 (2013) 617–628
the immune system. The disease course is characterized by flares of
inflammation in multiple organs, which may result in (permanent)
organ damage or even death.
The discovery of compound E (hydrocortisone) by Kendall and
Reichstein, its use in arthritis patients by Philip Hench in 1949 and short-
ly afterwards in SLE patients, made glucocorticoids (GCs) the cornerstone
of lupus-therapy. However, GC-therapy—especially in higher dosages—
comes at a considerable price in terms of side effects; among others
hypertension, osteoporosis and diabetes mellitus. The use of GCs
has therefore been governed by the effort of applying the appropriate
dose of GCs for particular disease manifestations. However, with
60 years ofexperience, consensus about “appropriate” dosages, route of
administration, and tapering regimes has not been reached and is the
scope of this systematic review. To place this into perspective, first some
relevant items on pathogenesis of SLE in relation to GCs and relevant
working mechanism of GCs and resistance to GCs will be discussed.
2. SLE pathogenesis
The crucial point in SLE is the breach of self-tolerance, caused by
an overzealous interplay of adaptive and innate immune system.
Some aberrations within these systems will be discussed separately:
2.1. Adaptive immune system
Hallmark of SLE are auto-antibodies (aAb) directed against nuclear
structures as dsDNA and RNPs (ribonucleoproteins), allocating a promi-
nent role to the auto-reactive B-cell in the disease process. In contrast to
aAb occurring in healthy controls, aAb in SLE patients are usually class
switched (IgG) and have undergone affinity maturation, implying cog-
nate help of (auto-reactive) T-cells. Indeed, several auto-antigen-specific
T cells have been described, including T-cells directed against Histones,
Nucleosomes and RNPs [1]. Apart from the occurrence of auto-reactive
T- and B-cells, also the composition of both cell populations is altered in
SLE and a plethora of signaling abnormalities has been described, leading
to a lower stimulation threshold and excessive activation [2]. Subsequent-
ly, lymphocytes of SLE patients are to a greater extent Ag-experienced
cells [3,4] indicating a higher turnover of cells. Additionally, more Th17
and fewer and functionally disturbed regulatory T cells have been de-
scribed in SLE compared to healthy controls contributing to the inflam-
matory milieu [2]. Altogether, SLE is marked by a hyper-activated
state of the adaptive immune system, partly causing, partly flanking
the emergence of pathognomonic auto-antibodies.
2.2. Innate immune system:
The intrinsic inability of the cellular and humoral components of
the innate immune system (including phagocytes and complement) to
adequately remove apoptotic debris leads to secondary necrosis and
accessibility of modified auto-antigens to the immune system. Instead
of the physiological non-inflammatory clearance process of apopto-
tic cells an inflammatory process takes place. [5]. After formation of
autoantibodies, the auto-antigens participate in immune complex
(IC) formation and, after deposition in tissues, cause inflammation
through activation of complement and Macrophages. Besides being
taken up by B-cells, and hereby inducing further aAb production, IC
are taken up by plasmacytoid Dendritic cells (pDC) via their FcγR and
after interaction with intracellular TLRs (toll like receptors) stimulate
them to produce IFNα. The role of IFNα in SLE has gained prominent
interest in recent years, after the discovery of the Interferon- signature
of SLE, and IFNα levels correlating with disease activity [6,7]. IFNα
has both direct and indirect (e.g. via the maturation of myeloid DC)
stimulatory effects on T- and B-cells and Neutrophils, which puts
IFNα center stage in lupus.
Recently, a new aspect of the innate immune system in SLE was
discovered: “Netosis”, which is a special form of cell death occurring
in Neutrophils. Its physiological role is the killing of microbes through
extrusion of chromatin and bactericidal proteins from neutrophilic
granules. In SLE, the extruded chromatin stimulates pDC through
engagement of their TLR9 (toll like receptor 9) to produce IFNα
[8,9], constituting yet another trigger of IFN secretion.
Altogether the important cellular components of both adaptive and
innate immune system, namely T- and B-cells, Monocytes/Macrophages,
Dendritic cells and Neutrophils have all become recognized as major
players in SLE pathogenesis. Importantly, all these cells are targets of
glucocorticoid therapy, accounting for the crucial role of GCs in SLE treat-
ment (Fig. 1).
3. Glucocorticoid mechanisms of action:
Anti-inflammatory effects of glucocorticoid-treatment are carried
out by classic genomic pathways. GCs bind to the cytosolic glucocorti-
coid receptor (GCR), which leads to transactivation or transrepression
(Fig. 2). The extent of receptor saturation is directly dependent on GC
dosage. (b50% in low-dose steroids- i.e.: up to7.5 mg prednisone/d-,
50–99% in medium and high dose—i.e. 7.5–30 mg prednisone/d, resp.
30–100 mg prednisone/d- and 100% in very high dose—i.e. >100 mg
prednisone/day and pulse therapy—i.e. >250 mg prednisone/day for
normally 1–5 consecutive days) [10]. Using higher dosages (>30 mg),
also non-genomic mechanisms are involved to dampen the ongoing in-
flammation [11]. These non-genomic mechanisms can be elicited
through nonspecific interpolation of GC molecules into cell membranes
influencing cation transport and increasing mitochondrial proton leak.
Both can alter cell functions. The inhibition of calcium and sodium cy-
cling across the plasma membrane of immune cells is thought to
contribute to the observed rapid immune suppression and reduced
inflammation. A different non-genomic mechanism is carried out by
membrane-bound glucocorticoid receptor (mGCR), which is expressed
by a small number of monocytes and B-lymphocytes [12]. In SLE the
number of mGCR positive monocytes (but not mGCRpositive B-cells)
correlates with disease activity. An inverse correlation between the
number of mGCRpositive monocytes and GC dosages was found, indi-
cating a negative feedback loop of GC action [13]. The treatment of
acute and severe exacerbations of diseases like SLE and rheumatoid
arthritis usually consists of high dose GCs (>30 mg/day). Immunosup-
pressive properties at that dose are mediated by both genomic and
non-genomic pathways; it is not clear which GC-actions should be
attributed to which pathway. As a rule of thumb, it is believed that
the non-genomic actions of GCs are especially elicited by higher
dosages (prednisone equivalent of 30 mg/day or more).
3.1. Glucocorticoid-resistance
Most patients with active SLE benefit from the anti-inflammatory
action of GCs, however up to a third do not respond sufficiently. In
1968 Schwartz et al. reported the first patients with GC-resistant
asthma [14], and since then several mechanisms of GC-resistance
have been described. The first crucial step of GC action is binding to
its receptor (GC receptor, GCR) of which two major isoforms are
recognized: GCRα and GCRβ. Whereas the binding of GC to GCRα
is followed by the aforementioned genomic effects, GCs do not bind to
GCRβ GCRβ functions as a dominant-negative inhibitor of GC action
and is induced by inflammatory cytokines. In SLE increased GRbeta
transcript levels and corresponding protein levels have been found
in PBMCs of active SLE-patients [15]. Furthermore, a decreased ex-
pression of GCR (not distinguishing between α and β isoform) has
been reported in T-cells and monocytes of GC-resistant SLE patients
compared to GC-sensitive SLE patients [16]. Another issue in GC
resistance is the modification (e.g. phosphorylation, nitrosylation,
ubiquitination) of the GCR. This can affect the binding of GCs to GCR,
the stability of the GCR, translocation to the nucleus and interaction
with other proteins.
 R.K.M.A.C. Luijten et al. / Autoimmunity Reviews 12 (2013) 617–628 619

Fig. 1. SLE pathogenesis. In SLE aberrations of the innate and the adaptive immune system both contribute to the systemic inflammation: Through triggers as UV-radiation and in-
fections, apoptosis is induced. Due to clearance defects in the innate system, apoptotic debris accumulates and is taken up and processed by antigen presenting cells such as myeloid
Dendritic cells (mDCs). These present the processed antigen (e.g. dsDNA) to auto-reactive T-cells thereby activating them. T-cells in turn stimulate auto-reactive B cells to produce
autoantibodies. Auto-antibodies and auto-antigen form immune complexes, resulting—among others—in activation of the complement system, which is followed by inflammation
and tissue destruction. Additionally, immune complexes are ingested by plasmacytoid Dendritic cells (pDCs), which leads via activation of intracellular Toll-like-receptors to the
secretion of Interferon alpha (IFNα). IFNα directly and indirectly enhance the above mentioned cascade by stimulating lymphocytes and mDCs. Furthermore, IFNα induces netosis
in Neutrophils, a process in which DNA is expelled together with bactericidal proteins and form neutrophil extracellular traps (NETs). Antibodies to DNA and/or other proteins bind
to the NETs, again forming immune complexes, which are taken up by pDCs, and stimulate further IFNα production.

A frequent cause of GC-resistance is the over-expression of inflamma-
tory transcription factors like AP-1 or NFκB. Recently it was suggested that
in SLE-patients constant activation of pDC results in GC-resistance
through NFκB activation, a situation that enhances IFNα secretion and
SLE activity. [17].
A totally different mechanism of drug-resistance lies in the ex-
pression of P-gp (P-glycoprotein), a membrane-associated transport-
er, which transports intracellular drugs including GCs out of cells.
P-gp expression is increased in GC-resistant SLE patients [18].
In clinical practice an insufficient response of an SLE patient to a
given dose of GCs (GC-resistance) leads to prescription of a higher
dose or additional immunosuppressive drugs.
3.2. Literature search
specific features. Components were combined in a structured manner:
terms related to Patient (domain), Intervention (determinant), Compari-
son or Outcome (PICO) [19], were combined to create a search string,
which was sensitive enough to yield all available evidence (Table 1).
We included all types of studies from case reports to randomized con-
trolled trials. Subjects had to be adults, GC dosage had to be mentioned
and only systemic GCs were taken into account. In nephritis-trials only
studies with a precise description of induction regimens were analyzed.
Studies focusing on treatment of co-morbidities or complications of
lupus were excluded. Limits were set on articles between 1990 and Sep-
tember 2011 as protocols from before 1990 are less comparable to current
practice. Used levels of evidence are defined by the Oxford Centre for
Evidence-Based Medicine [20] and range from 1 (systematic reviews
with homogeneity) to 5 (expert opinion).

To evaluate the optimal dosage of GCs per manifestation, we 4. Results

conducted a Pubmed literature search.
The search string, was based on “Mesh terms” whenever available and The literature search yielded a total of 1494 hits. Of these only 304
consisted of different terms for GCs and any possible term for SLE or its were compatible with the inclusion and exclusion criteria and
620 R.K.M.A.C. Luijten et al. / Autoimmunity Reviews 12 (2013) 617–628

Fig. 2. Glucocorticoid resistance. Glucocorticoids bind to their intracellular Glucocorticoidreceptor α (GR), which upon ligation loses its chaperoning proteins, among which heat
chock proteins (hsp; blue ovals). Homodimers are formed, travel to the nucleus, bind to the Glucocorticoid response element and induce gene transcription of certain genes
(e.g.: lipocortin1 and genes involved in metabolism), a mechanism called transactivation. As monomer the GC–GRα complex can bind to transcription factors as AP-1 and
NF-κB, inhibiting the transcription of their target genes by a mechanism called transrepression (e.g.: IL2). Generally, transactivation is considered to be responsible for metabolic
side effects and transrepression is believed to cause the anti-inflammatory effects of GCs. Resistance to GCs can occur through different ways; three major manners are depicted: 1.
The GR α–isoform GRβ does not bind GCs and functions as a dominant-negative inhibitor of GC action. 2. A predominance of inflammatory transcription factors such as AP-1 or
NFκB “outweighs” the GC action and thus contributes to GC resistance. 3. The transporter P-glycoprotein (P-gp), actively shuffles GCs out of cells.

subsequently taken into account. Results per organ system are sum-
marized below. An overview of all results is given in Table 2.
4.1. General features
General symptoms, e.g. fever and malaise, often constitute a sign
of lupus activity, however other causes are seen more frequently
(e.g. infections). In our literature search only one cohort study, one
case series and two case reports on the treatment of fever in lupus
with GCs emerged. Zhou et al. described effects of prednisone use
on fever in SLE patients (after exclusion of infection and malignan-
cies). Fever in these patients was in most cases accompanied by
Table 1
Pubmed search string.
Patient “lupus erythematosus, systemic” [MeSH Terms] OR “lupus
erythematosus, cutaneous” [MeSH Terms] OR “lupus
erythematosus, discoid” [MeSH Terms] OR “lupus nephritis”
[MeSH Terms] OR “lupus vasculitis, central nervous system”
[MeSH Terms]
Intervention/ “Glucocorticoids/therapeutic use” [Mesh] OR glucocorticoids
Comparison [MeSH Terms] OR prednisolone [MeSH Terms] OR prednisone
[MeSH Terms] OR predniso* [Title/Abstract] OR dexametha-
sone [MeSH Terms] OR methylprednisolone [MeSH Terms] OR
budesonide [MeSH Terms] OR triamcinolone [MeSH Terms]
OR deflazacort [Title/Abstract] OR hydrocortisone [MeSH
Terms] OR cortisone [MeSH Terms] OR solumedrol [Title/
Abstract] OR “solu medrol” [Title/Abstract] OR depomedrol
[Title/Abstract] OR “depo medrol” [Title/Abstract]
Limits full text [sb] AND Humans [Mesh] AND (English [lang] OR
Dutch [lang]) AND (“1990/01/01” [PDat]: “2011/12/31”
[PDat])
other organ involvements. The oral dose of prednisone used ranged
from 0 to 1250 mg/day. The authors found that a prednisone dosage
≤100 mg/day suppressed fever in 80.6% of patients [21]. Rovin et al.
found fever due to SLE (n = 22) to respond within 24 h at oral daily
dosages of 20–40 mg (mean 28 mg) [22].
Of interest although rare, fever has been reported in cases as a side
effect of GCs and the distinction between fever as lupus manifestation
and fever as side effect of GC therapy can be challenging [23].
Another general feature of SLE is lymphadenopathy. In a small
cohort study of 23 patients lymphadenopathy responded to an aver-
age oral dose of prednisone of 20 mg [24]. Also a case report describes
a patient with SLE with lymphadenopathy that was successfully treat-
ed with 20 mg of prednisone [25].
4.2. Cutaneous
Cutaneous features of SLE are rarely an indication for systemic use
of glucocorticoids as most lesions respond well to topical ointments.
Usually hydroxychloroquine is the first line systemic treatment in
cutaneous manifestations of SLE most often in combination with sun-
screens to prevent rashes. There are few data on systemic GC therapy
for cutaneous manifestations and most come from case reports. The
use of intravenous pulse therapy with GCs is only reported in case
reports on patients with digital gangrene, bullous lupus and severe
chronic discoid lupus erythematosus (CDLE) [26–29]. Oral GC dosages
range from 10 mg to 1 mg/kg/day (maximal 80 mg/day) [30–45]
with the higher doses being applied in bullous lupus (30–90 mg)
and lower doses in manifestations like erythema multiforme and
CDLE (10–30 mg). Outcome is often insufficiently described. Ranges,
mean dosages and level of evidence per feature are given in Table 2.
Table 2
Dosing per manifestation.

Indication Reference Total number Pulse Range oral pred Mean dose Combination Level of
(total numbers) of patients evidence

General Fever 4 283 None 10–100 mg 40–100 mg 2b

Lymfadenopathy 2 24 None 20–30 mg 20–30 mg 4
Mucocutaneous Bullous 6 6 None 30–90 mg 30–40 mg Dapsone 4
Erythema multiforme 4 5 None 20–60 mg 20–30 mg None 4

R.K.M.A.C. Luijten et al. / Autoimmunity Reviews 12 (2013) 617–628

Discoid LE 2 4 None 10 mg–1 mg/kg 10–30 mg None 4
SCLE 2 2 None 40 mg–1 mg/kg 20–40 mg None 4
Lupus panniculitis 3 4 Not necessary 32–40 mg 40 mg None 4
Necrotizing vasculitis 4 24 Possibly MP 3 × 500 mg 0.5–1 mg/kg 1 mg/kg (max 60 mg) Possibly icw cyclo 2b
Neuropsychiatric Myelitis 11 24 MP 3 × 1000 mg 20 mg–1 mg/kg 1 mg/kg (max 60 mg) Possibly icw cyclo 4
Psychosis 6 85 MP 3 × 1000 mg 20 mg–2 mg/kg 30 mg–1 mg/kg Possibly icw cyclo 2b
NP-SLE general 21 405 MP 3 × 1000 mg 10 mg–2 mg/kg 1 mg/kg (max 60 mg) icw cyclo 2a/b
Nephritis WHO classes III + IV + V 36/54 3914 MP 3 × 1000 mg 10 mg–2 mg/kg 0.8–1 mg/kg icw cyclo/MMF 1A
WHO pure class V 34 206 None 10 mg–2 mg/kg 0.8–1 mg/kg Possibly icw cyclo/MMF 1B
Haematologic Thrombocytopenia 9 45 None 25 mg–1 mg/kg 0.5–1 mg/kg Possibly icw IVIG 2b
Auto-immune anemia 12 86 MP 3 × 500 mg 10 mg–2 mg/kg 1 mg/kg (max 60 mg) Possibly icw IVIG,MMF,danazol,cyclo 2b
Pure red cell aplasia 6 7 MP 3 × 500 mg 0–1 mg/kg 1 mg/kg (max 60 mg) 4
Hemophagocytosis syndrome 8 24 MP 3 × 1000 mg 60–100 mg (1–2 mg/kg) 1 mg/kg (max 60 mg) Possibly icw IVIG, cyclosporin, cyclo 4
TTP/ITP 7 13 MP 3 × 1000 mg 0–100 mg 1 mg/kg (max 60 mg) Possibly icw plasmapheresis,cyclo 4
Gastro-intestinal Pancreatitis 10 44 MP 3 × 500 mg 10 mg–1.5 mg/kg 0.5–1 mg/kg Possibly icw cyclo, plasmapheresis 4
Auto-immune hepatitis 7 13 None 20–60 mg 40 mg 4
Lupus enteritis 2 50 None 10 mg–1 mg/kg 1 mg/kg (max 60 mg) Possibly icw cyclo, rituximab 2b
Gastro-intestinal vasculitis 2 3 MP 3 × 1000 mg 40–100 mg 1 mg/kg (max 60 mg) icw cyclo 4
Protein losing enteropathy 5 34 MP 3 × 1000 mg 40–60 mg (0.8-1 mg/kg) 1 mg/kg (max 60 mg) 2a
Lupus peritonitis 3 3 MP 3 × 1000 mg 40–100 mg 1 mg/kg (max 60 mg) 4
Ocular Neuromyelitis optica (devic) 11 19 MP 3-5 × 1000 mg 25 mg–2 mg/kg 1 mg/kg (max 60 mg) 4
Other Lupus cystitis 8 9 MP 3 × 1000 mg 20–60 mg 40 mg 4
Pulmonary Pleuritis 4 40 None 33.6 mg–2 mg/kg 40–60 mg Possibly icw cyclo, AZA 2b
Shrinking lung syndrome 3 13 MP 3 × 1000 mg 20–40 mg 40 mg Possibly icw cyclo, AZA 4
Pulmonary hemorhage 3 64 MP 3 × 1000 mg 40 mg–3 mg/kg 1 mg/kg (max 60 mg) Possibly icw cyclo 2b
Cardiovascular Myocarditis 8 27 MP 3 × 1000 mg 30 mg–1 mg/kg 1 mg/kg Possibly icw cyclo (38%) 3a/4
Pericarditis 4 47 None 30–60 mg 30–40 mg Possibly icw cyclo, AZA 2b
Musculoskeletal Polyarthritis 3 3 None Low-dose—10 mg b10 mg 4
Myositis 1 1 None 60 mg 1 mg/kg (max 60) icw cyclo 5

Legend: icw = in combination with. MP = methylprednisolon. Cyclo = cyclophosphamide. AZA = azathioprine. MMF = mycophenolate mofetil. IVIG = intravenous immunoglobulines.
Levels of evidence: 1a = systematic review (SR) of RCT's. 1b = individual RCT. 2a = SR of cohort studies. 2b = cohort study. 3a = SR of case-control studies. 3b = case control studies. 4 = case series. 5 = expert opinion.

621
622 R.K.M.A.C. Luijten et al. / Autoimmunity Reviews 12 (2013) 617–628
4.3. Nephritis
Of all lupus manifestations, the use of GCs in lupus nephritis
(LN) treatment is best described. Many randomized clinical trials
(RCTs) as well as open label and cohort studies have been pub-
lished in lupus nephritis. The studies have significant differences
in the GC regimens, both with respect to route of administration
of the initial dose (pulse vs. oral administration), dosage and taper-
ing schedule. The regimens differ for both induction and mainte-
nance therapy with GCs, and co-medication. For induction, most
regimens apply high dose GCs in combination with cyclophospha-
mide, mycophenolate mofetyl (MMF) or azathioprine. Intravenous
pulse therapy is mostly used in a range of GC dosages of 3 × 500 mg
to 5 × 1000 mg methylprednisolone (MP) followed by oral predni-
sone ranging in the daily dose from 10 mg to 2 mg/kg. In general,
GC dosages in induction therapy for proliferative LN (WHO classes
III and IV) and for membranous LN (WHO class V) are similar, using
prednisone 0.5–1 mg/kg orally after an initial iv pulse therapy with
MP. Concomitant immunosuppression however is different between
lupus nephritis WHO classes III/IV and V, with the more aggressive
treatment in class III/IV. Outcomes differ in all trials without any
correlation with glucocorticoids dosages. Treatment effect is also
dependent of concomitant therapy, race, chronicity and glomerular
filtration rate at start of therapy. Therefore no recommendation can
be given concerning the optimal steroid dose in individual patients.
[46–95].
4.4. Cardiac
Cardiac manifestations are relatively rare in SLE but can be life
threatening. Among them are pericarditis and myocarditis. Data on
the use of GCs in these manifestations come from case reports and
case series with small numbers of patients. Intravenous pulse therapy
is given in most patients with acute myocarditis, but is not described
in pericarditis. Oral prednisone dose ranges from 30 mg to 1 mg/kg
in both groups with the lower dosages in the pericarditis group
(about 30 mg) and higher dosage in myocarditis (about 1 mg/kg).
Most publications report a high response rate (defined by normali-
zation of ejection fraction and/or resolution of pericardial effusion)
[96–111].
4.5. Pulmonary
Treatment of pulmonary manifestations with GCs is scarcely pub-
lished in the literature. Only three cohort studies (2× pulmonary
hemorrhage and 1 × serositis) were found with respectively 34, 22
and 37 patients [102,112,113]. Besides, several case reports or case
series have been published on pulmonary manifestations and shrink-
ing lung disease [114–121]. In all patients with pulmonary hemor-
rhages, iv pulse therapy was given followed by 40 mg prednisone/
day up to 3 mg/kg/day orally. Treatment was effective with survival
rates of 60–100%. Serositis, in most (92%) of SLE patients accompa-
nied by activity in other systems, is usually treated with an oral
high GC dosage (mean: 33 mg/day ± 15 mg to 2 mg/kg/day) with
good responses (resolution of symptoms and effusions). Shrinking
lung syndrome is a rare complication of SLE characterized by dys-
pnea, small lung volumes in pulmonary function tests and clear
lung fields with elevated diaphragm on chest X-ray. Its pathogenesis
remains controversial but is hypothesized to be a mono-neuropathy
of the phrenic nerve. Treatment with GCs is effective (dyspnea and
pulmonary function tests) and iv pulse therapy as well as oral doses
of 20–40 mg are used. The best results are seen with an oral GC
dose of ≥ 0.5 mg/kg/day in combination with cyclophosphamide,
azathioprine or methotrexate [115,120,121].
4.6. Gastrointestinal
Forty articles were found on GC use in gastrointestinal lupus: 32 case
reports, 4 case series and 4 cohort studies. The focus is on lupus
enteritis [90,122–129], protein losing enteropathy [130–134] and
pancreatitis [135–143] and few data on auto-immune hepatitis
[144–147], gastrointestinal vasculitis [148–150] and lupus perito-
nitis [151–153] exist. About half of all patients, equally distributed
over the different manifestations, were treated with iv pulse GCs in
a dosage of 3 × 1 g. Oral treatment ranged from 20 mg to 1.5 mg/kg
in all gastrointestinal manifestations independent of induction
pulse therapy. Remission rates were high in all publications, rang-
ing 80–100%. Co-medication consisted mainly of azathioprine and
in some cases cyclophosphamide, plasmapheresis or intravenous
immunoglobulines.
4.7. Musculoskeletal
There are no RCT, cohort studies or case series on the treatment of
musculoskeletal manifestations of SLE with GCs. Only 4 case reports
were found; 4 on arthritis [140,145,154,155] and one on myositis
[156]. Pulse therapy was only used in one case report on arthritis.
Oral prednisone was used in a low dosage up to 10 mg. Myositis
was treated with 60 mg prednisolone in combination with cyclo-
phosphamide and resulted in remission of symptoms with normal-
ization of serum creatine kinase.
4.8. Neurologic
Neurologic manifestations of SLE are diverse, and some can be life
threatening, prompting a variety of reports on treatment possibili-
ties. However, most are case reports [105,155,157–185], with some
case series [186–188], four cohort studies [189–192], two open
label studies [193,194] and only one RCT [195]. The RCT investigated
cyclophosphamide versus methylprednisolone in severe neurologic
manifestations of SLE, like seizures, coma, peripheral neuropathy,
optic neuritis and transverse myelitis. All patients received induction
with methylprednisolone (MP) 1 g daily for 3 days and were then ran-
domized to either cyclophosphamide 0.75 g/m 2 every month for one
year followed by 3 monthly for one year, or 3 days 1 g MP daily every
month for 4 months, then bimonthly for 6 months and subsequently
every 3 months for 1 year. In total 32 patients were treated. One of
the 19 patients in the cyclophosphamide group compared to 7 of 13
in the MP group was categorized as treatment failure. Combination
therapy with Cyclophosphamide was clearly better than GCs alone in
reducing most symptoms (except coma and transverse myelitis) and
disease activity (SLE Disease Activity Index). [195].
Intravenous pulse therapy methylprednisolone was used in 75%
of patients in a dosage ranging from 3 × 500 mg to 5 × 1000 mg. In
the remaining publications patients were treated with only oral
GCs, mostly in combination with cyclophosphamide and/or plasma-
pheresis. Oral maintenance therapy was usually at least 1 mg/kg
prednisolone with the exception of psychosis-treatment, which
was treated with low dose to 2 mg/kg with similar response rates
(complete remission 50–100%). Results of the different manifesta-
tions are listed in Table 2.
4.9. Ophthalmologic
The best described ocular manifestation of SLE is neuromyelitis
optica, also known as M. Devic. Its treatment is only described in
case reports [196–203] and two case series of 6 patients [204,205].
Iv pulse therapy is prescribed in 65% of cases in a dosage of 3 × 1 g
to 7 × 1 g. Oral prednisone dose as induction or maintenance ranged
from 25 mg to 2 mg/kg with recovery in all but one patient. In
 R.K.M.A.C. Luijten et al. / Autoimmunity Reviews 12 (2013) 617–628
three case reports GC treatment was combined with plasmapheresis
and in two case series with azathioprine.
4.10. Hematologic
Hematologic manifestations are common in routine clinical prac-
tice in SLE patients. The most frequent abnormalities are mild
leucocytopenia and thrombocytopenia, which often do not require
treatment. Pulse therapy (MP 3 × 40 mg–3 × 30 mg/kg) has been
given for severe leuco- and thrombocytopenia's [37,206–213],
hemophagocytosis syndrome (HPS) [214–221] and aplastic anemia
[222–224]. Auto-immune hemolytic anemia (AIHA) was treated
with pulse therapy in 17% of described cases, generally in a dose
of 3 × 500 mg MP. [209,223,225–233]. Oral GC dose ranges from
30 mg in AIHA to 1–2 mg/kg in severe HPS.
Thrombocytopenia is usually treated with 40 mg up till1mg/kg
and aplastic anemia with 1 mg/kg. Efficacy, measured by resolving
hematologic abnormalities, is documented with response rates
around 70%, in which GC treatment is often combined with e.g.
intravenous immunoglobulines, cyclophosphamide, plasmaphere-
sis or Rituximab. Case reports or series without co-medication
show no effect or quick relapse in approximately 40–50%. A case
series of steroid refractory TTP showed recovery after adding cyclo-
phosphamide and one case report showed complete recovery after
plasmapheresis.
4.11. Lupus cystitis
In 8 case reports, 7 out of 9 patients with lupus cystitis were treated
with pulse therapy in dosages ranging from 3 times 750 mg to
1000 mg. This was followed in all patients by an oral prednisone dose
of 20–60 mg with a complete recovery in all patients [90,129,234–238].
5. Intravenous pulse treatment
As shown above intravenous pulse therapy is variably used in all
disease manifestations. The rationale behind this is a more rapid,
longer lasting and stronger immunosuppressive effect via genomic
and non-genomic pathways compared to lower oral prednisone
dosages [239]. The most frequently (> 95%) used drug in pulse
therapy is methylprednisolone (MP) in a dose of 1000 mg once
daily for 3 subsequent days. With regard to efficacy, a double blinded
RCT showed that 3 × 100 mg was as effective as 3 × 1000 mg on a
4-point scale (ideal response, useful response, static state or worsening)
at three months. Patients in this study suffered from fever, rash and
involvement of one or more organs, such as kidneys or brain and
showed 3 ideal responses, 8 useful responses, 6 static states and 4
worsening [240]. A retrospective study compared the effects of
different dosages of iv pulse therapy: 1–1.5 g methylprednisolone
(MP) vs. 3–5 g MP in SLE patients with flares in different organs.
Both dosages were equally effective (quantified by a decrease in
SLEDAI score), but the higher prednisone dose group experienced
more infections in (OR 3.34 (90%CI 1.29–8.65)) [241]. This was
confirmed in a literature review by the same author a year later
[239].
On the other hand iv pulses cause less hypothalamic–pituitary–
adrenal axis (HPA) suppression compared to oral prednisone. After
intravenous methylprednisolone, endogenous cortisol and HPA is
reduced for respectively 24 h and 2–3 days, while 20 mg oral pred-
nisone for as few as 5 days causes HPA suppression for several
months [242].
The generally accepted use and dose of pulse therapy per manifes-
tation is described in Table 2.
623
6. Tapering
To avoid side-effects of long-term use of GCs, the cumulative
GC-dose should be kept as low as possible. A sudden cessation of GC
medication may result in GC withdrawal symptoms, caused either by
flaring of the underlying disease or by insufficiency of the adrenal
gland, which has been suppressed through long-term GC medication.
For daily clinical practice an optimal tapering regimen remains a chal-
lenge. Tapering schedules are rarely mentioned in literature reports
with the exception of randomized clinical trials (mainly nephritis trials)
which in turn describe very different induction regimes. In these trials
the first weeks/months of tapering is described, however tapering on
the long term after induction therapies is not described in recent litera-
ture. In early nephritis trials (before 1990) tapering was mentioned
more often; however concomitant therapies used back than are not
comparable with those used nowadays.
In clinical practice tapering is carried out based on the physician's
own insight and experience. GCs can be tapered 4–6 weeks after start
of therapy with 5–10 mg every 2–4 weeks down to a daily dose of
20 mg and thereafter with 2.5-5 mg every 2–4 weeks to a mainte-
nance dose of 10 mg for at least 6 months as described by two trials
on withdrawing of medication in lupus nephritis. [243,244].
Thereafter tapering is possible in many, but not in all patients; in
daily practice many SLE patients are doing well on 2.5–5 mg GCs
daily.
7. Conclusions and discussion
In this review we accumulated published reports in order to sug-
gest evidence based recommendations about GC treatment of diverse
SLE manifestations. It appears that despite 60 years of experience, no
guidelines can be formulated on the optimal GC dose in different SLE
disease manifestations based on current literature reports [245]. It is
striking that nearly all reports are descriptive and heterogeneous in
oral dosages, application of pulse therapy and in tapering schemes.
An alternative way to tackle the problem of appropriate use of
GCs per SLE manifestation is to adjust the dose to the predominant
cell type responsible for the respective manifestation, assuming a
difference in reactivity to GCs in different cell types. However,
although different cell types have been implicated in organ specific
damage, e.g. certain subsets of T cells in nephritis [246,247] or pDC
in skin inflammation, SLE is a multi-organ systemic disease, and a
flare in one organ often carries a systemic immunological reaction
with it, making such a targeted approach difficult. Furthermore,
little is known about the different GC-sensitivity in blood cells of
SLE patients. A direct extrapolation of the situation in healthy sub-
jects does not seem appropriate, as suggested by a study showing
that pDCs of SLE patients responded to much higher GC dosages
than “healthy” pDCs [17]. Our increased knowledge on the patho-
physiology of SLE and mode of action of GCs is far from incorporat-
ed in daily practice. Further research is needed to investigate
whether GC-dose can be based on pathophysiologic grounds in
different manifestations.
Table 3
Stratified glucocorticoid dosages.
Eular-grading Stratification Indications
Low dose (b7.5 mg) b7.5 mg Musculoskeletal
Medium dose (7.5–30 mg) 7.5–30 mg General, skin, serositis
High dose (30–100 mg) 30–40 mg Skin, serositis, psychosis
40–100 mg Gastro-intestinal, hematologic,
renal, neuropsychiatric
Very high dose (>100 mg) >100 mg Neuropsychiatric
624 R.K.M.A.C. Luijten et al. / Autoimmunity Reviews 12 (2013) 617–628
This review shows that our clinical decision making concerning
the use of GCs in SLE patients is often based on clinical experience,
making it more an art than science. The heterogeneity of published
data makes it impossible to give adequate evidence based recommen-
dations for the appropriate GC dose per manifestation.
In an attempt to give guidance in GC treatment for different
manifestations of SLE we propose the recommendations listed in
Table 3. However, we realize that judgment and experience of the
treating physician still is the most important guide for the use of
GCs in the treatment of SLE.
Take-home messages
• Glucocorticoids are the cornerstone of treatment in Systemic Lupus
Erythematosus.
• There is scarce scientific evidence for dosage and duration of steroid
use in different lupus manifestations.
• Clinical decision making is often based on clinical experience rather
than evidence.
• Based on all trials, case series and case reports we made stratified
recommendation as shown in Table 3.
Acknowledgement
We thank Jonas Kuiper for designing the illustrations.
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Intravenous cyclophosphamide is superior to azathioprine in preventing renal flares in a long term follow-up in patients affected with
systemic lupus erythematosus

The first Duch Lupus Nephritis Study enrolled 87 patients with biopsy proven lupus nephritis and randomly assigned azathioprine (AZA, 2 mg/
kg/die) plus intravenous methylprednisolone (ivMP, 3 pulses of 1000 mg repeated after 2 and 6 weeks), or intravenous cyclophosphamide
(ivCYC, 750 mg/m2 every 4 weeks for 6 month and then 7 pulses every 12 week), both combined with oral prednisone (OP). After 2 years both
groups were treated with AZA and OP. No differences in doubling of creatinine, renal relapses rate, renal function at last visit was found after a
median follow-up of 6.4 years. Notably, the 2-year repeat biopsy showed a higher increase of cronicity index in patients treated with ivMP and
AZA compared with ivCYC group.
Arends et al. (Ann Rheum Dis 2012;71:966-73) investigate the renal outcome in patients enrolled in the Duch Lupus Nephritis Study after a
longer follow-up.
The Authors did not found any difference between AZA/ivMP and ivCYC group in doubling of creatinine, end stage renal disease and overall
mortality rates after a median follow-up of 9.6 years. However, renal relapse occurred more often in the group of patients treated with AZA
and ivMP compared with patients treated with ivCYC (38% vs 10% respectively, p=0.002, HR: 4.5).
The Authors concluded that ivCYC is superior in the prevention of renal flare when compared with AZA plus ivMP. Moreover, the Authors
suggest that AZA plus ivMP might be an alternative treatment for patients with lupus nephritis, especially for those patients who wish to avoid
infertility or have high risk of premature gonadic failure. However, it should be considered that an increased follow-up might be required to
bring out the differences between the two treatment groups in other renal outcome parameters.

Luca Iaccarino