Out line

o Introduction
o The Mechanism of Action of Corticosteroids
o Forms of Corticosteroids
o Should High Doses of Prednisonse Be Still Considered the Standard
Starting Dose ?
- The ‘’classical paradigm’’ in SLE therapy
- The ‘’new paradigm’’ in SLE therapy
o Can Cs-Related Damage Be Avoided without Reducing Efficacy?
o How Can the Risk of Infections Be Reduced during Cs treatment?
o The Current Recommendation
o Standard of Care for Cs Use
o Summary
Introduction
• Systemic Lupus Erythematosus (SLE) is a complex disease, characterized
by autoimmunity, inflammation, and a variable degree of organ damage.
• The progression depends on the number of organ damage, severity of
flares and the treatments received.
• Most guidelines refer to “standard of care” as a combination of ;
Hydroxychloroquine and Corticosteroids (Cs).
Sometimes added by an immunosuppressive agent.
• The therapy often achieves disease remission, but many times the degree of
damage accrual.
Introduction (con’t)
• Irreversible organ damage is relatively frequent in SLE, and
most of the patients are young or middle-aged women.
• Based on some of the scientific evidence, use of Cs can be associated with; -
- Serious side effects and
- Secondary infections
→ Irreversible damage,
• Recently updated European League Against Rheumatism (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.
The Mechanism of Action of Corticosteroids

o The steroid is present in the blood bound to corticosteroid-

binding globulin (CBG) but enters the cell as the free
molecule.
o The interaction of a steroid (S; eg, cortisol), with its
receptor (R)and the subsequent events in a target cell.
oThe intracellular receptor is bound to stabilizing proteins,
including heat shock protein 90 (Hsp-90) and several
others.
o When the complex binds a molecule of steroid, the Hsp-90
and associated molecules are released.
o The steroid-receptor complex enters the nucleus as a
dimer, binds to the glucocorticoid response element (GRE)
on the gene,and regulates gene transcription.
o The resulting mRNA is edited and exported to the cytoplasm
for the production of protein that brings about the final
hormone response.

S : Steroid ; CBG : Corticosteroid Binding Globulin ; R : reseptor Hsp 90 : Heat – shock protein 90;
GRE : Glucocorticoid Response Element

Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009
The Mechanism of Action of Corticosteroids (con’t)
The first mechanism of action of Glucocorticoids (GCs)
→ - GCs binding the cytosolic-GC receptor (cGR) → GC-cGR complex
- The GC-cGR complex is translocated into the nucleus where it modulates
gene expression [ GENOMIC PATHWAY]

- The GC-cGR complex effect → transrepression (inhibition the genes which

promote cytokine and other protein synthesis involved in the inflammatory
process) → resulting anti-inflammatory effect.

J. Clin. Med. 2020, 9, 2709

The Mechanism of Action of Corticosteroids (con’t)
The second mechanism of action of Glucocorticoids (GCs)
→ By modulating inflammatory and Immune cells :
1. The GC-cGR complex block the activation of phospholypase A (PLA)-2
→ Arachidonic acid
2. The reduction of Lymphocyte activity
3. Inhibition of ATP production → reduction of Immune cells activity
[NON-GENOMIC PATHWAY]
The activation of non-genomic pathway :
- Starts at doses > 100 mg/day of prednisone.
- This pathway is especially sensitive to MP and dexamethasone
- Responsible for efficacy of pulse therapy with GCs at doses over 125 mg of MP .
J. Clin. Med. 2020, 9, 2709
Forms of Corticosteroids
Corticosteroid Equivalent Plasma Biologic Relative Anti- Relative Protein
Commercial Halflife Halflife inflammatory Mineralocorticoid Binding
(min) (h) Effect Effect

Short Acting
Cortisone 25 30 8-12 0.8 0.8 None
Cortisol 20 90-120 8-12 1 1 Very High
Intermediate Acting
Methylprednisolone 4 >180 12-36 5 0.5 None
Prednisolone (Lupred) 5 200 12-36 4 0.6 High
Prednisone 5 200 12-36 4 0.6 Very High

Triamcinolone 4 200 12-36 5 0 High

Long Acting

Dexamethasone 0.75 180-270 48 25 0 High

Betamethasone 0.65 180-300 48 25 0 High

Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-801917-7.00061-9

Should High Doses of Prednisonse Be Still
Considered the Standard
• The “classical” standard 1 mg/kg/day prednisone dose is not supported by
either basic pharmacology or clinical evidence (Figure 1).
• Recent data suggest, higher initial doses of prednisone are associated with higher
cumulative doses with the well proven result of increasing damage accrual.
• A European multicenter randomized controlled study; The comparison
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 LN. The complete remission rates at week 24
were similar for both groups, with fewer infections in the reduced prednisone
dose group.
The ‘’classical paradigm’’ in SLE therapy
(Figure 1)
Hydroxychloroquin 200 mg (Farneltik)(eventually)

Introduction of Immunosuppressive agents once the patient is stable

Not defined
500-1000 Prednisone PDN
tapering
mg/pulse 1 mg/kg/day 2.5 – 5 mg/day
schedule
Clinical
Flare 3 days 4 to 6 weeks Response

Clinical picture

Months (up to 1 year)

MP x 3
(rarely in a
mild to
Adverse
moderate
effects Effectiveness
flares)

J Clin Med, 2020, 9: 2709

PDN = prednisone MP = methylprednisolone
Should High Doses of Prednisonse Be Still Considered
the Standard (con’t)
o The combination of MP pulse doses (125-500 mg/day), followed by doses of
prednisone up to 30mg/day, depending on severity, is more effective, more
rapid, and safer than the use of the “classical” 1 mg/kg/day (Figure 2).
o 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.
The ‘’new paradigm’’ in SLE therapy
(Figure 2)

Hydroxychloroquine 200 mg (Farneltik)(rarely contraindicated)

Early introduction of immunosuppressive agents

PDN PDN
125-500 PDN 30 PDN 15
7.5 5-2.5
mg/pulse mg/day mg/day
mg/day mg/day
Clinical
Flare 3 days 2 weeks 2 weeks 2 weeks 2 weeks 4 weeks onwards Response

PDN PDN
20 10 Clinical picture
mg/day mg/day
Adverse
MP x 3
(rarely in a
effects
mild to
moderate
12 weeks
Effectiveness
flares)

J Clin Med, 2020, 9: 2709

Can GCs-Related Damage Be Avoided without
Reducing Efficacy?
o There are several factors that contribute to organ damage accrual in patients
with SLE. The role of GCs has proven fundamental.
o In the Hopkins cohort, has been shown that GC-related irreversible damage
depend on the cumulative dose of prednisone.
o Hydroxychloroquine helps spare prednisone and, by it self, also prevents
damage accrual.
o Ruiz-Arruza et al, found that the use of this treatment scheme
(The New Paradigm in SLE therapy) achieved the same efficacy , with
no increase in SLE-related damage.
Can GCs-Related Damage Be Avoided without
Reducing Efficacy?
o The study reported 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.
o Therefore, long-term therapy with low-dose GC may be necessary
in a number of SLE patients.
How Can the Risk of Infections Be Reduced
during GCs treatment?
• Infections as one of the most important causes of morbidity and
mortality in patients with SLE.
• The predisposing factors of infection in lupus patients are; not only
disease activity and the malfunction of the immune system, but also the
use of immunosuppressive drugs, particularly GCs.
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.
The Current Recommendation
• The current recommendations are ;
- a SLE flare is diagnosed,
- to achieve remission or low disease activity as soon as possible,
- prevent new flares.
• 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 that low doses is 7.5–5 mg/day of prednisone or
equivalent.
• Since no consensus about tapering has been established, such doses can be
reached within variable periods ranging from 4 weeks to up to 12 months.
Standard of Care for Corticosteroids Use
HCQ + photo protection + adequate levels of vitamin D + control of cardiovascular risk factors + tobacco cessation

Mild activity Moderate activity Severe activity

MP(250-500 mg/day for 3 days) OR

MP(125-250 mg/day for 3 days)
Dexamethasone 40 mg/day x 4 days

Mepacrine PDN 5-10 Cyclosphosphamide 500 PDN 20-10

PDN 2.5-7.5 and/or* mg (+MP 125 mg) every
mg/day mg/day mg/day
2 weeks for 3-6 months
Methotrexate
and/or*
and/or*
Mycophenolate and/or*
Azathioprine Tapered down within 12
Tapered down Tacrolimus/Cyclosporin
Tapered down over 1-2 and/or* weeks maximum to 5
over 1-2 weeks and/or*
weeks to 2.5 mg/day Belimumab* to 2.5-5 mg/day
mg/day (20-15-10-7.5)
Rituximab*

Improvement? Improvement? Improvement?

NO: Repeat in 2-4 weeks MP (125-250 mg/day for 3 NO: Repeat in 2-4 weeks MP (250-500 mg/day for 3 days)
NO: Treat as moderate activity days) OR Dexamethasone 40 mg/day x4 days

YES: HCQ 200 mg/day + PDN 2.5-5 mg/day + YES: HCQ 200 mg/day + PDN 2.5-5 mg/day +- Azathioprine
YES: HCQ 200 mg/day + PDN 2.5 mg/day Mepacrine/Methotrexate/Azathioprine/Belumumab* / Mycophenolate /Tacrolimus/Cysclosporin/Rituximab*

HCQ = Hydroxychloroquine MP = methylprednisolone PDN = prednisolone J. Clin. Med. 2020, 9, 2709

Summary
▪ Systemic Lupus Erythematosus (SLE) remains a challenging
disorder that requires an interdisciplinary approach
▪ The classic glucocorticoid dose of 1 mg/kg/day is not evidence-
supported and has a well-known range of serious adverse effects
▪ By giving methylprednisolone pulse doses followed by a reduced
dose scheme of prednisone may avoid adverse effect and chronic
damage.
Summary (con’t)
▪ Immunosuppressive agents should be early introduced in the
treatment of moderate-severe SLE to spare glucocorticoids
▪ 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.