(updates in) drug therapy for sle - academy of medicine ... management of lupus nephritis • has...
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10th Medicine Review Course 2018
(Updates in) Drug Therapy for SLE
Dr. Tay Sen Hee, Frank
Consultant
Division of Rheumatology
Department of Medicine
National University Health System
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Disclosures
• None
• This presentation may refer to the off-label use of medications that are not FDA-approved for SLE
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Has treatment in SLE changed?
• FDA-approved medications in 2008
• Aspirin, corticosteroids and hydroxychloroquine (HCQ)
• FDA-approved medications in 2018
• Aspirin, corticosteroids, HCQ and belimumab
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The Disturbing Landscape of SLE Trials
B cell and plasma cell -
targeting trials
Anti-CD20
• Rituximab (Failed) • Ocrelizumab (Failed)
Anti-CD22
• Epratuzumab (Failed) Anti-BAFF • Tabalumab (Failed) • Belimumab (Positive) • Blisibimod (Failed)
Proteazome inhibitor • Bortezomib (Toxicity)
Costimulatory pathway -
targeting trial
CTLA4Ig
• Abatacept (Failed)
Type I IFN - targeting
trials
Anti-IFNα
• Rontalizumab (Failed) • Ocrelizumab (Failed)
Anti-IFNAR
• Anifrolumab (Ongoing)
1) Merrill JT et al. Arthritis Rheumatol 2010.
2) Rovin BH et al. Arthritis Rheumatol 2012.
3) Clowse ME et al. Arthritis Rheumatol 2017.
4) Isenberg DA et al. Ann Rheum Dis 2016.
5) Navarra SV et al. Lancet 2011.
6) Furie R et al. Arthritis Rheumatol 2011.
7) Merrill JT et al. Ann Rheum Dis 2018.
8) Ishii T et al. Mod Rheumatol 2018.
9) Furie R et al. Arthritis Rheumatol 2014.
10) Kalunian KC et al. Ann Rheum Dis 2016.
11) Mysler EF et al. Arthritis Rheumatol 2013.
12) Furie R et al. Arthritis Rheumatol 2017.
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80 patients with 5 or more visits
ER: Erythropoiesis
IFN: IFN response/neutrophils
ML: Myeloid lineage/neutrophils
PB: Plasmablasts
LL: Lymphoid lineage
IFN blockade?
B cell/Plasma cell
- targeted therapy?
Both?
Personalized Immunomonitoring in SLE
Banchereau R JT et al. Cell 2016.
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Individualized Treatment in SLE
Vasculitis
Lupus nephritis (LN)
NPSLE
Pulmonary
hemorrhage
Lupus enteritis
TTP
Oral ulcer
Arthralgia
Mild cytopenia
Cutaneous LE
Fever
Myositis
Arthritis
Serositis
Cytopenia
Major Minor
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Individualized Treatment in SLE
Aggressive immunosuppression
IV methylprednisolone (500 mg - 1
g/day × 3)
IV cyclophosphamide (CYC)
Mycophenolate mofetil (MMF) (500
mg - 2 g/day)
Cyclosporin (3-5 mg/kg/day)
[IVIG, rituximab, HSCT]
Less aggressive immunosuppresion
Prednisolone (< 0.5 mg/kg/day)
Azathioprine (1-2 mg/kg/day)
HCQ (200-400 mg/day)
NSAIDs
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Changing Treatment Paradigms in SLE
• MMF as an option to NIH protocol of IV CYC in the treatment of LN
• Euro-Lupus regimen of low dose IV CYC in Europe
• More use of MMF in general
• Off-label use of rituximab in moderate-to-severely active SLE
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Corticosteroids
• Corticosteroids are one of the main pillars of therapy in SLE
• Effective in vast majority of patients
• Many formulations, doses and routes of administration
• Systemic therapy: oral and intravenous routes
• Pulse therapy: organ threatening disease
• Cutaneous disease: Topical, intralesional
• Musculoskeletal: Intra-articular
• Ophthalmic: intra-occular
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Double-Edged Sword
• Controls disease activity and improve outcomes
• Prolonged use leads to increase risk of complications
• Diabetes, hypertension, hyperlipidemia, weight gain, infections, osteoporotic fractures, osteonecrosis, myopathy, cataracts, skin fragility and neuropsychological effects
• In SLE: increased organ damage and cardiovascular risk with prolonged use of steroids
• Both current and cumulative doses are important contributors
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Cardiovascular risk
Magder LS et al. Am J Epidemiol 2012.
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Is there a safe dose or duration?
Thamer M et al. J Rheumatol 2009. Gladman D et al. J Rheumatol 2003.
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Consensus for glucocorticoid use in SLE
• There is no safe dose or duration for chronic use
• Risk goes higher with increasing doses
• Use lowest possible dose
• Early use of steroid sparer
• Attempt steroid withdrawal
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Antimalarial Agents
• HCQ: commonly used anti-malarial in SLE patients
• Multiple beneficial effects documented
• Reduces disease activity and flares
• Reduces damage accrual
• Improves survival
• Protects against thrombosis, even in aPL-positive patients
• Lipid-lowering properties and improved glycaemic control, even in patients on steroids
• Improves response to other immunosuppressants (e.g. MMF)
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Antimalarial Agents
Wallace DJ et al. Nat Rev Rheumatol 2012.
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Caution: Ophthalmic toxicity
• Concerns often leads to underutilization
• Bull’s eye maculopathy
• <1% with HCQ use >5 years
• Cumulative dose of 1000 g is considered safe limit
• Adjust dose according to lean body mass
• Screen at baseline and then 5 yearly (if no risk factors)
• Caution in elderly, renal and liver impairment
• Underlying retinal disease: relative CI
• Corneal deposits
• 10% with hydroxychloroquine, reversible
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Current Recommendations
• HCQ should be given to all SLE patients unless contra-indicated or intolerant
• Continue even if patient is on other immunosuppressants
• Continue during pregnancy
• Be mindful of cumulative dose
• Screen for ophthalmic toxicity according to standard guidelines
Marmor MF et al. Ophthalmology 2011.
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Management of Lupus Nephritis
• Has evolved over the decades
• 1980s: CYC in combination with steroids superior to azathioprine (with steroids) or steroids alone
• NIH Protocol: IV CYC 0.5–1 g/m2 monthly for 6 months, associated with significant toxicity
• Alternate options emerged:
• Low dose Euro-Lupus regimen (500 mg every 2 weeks for 3 months), similar efficacy to high dose CYC
• MMF
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Mycophenolate in Lupus Nephritis
• Trials have shown mixed results
• Conclusion: another option for treatment of LN
• Pros and cons: less toxic, no long term data
Dall’Era M. Curr Opin Rheumatol 2011.
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Refractory Lupus Nephritis
• Calcineurin inhibitors:
• Accumulating evidence of efficacy
• Beneficial effects on proteinuria (podocyte effect)
• Safe during pregnancy
• Caveat: rebound proteinuria, toxicity profile (hypertension, renal impairment)
• Combination therapies:
• MMF + tacrolimus
• Limited data
Zavada J et al Lupus 2014.
Bao H et al. J Am Soc Nephrol 2008.
Lee YH et al. Lupus 2011.
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Voclosporin (VCA) vs Cyclosporin (CSA)
https://investorshub.advfn.com/Aurinia-Pharmaceuticals-Inc-AUPH-17672/
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AURA LV – global phase II trial in patients with active LN (NCT02141672) (n =
265, 20 countries)
• DB-RCT, on top of SOC (MMF 2 g/day + steroid taper 20-25 mg/day 5 mg/day at week 8 2.5 mg/day week16-24)
• Definition of CR = UPCR < 0.5 mg/mg, eGFR > 60 mL/min without a decrease of > 20% from baseline, low-dose steroid at least > 8/52 prior to endpoint assessment
• Definition of partial response (PR): 50% reduction in proteinuria from baseline
N=89 N=88 N=88
N=265
VCS 23.7mg BD SOC
VCS 39.5mg BD
10 endpoint CR at 24 weeks
20 endpoint CR at 48 weeks Times to CR and PR at 24 & 48 weeks
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AURA LV – global phase II trial in patients with active LN (NCT02141672) (n =
265, 20 countries)
24-week:
Low dose vs PBO: CR 32.6% vs 19.3% (OR 2.03, p = 0.045)
High dose vs PBO: CR 27.3% vs 19.3% (p = ns)
PR – superior in all Tx groups c.f. PBO
48 week:
Low dose vs PBO: CR 49.4% vs 29.6% (OR 3.21 p < 0.001)
High dose vs PBO: CR 39.8% vs 29.6% (OR 2.1, p = 0.026)
All low-dose patients in CR at 24 weeks remained CR at 48 weeks
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Belimumab
• Two large phase-III randomised controlled trials (BLISS-52, BLISS-76)
• Compared to placebo, belimumab in addition to standard of care leads to:
• Improved overall SLE disease activity
• Reduced risk of severe flares
• Reduced steroid use
• Reductions in autoantibody levels
• Well tolerated with no safety signal
Navarra SV et al. Lancet 2011.
Furie R et al. Arthritis Rheumatol. 2011.
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Belimumab – A note of caution
Navarra SV et al. Lancet 2011.
Furie R et al. Arthritis Rheumatol. 2011.
Manzi S et al. Ann Rheum Dis 2012.
• Patients with severe disease including LN and NPSLE were excluded
• High response rate in placebo group
• Indications for clinical use are limited and yet to be defined clearly
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Endogenous Anti-BAFF in Local SLE Patients
Howe HS et al. Clin Exp Immunol 2017.
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Anifrolumab – global phase II trial in patients with active SLE (n = 307, 15
countries) -> phase III trial
• 305 patients stratified 1:1:1 to
placebo: anifrolumab 300 mg:
anifrolumab 1000 mg
• Stratified by type I IFN gene
signature (high or low)
• Primary endpoint of SRI and
sustained corticosteroid tapering
at week 24 Furie R et al. Arthritis Rheumatol 2017.
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Anifrolumab – global phase II trial in patients with active SLE (n = 307, 15
countries) -> phase III trial
Furie R et al. Arthritis Rheumatol 2017.
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Take Home Message
• SLE is a heterogenous autoimmine disease
• Personalized medicine to stratify SLE patients for future trial enrolments
• Treatment of SLE is ultimately individualized
• Non-pharmacological approach: holistic multidisplinary management
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10th Medicine Review Course 2018
Thank You