Nou si vechi in tratamentul lupusului

eritematos sistemic

Dr. Daniela Opris-Belinski

Spitalul Clinic Sf. Maria-UMF Carol Davila
Bucuresti
 LUPUSUL ERITEMATOS SISTEMIC

Caracteristici:
Boala inflamatoare cronica cu afectare multisistemica
Pierderea tolerantei la self si aparitia fenomenelor autoimune
Prototip de boala autoimuna cu aparitia unei game largi de autoAc
Autoanticorpii determina distrugeri celulare si tisulare prin reactia
de citotoxicitate sau prin formarea complexe imune.
 Frecventa cumulativa a manifestarilor clinice: LES
 Alegerea tratamentului ghidata de simptome principale/organul afectat

Manifestare Frecventa
Simptome constitutionale 90%-95%
Leziuni cutaneo-mucoase 80%-90%
Afectare musculo-scheletala 80%-90%
Serozita 50%-70%
Glomerulonefrita 40%-60%
Afectare neuropsihiatrica 40%-60%
Citopenie autoimuna 20%-30%
 Date limitate referitoare la managementul manifestarilor specifice cu exceptia
celor cutanate si renale
Vitali C et al.Clin Exp Rheumatol 1992
Optiuni terapeutice in Lupusul Eritematos Sistemic

 Singurele tratamente aprobate : 1955 - CS, Hidroxicloroquin

2011 – Belimumab
 Off-label: CYC, MMF, AZA, RTX, ciclosporina, tacrolimus

 Medicamentul ideal:
- reduce activitatea bolii
- asigura supravietuirea pe termen lung
- previne leziunile ireversibile de organ
- amelioreaza calitatea vietii
- toxicitate minima
1.van Vollenhoven RF, et al. Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Ann Rheum Dis 2014
2.Bertsias G, et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing
Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis 2008; 67:195.
Boala cu 1000 de
feţe!

Cimitirul
terapiilor!
 Trialuri clinice in LES (2018)
607 studii inregistrate 177: active/recruteaza/vor incepe

Cimitirul
terapiilor!

https://www.clinicaltrials.gov/ct2/results/map?recrs=abd&cond=Lupus+Erythematosus&map=
 Ce e “vechi” in tratamentul LES: CS

Utilizati in majoritatea tipurilor de afectare

Actiune rapida cu facilitarea controlului manifestarilor de boala
Administrarea prelungita de doze mari:
- creste riscul cardiovascular (1)
- cresterea comorbiditatilor (1-3)
- influentarea mortalitatii pe termen lung (3,4)
1. Gustafsson J, et al. Risk factors for cardiovascular mortality in patients with systemic lupus erythematosus, a prospective cohort study. Arthritis Res Ther 2012;
2. Gladman DD, Urowitz MB, Rahman P, et al. Accrual of organ damage over time in patients with systemic lupus erythematosus, J Rheumatol , 2003, vol. 30 (pg. 1955-59)
3. Faurschou M, Dreyer L, Kamper A, et al. Long-term mortality and renal outcome in a cohort of 100 patients with lupus nephritis, Arthritis Care Res , 2010, vol. 62 (pg. 873-80)
4. Toloza SM, et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXII. Predictors of time to the occurrence of initial damage. Arthritis Rheum 2004; 50:3177.
5. Al Sawah S, et al. Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus—the Hopkins Lupus Cohort. Lupus Sci Med 2015
 Analiza the Hopkins Lupus Cohort privind impactul dozei de CS asupra
aparitiei afectarii de organ, 2265 pts: 1987-oct 2012

≥20mg/zi RR x 2 vs <7,5 mg/zi (HR=2.514, p<0.001)

RR pentru afectarea de organ doze ≥7,5 mg/zi vs <7,5 mg/zi:
 Semnificativ pentru: - cataracta (HR=2.41, p<0.001)
- fr. osteopototice(HR=2.16, p<0.001)
- afectare cv (HR=1.54, p=0.041)
 Nesemnificativ pentru afectarea renala (HR=1.44, p=0.163)
 Ce e “vechi” in tratamentul LES: Hidroxicloroquin
• 1955 - afectarea cutanata si articulara
• ……………………
• >1990 - scade probabilitatea de aparitie a acutizarilor de boala (1,2)
• > 2000 - posibil efect antitrombotic (3)
- faciliteaza raspunsul nefritei lupice la MMF (4)
- amelioreaza supravietuirea (3-8)
- scade necesarul de cortizon (5)
• 2017 - preventie primara a afectarii cardiovasculare in LES (8,9)
1. Tsakonas E, et al. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. Canadian Hydroxychloroquine Study Group. Lupus 1998
2. Fessler BJ, et al. Systemic lupus erythematosus in three ethnic groups. XVI: Association of hydroxychloroquine use with reduced risk of damage accrual, Arthritis Rheum 2005
3. Ruiz-Irastorza G, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 2006
4. Kasitanon N, et al Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis. Lupus 2006
5. Andrade RM, Alarcon GS. Antimalarials in systemic lupus erythematosus: benefits beyond disease activity. Future Rheumatol 2006
6. Alarcon G et al, Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort, Ann Rheum Dis 2007
7. Akhavan PS, et al, The early protective effect of hydroxychloroquine on the risk of cumulative damage in patients with systemic lupus erythematosus, J Rheum 2013
8. Ponticelli C, Hydroxychloroquine in systemic lupus erythematosus (SLE), Expert Opinion on Drug Safety, 2016
9. Fasano S, et al, Primary prevention of cardiovascular disease in patients with systemic lupus erythematosus: case series and literature review, Lupus 2017
 Evolutia mortalitatii in functie de progresul
terapeutic
1970-1990
Methotrexat
Transplant renal
2011
1950-1954 Plasmafereza
Belimumab
CORTICOSTEROIZI Ciclosporina
Supravietuire la 5 ani 50% 10 year survival >80%

2000-2010
1960-1970 Mycophenolate mofetil
1940-1950
CICLOFOSFAMIDA Biologice , Rituximab
ANTIMALARICE
AZATIOPRINA
Dializa
Supravietuire la 10 ani Imbunatatirea tratamentului
>60% antibiotic, antihipertensiv si
antitrombotic
Adapted from Manzi S ,ACR 2012
 Utilizarea Ciclofosfamidei in LES
Agent alchilant, unul dintre cele mai potente imunosupresoare
Prodrog convertit la forma active (in principal) in ficat
Indicat: nefrita lupica si forme severe de boala (SLEDAI >12) (1971)

2012

2018

1. Gourley MF, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996
2. Houssiau FA, et al. Immunosuppressive therapy in lupus nephritis: the EuroLupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.
Arthritis Rheum 2002
3. Houssiau FA, et al. The 10year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis 2010
 2012

NL III, IV CYC 3 g/3l sau MMF 3g/zi 6l + CS

Daca exista factori de prognostic prost CYC 0,75-1 g/m2 6l
Pentru cresterea eficientei initial 3 pulsuri consecutive de Mp 500-
750 mg, apoi Prednison 0,5 mg/kc/zi 4 sapt cu scadere ulterioara
Cls V MMF 3 g/zi 6 luni + 0,5 mg/kc/zi Prednison (alternative
ciclosporina, RTX)
AZA 2 mg/kc/zi la pacientii fara f prognostic prost/cu contraindicatii
 CICLOFOSFAMIDA siguranta…
Leucopenie, imunosupresie, infectii (B)
Cistita hemoragica (MESNA), carcinom scuamos vezica urinara
Mielo/limfoproliferari
Hiponatremie severa - SIADH (administrare iv)
CYC VARSTA CREAT Leu la 10-14 zile Leucocite
Iv  60 12,5 mg/kc >3,4 2-3000/mm3
15 mg/kc mg/dl Puls viitor - 20%
max 1,2  70 10 mg/kc
g/puls 12,5 1-2000/mm3
mg/kc Puls viitor - 40%
Po 2 mg/kc/zi  60 – 25% <4000/mm3
Max 200mg/zi  70 – 40% oprit pana la
revenire,
reintrodus la 50
mg /zi
 Ciclofosfamida si toxicitatea gonadala

INFERTILITATE ! (interfera cu ovo/spermatogeneza – ireversibil)

FACTORI DE RISC:
Varsta: 25 ani (12-15%)< risc> 30 ani¹³ (62-70%)
Doza medie cumulativa indiferent de calea de administrare
(utilizarea po cumuleaza doze + 60%)

Doza cumulativa CYC (g) Varsta (ani)

20,4 20-30
9,3 30-40
5,2 > 40
1. Huong DL, et al. Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients. J Rheumatol 2002; 29:2571.
2. Clowse ME, et al. Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's). Arthritis Care Res 2011; 63:177 7.
3. Rivkees SA, Crawford JD. The relationship of gonadal activity and chemotherapy-induced gonadal damage. JAMA 1988; 259:2123.
 2009

370 pts MMF (S1 0.5g x2, S2 1g x2, S3 1,5g X2) vs CYC (0,75
g/m2 initial apoi 0,5-1 g/m2)
End-point: reducerea raport proteinurie/creatinina <3 si
imbunatatirea sau stabilizarea creatininei serice
 Iun
2018

74 RCT compara imunosupresoare pt NL III, IV, V (PBR): 5175 pts

Inductie:
- nu s-a putut preciza efectul asupra mortalitatii si BRT (f putine cazuri)
- posibil diferenta pt inductie completa a remisiunii MMF vs CYC
- MMF+tacrolimus vs CYC mai eficient pt inductia completa
- Comparat cu CYC sau MMF biologicele nu s-au dovedit mai eficiente
 Mentinere: rata de recadere mai mare AZA vs MMF
2014
Posibile tinte terapeutice in LES
 Ce este (relativ) nou in LES: Belimumabul
Ac. monoclonal uman, inhiba forma solubila a factorului de
supravietuire LyB (BLyS): aprobare FDA/EMA, BLISS-52 si 76 (1,2)
Indicat in b. activa, Ac anti ADNdc+ si hipocomplementemie
Analiza post-hoc (3) a studiilor: scaderea necesarului de CS
Open-label 5-7 ani : ↓ disfunctiei de organ si a ep. de flare (4-6)
Registrul german OBSErve (102 pts): 78% pts ↓ SLEDAI si CS (7)

Tabalumab - III (8) si blisibimod – I (9) – fara rezultate

1. Navarra SV, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011
2. Furie R, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in lupus patients Arthritis Rheum 2011
3. van Vollenhoven, et al.: Cumulative corticosteroid dose over 52 weeks in patients with systemic lupus erythematosus: pooled analyses from the phase III belimumab trials. Arthr heuma 2016
4. Bruce IN, et al.: Long-term organ damage accrual and safety in patients with SLE treated with belimumab plus standard of care. Lupus 2016
5. Iaccarino L,et al.: Effects of belimumab on flare rate and expected damage progression in patients with active systemic lupus erythematosus. Arthritis Care Res 2017
6. Furie RA,et al, Long‐term safety and efficacy of belimumab in patients with systemic lupus erythematosus: a continuation of the Phase 3 United States BLISS‐76 trial , Arthritis& Rheum 2018
7. Schwarting A et al.: First real-world insights into belimumab use and outcomes in routine clinical care of systemic lupus in Germany: results from the OBSErve Germany study. Rheum Ther 2016
8. Isenberg DA, et al. Efficacy and safety of subcutaneous tabalumab in patients with lupus : Results from ILLUMINATE-1, a 52-week, phase III, study. Ann Rheum Dis 2016
9. Stohl W, et al.Treatment of lupus with the BAFF antagonist “peptibody” blisibimod:Results from randomized, double-blind phase 1a and phase 1b trials. Arthritis Res Ther 2015
 Ce este (relativ) nou in LES – actiunea
asupra LyB
Rituximabul: Ac. monoclonal chimeric anti CD20
 Lupus Nephritis Assessment with Rituximab (LUNAR) (1)
Exploratory Phase SLE Evaluation of Rituximab (EXPLORER) (2)
 Off-label dar rambursat in unele tari UE (UK) – b intens activa cu
afectare renala fara raspuns CYC/MFM
 International Registry for Biologics in SLE estimeaza utilizarea la 0.5–
1.5% din pacientii lupici (3)
Ocrelizumabul (Ac monoclonal uman anti CD20) – oprit (4)
Epratuzumabul (Ac monoclonal anti CD22) – oprit (5)

1. Merrill JT, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: The randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab
trial. Arthritis Rheum 2010
2. . Jónsdóttir T, et al. Long-term follow-up in lupus nephritis patients treated with rituximab – Clinical and histopathological response. Rheumatology 2013
3. Ryden-Aulin M, et al.: Off-label use of rituximab for systemic lupus erythematosus in Europe. Lupus Sci Med 2016
4. Mysler E, et al, Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study, Arthritis Rheum 2013
5. Clowse et al, Efficacy and Safety of Epratuzumab in Moderately to Severely Active Systemic Lupus Erythematosus: Results From Two Phase III Randomized, Double‐Blind, Placebo‐Controlled Trials, Arth
Rheum 2017
 Ce este (relativ) nou in LES – actiunea
asupra LyT

Abatacept – oarecare eficacitate pt manifestarile non amenintatoare

de viata (1), fara efect asupra nefritei lupice, inclusiv in regim tip
Euro-lupus la GNF III si IV (ABA+CS+ CYC iv) (2)
Peptide imunomodulatoare – Rigerimod (Lupuzor) – faza IIII
rezultate submise FDA/EMA (3)
Terapie anticitokinica (anti interferon ) –Anifrolumab (anti IFN1R)
– faza III (4-5), Sifalimumab (Ac monoclonal anti IFNɑ) (6)

1. Nandkumar P, Furie R. T-cell-directed therapies in systemic lupus erythematosus. Lupus 2016

2. Access Trial group, Treatment of lupus nephritis with abatacept: the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study, Art Rheum 2014
3. Zimmer R et al, . Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial., Ann Rheum Dis, 2015
4. Crow MK. Autoimmunity: Interferon α or ß: which is the culprit n autoimmune disease? Nat Rev Rheumatol 2016;12:439-40.
5. Peng L, et al, Molecular basis for antagonistic activity of anifrolumab, an anti-interferon-a receptor 1 antibody. MAbs 2015
6. Zheng Bt al.: Pharmacokinetics Population pharmacokinetic analysis of sifalimumab from a clinical phase IIb trial in systemic lupus erythematosus patients. Br J Clin Pharmacol 2016
2017
 Noi tratamente in Lupus…
- pana 2011 nu a mai fost aprobat nici un medicament (56 ani)
- din 2011 niciun medicament nou aprobat

DE ce?
•Lupusul este greu de studiat:
• expresia clinica este foarte heterogena
• activitatea bolii este intermitenta
• lipsa unui acord asupra masurarii activitatii bolii si a end-points
• numar redus pacienti – boala rara
•Costurile dezvoltarii unui biologic :$1 miliard din stadiu de cercetare
pana la aprobare
2013
Q &A