Tratamiento del LES Dra Maria Jose Cuadrado Consultor

Tratamiento del LES Dra. Maria Jose Cuadrado Consultor Senior Servicio de Reumatologia Clinica Universitaria de Navarra-Madrid

PROBLEMAS • Multiples manifestaciones • Heterogeneicidad de los pacientes • Diferente respuesta a la misma droga

Hidroxicloroquina Marmor MF et al. Ophtalmology 2011

Hidroxicloroquina Marmor MF et al. Ophtalmology 2011

Inmunosupresores • Permitir reducer las dosis de esteroides • Tratar manifestaciones concretas del LES

Esteroides: Efectos adversos Risk factors for the first side effect Final model variable OR 95%CI p value Average Prednisolone >10 -15 mg 32. 3 4. 6 -22 0. 0004 5 -10 mg 4. 1 2. 1 -9. 6 0. 0001 0 -5 mg 1. 9 0. 8 -4. 7 0. 15 Kinnet G Am J Med 1994

Predictores de infecciones graves Ruiz-Irastorza G Arth Res Ther 2014

Consensus • • • Situaciones agudas: i. v. pulses 500 mg Evitar las dosis de 1 mg/kg/dia Mantenimiento: <7. 5 mg Dosis de 5 mg: pocos efectos adversos Introducir siempre otras drogas: HCQ e inmunosupresores

Immunosupresores Efficacy and safety of non-biologic immunusuppresants in the treatment of non -renal systemic lupus erythematosus: A systematic review. Pego-Reinosa JM et al, Arthritis Care Res 2013

Inmunosupresores • Several immunosuppressants demonstrated their safety and efficacy in non-renal SLE • A specific drug for each particular manifestation cannot be recommended • Cyclophosphamide may be used in more severe cases • Methotrexate may be the first option in most cases of moderately active SLE. Pego-Reinosa JM. Arthritis Care Res 2013

Metotrexate • Methotrexate in systemic lupus erythematosus: a systematic review of its efficacy » 9 estudios (incluyendo 3 RCT y 6 observ) » Pacientes con artritis y manifestaciones muco-cutaneas » MTX is associated with significant reductions in SLEDAI and the average dose of corticosteroids Sakthiswary R et al, Lupus 2014

Micofenolato Mofetil • MMF for non-renal manifestations of SLE: a systematic review. » Favourable results were reported with haematological disease » Efficacy in refractory lupus skin lesions was conflicting » Efficacy in neuropsychiatric lupus was only modest Mo. K CC. Scand J Rheumatol 2007

Micofenolato Mofetil • Limited efficacy in cutaneous and musculoskeletal manifestacions Pisoni CN et al, J Rheumatol 2005 • Skin manifestations of SLE refractory to multiple treatment modalities: poor results with MMF Obermoser G et al, Clin Exp Rheum 2005

Medicion de Niveles • Concentration–effect relationship. • MPAconcentration of > 3 mg/L has being associated with a higher chance of inducing disease remission, and a lower risk of disease recurrence. • These concentrations can be reached with dosages as low as 1 g of MMF per day or 3 g depending on patients variability. Teun van Gelder Nephrology, Dialisis and Transplantation 2014

Reference Neumann et al. 2003 Study type Prospective, consecutive, unblinded Assay Patients Patient characteristics Main finding EMIT vs. HPLC 16 10 ANCA+ vasculitis 6 SLE Prospective, consecutive, unblended Lertdumrongluk et a 6 month l. 2010 prospective, unblinded EMIT 38 26 ANCA+ vasculitis 12 SLE IMPDH 18 Kittanamongkolchai 6 month, et al. 2013 prospective, unblinded IMPDH 19 Active lupus nephritis C 1 > 13 mg/L associated with better outcomes Neumann et al. 2008 levels correlated with 24 -h area under curve Levels > 3. 5 mg/L associated with sustained remission Severe active lupus AUC 0– nephritis 12 > 45 mg/h/L correlate with improved outcomes Zahr et al. 2010 Consecutive, HPLC prospective, singleblinded, singlecenter 71 Mixed active and inactive SLE AUC 0– 12 > 35 mg/h/L associated with decreased activity Djabarouti et al. 2010 Prospective 6 month, singlecenter trial 25 Non-renal lupus Found steady state MPA < 3 mg/L correlated with flare HPLC

Medicion de Niveles • 29% of patients with MPA levels < 3 mg/L had ongoing active disease, compared to only 2% of those with levels > 3 mg/L. • Persistent remission over 6 months was found in all patients with levels > 3. 5 mg/L. • The best efficacy and safety data, were obtained with MPA between 3. 5 and 4. 5 mg/L. • There was no discernable relationship between MMF dose and clinical endpoints. Neumann I et al, Nephrol Dial Transplant. 2008

Azatioprina • Las mismas indicaciones que MMF • Similar eficacia para el mantenimiento de la remision en la NL • Medir siempre los niveles de TMPT: actividad enzimatica baja o diferentes alelos de TPMT estan asociados con mas mielosupresion Higgins I et al, Pharmacogenomic 2010

Ciclofosfamida • Manifestaciones severas: » Nefropatia Proliferativa » Sistema nervioso central » Hemorragia pulmonar » Enfermedad pulmonar intersticial » Miocarditis severa

Dosis bajas: Eurolupus Mini-pulsos: 500 mg iv/2 semanas (3 m) Mesna Prof. Graham Hughes. Lupus Unit. St. Thomas Hospital

Stop saying Eurolupus regime: This is british regime!!!

Nefropatia lupica • Ciclofosfamida • Micofenolato Inducion remision Wofsy D et al, Ann Rheum Dis 2008 • Micofenolato • Azatioprina Mantenimiento remision Dooley MA et al, N Engl J Med 2011

Tacrolimus • Tacrolimus use in lupus nephritis: A systematic review and meta-analysis » Evidence supporting efficacy in moderately severe lupus nephritis of TAC+MMF over IVCYC » No evidence TAC over MMF » TAC more effective at reducing proteinuria. Implications for longterm outcome Hannah J et al. Autoimmun Rev 2016

Tacrolimus topico • Tacrolimus ointment 0. 1% may be an effective alternative to steroids cream (triamcinolone) » Lupus discoide » Lupus cutaneo subagudo » Otras lesiones cutaneas del LES Lampropoulos CE et al, Rheumatology 2004 Wan X. J Clin Pharmacol 2015

Conclusiones • Inmunosupresores sinteticos siguen siendo muy utiles en el LES para reducir esteroides • Indicaciones concretas segun el organo afectado • Medicion de niveles y ajustes de dosis individualizadas antes de desestimar un farmaco

Belimumab • 2/3 of the patients remained on Belimumab and 1/3 discontinued due no detectable positive response. • The presence of adverse events was quite low • The subgroups with skin and joint manifestations appear to benefit the most. • Daily steroid use is reduced significantly • The addition of Belimumab to the conventional therapy in LN might be beneficial.

Belimumab • Efficacy of Belimumab on renal outcomes in patients with SLE: A systematic review. Sciascia S Autoimmunity Rev 2017 • 2004 patients with SLE were identified from 11 studies. • 326 patients had LN at baseline and 234 (71. 8%) of those received Belimumab. • 13(5. 5%) received Belimumab for active LN.

Belimumab • 129 (55. 1%) showed an improvement in renal parameters. • Patients with proteinuria>0. 2 g/24 h(n=687) had a median reduction in proteinuria during follow-up as high as 38%. • Patients with proteinuria≥ 1 g/24 h (n=228), 70. 7% achieved a renal response.

Rituximab • Short-term efficacy and safety of RTX therapy in refractory SLE: results from the BILAG Biologics Register. • 261 SLE patients on RTX from 2010 to 2015 • 250 (93%) glucocorticoids at baseline at a median dose of 10 mg (5 -20 mg) daily. • Response rates at 6 months were available for 68% of patients.

Rituximab • The median BILAG score was 15 (10 -23) at baseline and 3 (2 -12) at 6 months (P < 0. 0001). • The median SLEDAI-2 K reduced from 8 (512) to 4 (0 -7) (P < 0. 001). • Response was achieved in 49% of patients. • Reduction in glucocorticoid use to a median dose of 7. 5 mg (5 -12 mg) at 6 months (P < 0. 001).

Rituximab • Serious infections occurred in 26 (10%) patients, being more frequent in the first 3 months post-RTX therapy. • A higher proportion of early infections were non-respiratory (odds ratio = 1. 98, 95% CI: 0. 99, 3. 9; P = 0. 049).

Conclusiones • HCQ en todos los pacientes con LES. Mejores metodos para detector toxicidad ocular • Los inmunosupresores clasicos siguen teniendo un papel importante • Belimumab parece ser mas efectivo y tener mas indicaciones • Rituximab es una alternativa eficaz para el LES refractario