Management of Graves Orbitopathy

Transcription

1 Management of Graves Orbitopathy Mario Salvi Graves Orbitopathy Center, Endocrinology Fondazione Ca Granda IRCCS, Milan, Dept. of Clinical and Community Sciences University of Milan, Italy

2 Clinical course of GO Therapy Rundle Curve Active GO (CAS 4/10) time Inactive GO (CAS<3) Th2 Th1 Th1 Th2 IL-1 IFNg Disease activity Disease severity IL-4 IL-5 IL-10 IL-6 CXCL-10 Wiersinga e Prummel, 1995

3 Immunosuppressive therapy for Graves orbitopathy (GO)! Glucocorticoids (GC) represent the first-line treatment of active moderatesevere GO.! The i.v. route administration (IVGC) is more effective and better tolerated than the oral route (Marcocci et al, 2001; Kahaly et al, 2005, Siiebel-Kadish et al 2009)! GC have an anti-inflammatory effect but also an immunosuppressive effect (Vannucchi et al, 2012)! A cumulative dose of 8 g is considered safe, but monitor liver function tests, hepatitis virus markers, serum glycemia and blood pressure! Until 2012 the optimal treatment regimen was undefined (Bahn R, 2012)

4 Glucocorticoids treatment:eugogo recommendations Intermediate dose regimen in most cases Bartalena et al, EUGOGO, 2012 High dose regimen reserved to most severe GO patients SIDE EFFECTS Low dose" minor and later effect on eye inflammation; no effect on eye motility, but fewer side effects

5 Glucocorticoids in Graves orbitopathy The dose "All substances are poisons; there is not one which is not a poison The right dose differentiates a poison from a remedy Philippus Aureolus Theophrastus Bombastus von Hohenheim, Paracelsus o Paracelso Ineffectiveness Drug efficacy Toxicity GO Monotherapy Combination therapy Oral route I.v. route

6 Glucocorticoids in Graves orbitopathy Could the timing of the therapeutic response contribute to the therapeutic outcome as well as the dose of steroids?

7 The timing of therapeutic response Vannucchi et al, EJE 2014 Δ CAS (12-16 weeks) Not smokers Smokers Total X 2 Unchanged NS Improved P<0.04 worsened NS Total % of patients responded as early as 6-8 weeks after the beginning of therapy (cumulative dose 4.3 gr) - only another 10% of patients improved with the continuation of IVGC until weeks (cumulative dose 7.5 gr)

8 Glucocorticoids in GO Observation of the therapeutic response at 6-8 weeks (cumulative dose 4.3 gr) Response + Response - Development of DON To stop at 6-8 weeks with the infusion of 500 mg of MP by reduction to 250 mg for two further infusion To continue until 12 weeks if GO is more severe (not DON) Medical treatment: i.v.steroid in consecutives days ( mg x 3 for two weeks) Surgical treatment: orbital decompression Combination therapy or other immunosuppressive drugs Radiotherapy Mycophenolate Mofetil Cyclosporine Rituximab

9 Rituximab Chimeric murine/human monoclonal antibody with a human IgG1 constant region and a murine variable region binding to CD 20. variabile murine region binding CD20 human Fc region human constant κ region

10 Targets of immunotherapy in GO B and T CELLS BAFF BELIMUMAB Stem cell Pre-B cell Germinal center B cell Immature B cell Transitional B cell Mature B cell Long-lived plasmacells CD20 CD20 CD20 CD20 CD20 CD20 Memory B cell Short-lived plasmacells Salvi & Vannucchi: 2015, Springer RITUXIMAB CD20 T cell CD4+

11 Rituximab in GO Salvi et al, EJE 2007

12 Study Salvi et al El Fassi et al Khanna et al N. of patients treated RTX in GO: non randomized studies RTX dose 9 1g twice day 1 and mg/m 2 weekly 4 times 6 1g twice day 1 and 15 CAS before therapy CAS after therapy (16 wks) Severity after RTX NOSPECS class changes all improved Hertel -1.5 mm Motility -1 class all improved Hertel -2,0 mm Motility -1 class all improved Visual acuity in 4 patients with DON# Hertel no change N. of patients GO relapse with side effects 3 (minor) no 1 (minor) no 2 (minor) 1(major, cardiac death, unrelated to therapy) no Silkiss et al g twice day 1 and 15 Madaschi et al. 1 1g twice day and 15 Salvi et al mg single dose Mitchell et al mg or 1g 2013 day 1 and 15 Erdei et al., mg/m 2 Krassas et al Gess, weekly for 4 weeks 1g twice day 1 and all improved TAO score -4 points 5 0 improved Motility improvement all Hertel improved -2.1 mm pts. improved 6 NOSPECS 3 pt. unchanged -2 points 2 unchanged 1 worsened all improved 7 n.r. 7 n.r. Worsened Unchanged none no no no 2 (major but no transient) 4 (minor) no n.a. no no Developed DON DON Total (89.7%) 13 (27.6%) 0/47 n.r. no - -

13 RCT of RTX vs i.v. steroids in GO EUDRACT NUMBER eligible patients Randomization (blocks of 4) I.v. methylprednisolone (IVMP) N=16 Rituximab (RTX) N=16 1 patient refused therapy N=16 N=15 Daily dose: 830 mg/day weekly x 6 weeks, followed by 415 mg/day weekly x 6 weeks Cumulative dose: 7.5 g Before amendment N=5 After amendment N=10 Dose: 1000 mg /wk x 2 weeks Cumulative dose: 2000 mg Dose: 500 mg,single Cumulative dose: 500 mg

14 Study Endpoints Primary End point : reduction of clinical activity score 2 points or below CAS=3. Secondary End points: - reduction of disease severity by at least 2 NOSPECS classes; - reduction of proptosis 2 mm; - decrease of lid aperture of at least 3 mm; - reduction of Gorman score for diplopia 1 class; - improvement of eye muscle motility of at least 8 degrees; - number of therapeutic responses; - number of relapses of active disease; - quantification of signs of residual disease; - improvement of Go-Qol scale of at least 6 points.

15 Patients groups i.v. Methylprednisolone 4 men / 12 women yr (mean age 50.4 ± 11 yr) Smokers 9/16 (56%) Disease duration 1-10 mo. (mean 4.6 ± 2.6) Previous steroids 3-18 (mean 7.8) mo. prior - oral n.3 (variable dose) - i.v. n.3 (mean 6 mo. prior) Rituximab 2 men / 14 women yr (mean age 51.9 ± 13 yr) Smokers 10/16 (62%) Disease duration 2-10 mo. (mean 4.5 ± 2.9) Previous steroids (mean 33.3) mo. prior - oral n.3 (variable dose) - i.v. n.3 (mean 22 mo.prior)

16 Results: decrease of CAS (primary end point) Methylprednisolone RTX CAS 3 P<0.04 p= P< weeks Salvi et al., JCEM 2015

17 Disease inactivation (primary end point) Inactive Active 12 weeks 24 weeks P=NS P< % Patients % Patients RTX ivmp 0 RTX ivmp Salvi et al., JCEM 2015

18 RTX therapy: dose finding analysis RTX low dose vs RTX high dose P=N.S. CAS 3 2 RTX: P< (Anova) weeks Salvi et al., JCEM 2015

19 Secondary end points at 24 and 52 weeks (1) Therapy arm Total Eye Score 24w 52w MP p= n.s. p= RTX p=0.005 p=0.01 (Wilcoxon) Salvi et al., JCEM 2015

20 Secondary end points at 24 and 52 weeks (2) Lid Fissure Proptosis Gorman score Improvement of 1 class ivmp ns ns ns RTX ns ns ns NOSPECS Improvement of 2 classes ns (Wilcoxon) ns Salvi et al., JCEM 2015

21 Effects on eye muscle motility A Foerster-Goldman perimeter >35 Sum of degrees of ductions OD 210 OS 420 OO 65 B Weeks IVMP OD 179.2±8.6 OS 177.3±8.7 OD 178.6±6.7 OS 178.6±7.3 OD 188.2±7.0 OS 192.5±6.8 RTX OD 187.0±5.8 OS 186.7±6.2 OD 197.3±5.6 OS 191.7±6.5 OD 196.1±5.0 OS 196.4±5.8 P value OD = OS = ns OD = OS = Salvi et al., JCEM 2015

22 Effects on the quality of life GO-QoL questionnaire 2 scales F=function A=appearance Improvement 6 points weeks ivmp Wilcoxon RTX Wilcoxon F % 61% 53% 40% 77% 46% 46% 50% ns ns ns ns ns ns ns 50% 38% 75% 63% ns A 75% 61% 58% 63% ns Salvi et al., JCEM 2015

23 RCT of RTX vs placebo Stan et al, 2015 Months 10 (8.5-19) 12.4 (8-36) Outcome criteria Success: decrease in CAS =>2 Failure = decrease in CAS < 2 points or need for decompression surgery or steroids Salvi et al., JCEM 2015

24 RCTs of Rituximab in GO: comparison GO inactivation at 24 Weeks: Salvi et al: 100% after RTX and 69% after i.v. Steroid Therapy CAS Improvement >=2 Stan et al: 24% after Placebo and 27% after RTX Salvi Stan RTX effective? the time window for significant response to treatment in GO is short?

25 Low dose rituximab in GO Rituximab (2000 mg)??? B cell depletion-guided RTX therapy Follow-up (weeks) Rituximab (100 mg) Complete CD20, CD19 depletion Rituximab (100 mg) Persitence of CD20, CD19 B cells Evaluation of lymphocyte subpopulations Evaluation of lymphocyte subpopulations Salvi et al, Arch Ophthal 2012

26 Low dose rituximab in GO Salvi et al, Arch Ophthal 2012

27 Conclusions! IVGC remain the therapy of choice for active moderate-severe GO! A weekly administration of methylprednisolone for a cumulative dose of about 4.5 gr is recommended in most cases.! A more individualized treatment has to be sought in order to provide more effective treatment to as many as 20% of patients who may be only temporarily responsive or not responsive.! In patients not responding to IVGC, (low dose) RTX is one promising therapy either in term of efficacy and safety profile.! The time of therapeutic intervention is an important parameter for the choice of treatment.