1. GO-FORWARD TO REMISSION Dr. M.Salah Eldin Abd-Elbaky Prof. of Internal Medicine Division of Rheumatology Ain Shams University

2. Infliximab (Remicade) in Rheumatoid Arthritis

4. Longitudinal Course of RA Klareskog L et al. Lancet 2009;373:659-672

5. Time, Inflammation and Disability Severity (Arbitrary Units) 0 Duration of Disease (years) 51015202530 Intermediate InflammationDisabilityRadiographs adapted from Kirwan JR. J Rheumatol. 2001;28:881-886. Early RA L ate

7. ACR Recommendations: Early and Aggressive Treatment of RA “ Successful treatment to limit joint damage and functional loss requires early diagnosis and timely initiation of disease modifying agents. The goal of treatment is to achieve remission” 1 50% to 70% of patients have radiographic damage within the first 2 years of disease onset 2,3 Critical window of opportunity Early EstablishedEnd Stage Disease onset 1 American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum 2002;46:328-346; 2 Van der Heijde DM et al. Br J Rheumatol 1995;34(suppl 2):74-78; 3 Sundy JS, St Clair EW et al. J Musculoskel Med 2002;19:395-403

8.  The primary target for treatment of rheumatoid arthritis should be a state of clinical remission.  Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity.  Structural changes and functional impairment should be considered when making clinical decisions, in addition to assessing measures of disease activity. Recommendations of an international task force Josef S Smolen et al, Ann Rheum Dis,2010;69:631–637.  The primary target for treatment of rheumatoid arthritis should be a state of clinical remission.  Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity.  Structural changes and functional impairment should be considered when making clinical decisions, in addition to assessing measures of disease activity. Recommendations of an international task force Josef S Smolen et al, Ann Rheum Dis,2010;69:631–637.

9. Algorithm for Treating RA to Target Smolen J et al. Ann Rheum Dis 2010;69:631-637

10. General Consensus Regarding Optimum Treatment of RA Early use of DMARDs 2 Frequent follow ‑ up (FU) visits with systematic monitoring of therapy results 2 Rapid escalation of therapy 1 Use of combination therapies 2 Use of biologic agents in patients who fail to respond to DMARDs 2 Proper use of glucocorticoids as ancillary medications 1 1 Van Vollenhoven RF. Nat Rev Rheumatol 2009;5:531–541; 2 Smolen J et al. Ann Rheum Dis 2010;69:964-975

11. BeSt study

12. BeSt study (Treatment Strategies) Behandel-Strategieën  Multicenter randomized, single blind trial over 12 months  508 patients with early active RA  2 years and DMARD naive  Patients were randomized into four different treatment groups: 1) Sequential monotherapy (n=126): MTX  SSZ  LEF 2) Step-up therapy (n=121): MTX  MTX+SSZ  MTX+SSZ+HCQ 3) Step-down modified COBRA (n=133): Prednisone 60  7.5+MTX+SSZ 4) MTX+IFX 3 mg/kg (n=128)  Adjustment in treatment was dictated by 3-monthly calculations of the DAS44  Multicenter randomized, single blind trial over 12 months  508 patients with early active RA  2 years and DMARD naive  Patients were randomized into four different treatment groups: 1) Sequential monotherapy (n=126): MTX  SSZ  LEF 2) Step-up therapy (n=121): MTX  MTX+SSZ  MTX+SSZ+HCQ 3) Step-down modified COBRA (n=133): Prednisone 60  7.5+MTX+SSZ 4) MTX+IFX 3 mg/kg (n=128)  Adjustment in treatment was dictated by 3-monthly calculations of the DAS44 St. Clair W, et al. Arthritis Rheum. 2004;50:3432-3443.

13. BeSt study (Treatment Strategies) Objective: 1) To evaluate the efficacy and safety of four different treatment strategies for patients with RA. 2) To reach and sustain in each treatment a DAS44  2.4 (low disease activity)  The implementation of DAS measurements as a tool to adjust medication per patient until a low disease activity state (DAS≤2.4) was achieved  Regular step of tapering medication if low disease activity was sustained

14. Prevention of Rx Progression Prevention of Rx Progression Change in vdH-S Score after 1 year of follow up Overall p < 0.001 Goekoop YPM, et al. Arthritis Rheum 2005; 52: 3381-3390

15. 4-year follow-up

16. Low Disease Activity on the Initial Treatment at 4 Years Adapted from Van der Kooij SM et al. Ann Rheum Dis 2009;68:914-921 Treatment goal of DAS≤2.4 was achieved by 81% of patients overall (p=0.10)

17. Prevention of Rx Progression Prevention of Rx Progression Change in vdH-S Score after 4 years of Follow up Overall p = 0.005 v an der Kooij SM et al. Ann Rheum Dis 2009;68;914-921

18. Occurrence of Drug-Free Remission After 4 Years of Treatment Drug-free remission at 4 years Total SHS score>SDC of patients in Drug-free remission (n=67) p=0.14p=0.28 Adapted from Van der Kooij SM et al. Ann Rheum Dis 2009;68:914-921 Mean duration: 11 months

19. 7-year follow up

20. BeSt: Radiographic Progression over 7 years lowest in Group 4 Adapted from Dirven L et al. ACR 2010; Abstract 334 Mean SHS Progression After initial differences between the 4 groups, yearly radiological damage progression rates were similar between all groups, reflecting DAS-steered therapy

21. Conclusions  Tight control using DAS-driven therapy adjustments leads to prolonged reduction of disease activity and improvement of functional capacity, irrespective of treatment strategy  Initial combination therapy including prednisone or IFX results in less joint damage progression after 1 year and remains lower than initial monotherapy Van der Kooij SM et al. Ann Rheum Dis 2009;68:914-921

22. Conclusions  Achieving a continuous good clinical response with early effective treatment and continued tight control demonstrate the realistic possibilities of discontinuation of combination therapy and even drug-free remission 1  Percentages of patients experiencing AEs, SAEs or toxicity were not significantly different between the four strategies  After initial differences between the four groups, yearly radiological damage progression rates were similar between all groups up to 7 years, reflecting DAS-steered therapy Van der Kooij SM et al. Ann Rheum Dis 2009;68:914-921

23. Can we stop biologic therapy in patients who have responded well ?

24. What do we know about stopping biologic therapies?  The BeSt study is one of the first studies that incorporated a strategy for discontinuation of medication in the study protocol.  Patients were required to have low disease activity or be in clinical remission for at least 6 months before biological therapy was discontinued.  Significant joint damage progression in the first year after discontinuation was rare and functional ability was relatively stable in almost all patients in this year.  During the first 5 years of the study, 115/508 (23%) of patients at some time achieved drug free remission.

25. After 2 years 120 Patients Patients with ‘early RA’ that achieve good clinical response can discontinue infliximab treatment without relapse 67 23 30 56% 19% 25% ‘Off’ Infliximab ‘On’ Infliximab ‘Failed’ Infliximab Van der Bijl AD, et al. Arthritis Rheum. 2007;56:2129-2134. BeSt Trial: Infliximab Combination Therapy: 56% Discontinued Without Relapse After 2 years

26. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (Remission induction by Remicade in RA) study Y TanakaY Tanaka, T Takeuchi, T Mimori et al Ann Rheum Dis. 2010 July; 69(7): 1286–1291.T TakeuchiT Mimori et al

27. Objective To determine whether infliximab might be discontinued after achievement of LDA in patients with RA and to evaluate progression of articular destruction during the discontinuation. Methods 114 patients with RA who had received infliximab treatment, and whose (DAS28) was <3.2 (LDA) for 24 weeks, were studied. Results The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 After maintaining LDA for >24 weeks by infliximab treatment, the drug was discontinued. Fifty-six patients (55%) continued to have DAS28<3.2 and 43% reached DAS<2.6 at 1 year after discontinuing infliximab. Yearly progression of mTSS (ΔTSS) remained <0.5 in 67% of the RRR- achieved group. Conclusion After attaining LDA by infliximab, 56 (55%) of the 102 patients with RA were able to discontinue infliximab for >1 year without progression of radiological articular destruction.

28. Why Choose Remicade in RA? Remicade is ideally suited to meet today’s treatment goals in RA: 1)“Treat to Target” means monitoring the patients every 1-3 months. “Tight Control”. 2)“Treat to Target” means adjusting the dose as needed every 3-6 months – weight-based dosing, dose titration, interval. 3)Remicade stops inflammation quickly and powerfully 4)Remicade has outstanding efficacy in clinical trials and every treatment goal – including patients with high disease activity. 5)We know from BeSt and RRR that with Remicade, a physician can get patients into sustained remission – a biologic or even drug free remission.

29. Golimumab (Symponi) 50mg S.C Once Monthly

30. Efficacy Endpoints at Week 24 ACR 50 and ACR 70 at Week 24 DAS28 Response (ESR) at Week 24 Patients achieving ACR (%) *p < 0.5, **p ≤ 0.001 ** * * Patients achieving DAS28 response (%) *p < 0.5, **p ≤ 0.001 ** * Keystone EC et al. Ann Rheum Dis. 2009;68:789-796 GO-FORWARD

31. Clinically Significant HAQ Improvement Percentage of Patients (%) ** p<0.001 ** Genovese MC et al. J Rheumatol 2012; 39(6):1185-91. Physical Function at Week 24 GO-FORWARD

32. Infliximab (Remicade) in Spondyloarthritis

52. Why Choose Infliximab in Spondyloarthritis Infliximab is very effective:  In treating axial and peripheral disease  In treating early and late disease  In reducing MRI activity score  in treating the underlying inflammation present in extra- articular manifestations (uveitis and IBD)  in the treatment of psoriasis and PsA  IFX appears to be the best studied agent with a wide spectrum of proven efficacy over all aspects of SpA. Elewaut D & Matucci MC. Rheumatology 2009;48:1029-1035

53. Infliximab (Remicade)  A mouse-human chimeric monoclonal antibody directed against TNF  Licensed for use in RA, AS, PsA, psoriasis, CD and ulcerative colitis (UC)  The drug is given as a 2 h intravenous infusion with a dose of 3–5 mg/kg at weeks 0, 2 and 6, and then every 8 weeks thereafter.  In the event of waning efficacy, the dose may be increased up to 10 mg/kg, or the infusion frequency increased to four to six weekly.

54. Infliximab(Remicade) Binding Sites for TNFa Human (IgG1) Chimeric (mouse/human)IgG monoclonal antibody Binds to TNFa with high affinity and specificity Knight DM, et al. Mol Immunol. 1993; 30(16):1443-53

55. Neutralisation of TNF  by Infliximab Hsia EC, et al. APLAR J Rheumatol. 2006;9:107-118.

56. Algorithm for TB Testing Treat active TB to resolution inhibitor New TNF inhibitor patient PPD Test Positive and active TB Initiate latent TB treatment ? Initiate TNF inhibitor Appropriate TB screening History + Chest x-ray + PPD skin test Evaluate results Negative Negative Initiate TNF inhibitor PPD Test Positive and normal CXR

57. Benefit-Risk Profile of IFX Periodic Safety Update Report (PSUR) 23 >18 years of clinical trials experience – first trial in 1992 1 >12 years of post-marketing experience – launched in 1998 2 1,537,395 estimated number of patients exposed to IFX 3 Benefit-risk profile of IFX is well-defined and positive 4 Data on file, Janssen Biologics (formerly Centocor): 1 Remicade® (infliximab) Summary of Clinical safety, August 2005; pages 50-59; 2 PSUR 23, April 2011;page 24; 3 page s 33-34; 4 http://www.ema.europa.eu/humandocs/PDFs/EPAR/Remicade/190199en6.pdf http://www.ema.europa.eu/humandocs/PDFs/EPAR/Remicade/190199en6.pdf

58. Golimumab (Symponi) 50mg S.C Once Monthly Soon !