GO-FORWARD TO REMISSION

Dr. M.Salah Eldin Abd-Elbaky

Prof. of Internal Medicine Division of Rheumatology Ain Shams University

Infliximab (Remicade) in Rheumatoid Arthritis

Longitudinal Course of RA

Klareskog L et al. Lancet 2009;373:659-672

Time, Inflammation and Disability

Early RA Intermediate L ate Inflammation Disability Radiographs 0 5 10 15 20 Duration of Disease (years) 25 30

adapted from Kirwan JR.

J Rheumatol.

2001;28:881-886 .

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

Disease onset Early Critical window of opportunity Established End Stage 50% to 70% of patients have radiographic damage within the first 2 years of disease onset 2,3

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

  

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 .

Algorithm for Treating RA to Target

Smolen J et al. Ann Rheum Dis 2010;69:631-637

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

BeSt study

BeSt study (Treatment Strategies)

Be

handel-

St

rategieën

    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+HCQ MTX+SSZ  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 .

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

Prevention of Rx Progression

Change in vdH-S Score after 1 year of follow up

10 8 6 4 2 0 24 22 20 18 16 14 12 Overall p < 0.001

7.1

4.3

2.0

1.3

Seq. Monotherapy Step-up Modified COBRA IFX + MTX Goekoop YPM, et al. Arthritis Rheum 2005; 52: 3381-3390

4-year follow-up

Low Disease Activity on the Initial Treatment at 4 Years

Treatment goal of DAS≤2.4 was achieved by 81% of patients overall (p=0.10)

Adapted from Van der Kooij SM et al. Ann Rheum Dis 2009;68:914-921

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

Occurrence of Drug-Free Remission After 4 Years of Treatment

Drug-free remission at 4 year s p=0.14

Mean duration: 11 months Total SHS score>SDC of patients in Drug-free remission (n=67) p=0.28

Adapted from Van der Kooij SM et al. Ann Rheum Dis 2009;68:914-921

7-year follow up

BeSt: Radiographic Progression over 7 years lowest in Group 4

After initial differences between the 4 groups, yearly radiological damage progression rates were similar between all groups, reflecting DAS-steered therapy Adapted from Dirven L et al. ACR 2010; Abstract 334

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

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

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

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.

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

Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR ( R emission induction by R emicade in R A) study

Y Tanaka , T Takeuchi , T Mimori et al Ann Rheum Dis. 2010 July; 69(7): 1286–1291 .

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 .

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) 4) 5) Remicade stops inflammation quickly and powerfully Remicade has outstanding efficacy in clinical trials and every treatment goal – including patients with high disease activity.

We know from BeSt and RRR that with Remicade, a physician can get patients into sustained remission – a biologic or even drug free remission.

Golimumab (Symponi)

50mg S.C Once Monthly

GO-FORWARD

Efficacy Endpoints at Week 24

ACR 50 and ACR 70 at Week 24 *p < 0.5, **p ≤ 0.001

DAS28 Response (ESR) at Week 24 ** *p < 0.5, **p ≤ 0.001

** ** * * ** ** ** * ** ** ** Keystone EC et al. Ann Rheum Dis. 2009;68:789-796

GO-FORWARD

Physical Function at Week 24

Clinically Significant HAQ Improvement

** p<0.001

** ** ** Genovese MC et al. J Rheumatol 2012; 39(6):1185-91 .

Infliximab (Remicade) in Spondyloarthritis

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

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 .

Human (IgG1)

Infliximab(Remicade)

Binding Sites for TNFa 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

Neutralisation of TNF



by Infliximab

Hsia EC, et al.

APLAR J Rheumatol

. 2006;9:107-118 .

Algorithm for TB Testing Negative Initiate TNF inhibitor New TNF inhibitor patient Appropriate TB screening History + Chest x-ray + PPD skin test Evaluate results PPD Test Positive and normal CXR

Initiate latent TB treatment ?

Initiate TNF inhibitor PPD Test Positive and active TB Treat active TB to resolution Initiate TNF inhibitor

Benefit-Risk Profile of IFX

Periodic Safety Update Report (PSUR) 2

3 • • • >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

Soon !

Golimumab (Symponi)

50mg S.C Once Monthly