Infliximab (Remicade) in Rheumatoid Arthritis

Report
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
Late
Intermediate
Severity (Arbitrary Units)
Inflammation
Disability
Radiographs
0
5
10
15
20
25
30
Duration of Disease (years)
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 onset2,3
1American
College of Rheumatology Subcommittee on Rheumatoid
Arthritis Guidelines. Arthritis Rheum 2002;46:328-346;
2Van der Heijde DM et al. Br J Rheumatol 1995;34(suppl 2):74-78;
3Sundy 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 DMARDs2
• Frequent follow-up (FU) visits with systematic monitoring of
therapy results2
• Rapid escalation of therapy1
• Use of combination therapies2
• Use of biologic agents in patients who fail to respond to
DMARDs2
• Proper use of glucocorticoids as ancillary medications1
1Van
Vollenhoven RF. Nat Rev Rheumatol 2009;5:531–541;
2Smolen J et al. Ann Rheum Dis 2010;69:964-975
BeSt study
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
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
Mean vdH-S progression
Change in vdH-S Score after 1 year of follow up
24
22
20
18
16
14
12
10
8
6
4
2
0
Overall p < 0.001
Seq. Monotherapy
Step-up
Modified COBRA
IFX + MTX
7.1
4.3
2.0
1.3
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
van 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 years
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
Mean SHS Progression
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 remission1
 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
Patients with ‘early RA’ that achieve
good clinical response can
discontinue infliximab treatment
without relapse
After 2 years
67
56%
‘Off’ Infliximab
19%
‘On’ Infliximab
25%
‘Failed’ Infliximab
After 2 years
120 Patients
23
30
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 (Remission induction by Remicade
in RA) 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 RRRachieved 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) 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.
Golimumab (Symponi)
50mg S.C Once Monthly
GO-FORWARD
Efficacy Endpoints at Week 24
DAS28 Response (ESR) at Week 24
*p < 0.5, **p ≤ 0.001
** ** **
**
*
*
**
**
Patients achieving DAS28 response (%)
Patients achieving ACR (%)
ACR 50 and ACR 70 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
Percentage of Patients (%)
**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 extraarticular 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.
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
Neutralisation of TNF by Infliximab
Hsia EC, et al. APLAR J Rheumatol. 2006;9:107-118.
Algorithm for TB Testing
New TNF inhibitor patient
Appropriate TB screening
History + Chest x-ray + PPD skin test
Evaluate results
Negative
Initiate TNF inhibitor
PPD Test Positive
and normal CXR
PPD Test Positive
and active TB
Initiate latent TB
treatment ?
Treat active TB to
resolution
Initiate TNF inhibitor
Initiate TNF inhibitor
Benefit-Risk Profile of IFX
Periodic Safety Update Report (PSUR) 23
• >18 years of clinical trials experience – first trial in 19921
• >12 years of post-marketing experience – launched in 19982
• 1,537,395 estimated number of patients exposed to IFX3
• Benefit-risk profile of IFX is well-defined and positive4
Data on file, Janssen Biologics (formerly Centocor): 1 Remicade®
(infliximab) Summary of Clinical safety, August 2005; pages 50-59;
2PSUR 23, April 2011;page 24; 3 pages 33-34;
4 http://www.ema.europa.eu/humandocs/PDFs/EPAR/Remicade/190199en6.pdf
Soon !
Golimumab (Symponi)
50mg S.C Once Monthly

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