GO-FORWARD TO REMISSION Dr. M.Salah Eldin Abd-Elbaky Prof. of
Internal Medicine Division of Rheumatology Ain Shams
University
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Infliximab (Remicade) in Rheumatoid Arthritis
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Longitudinal Course of RA Klareskog L et al. Lancet
2009;373:659-672
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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
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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
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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;69:631637. 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;69:631637.
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Algorithm for Treating RA to Target Smolen J et al. Ann Rheum
Dis 2010;69:631-637
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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;5:531541; 2 Smolen J et al. Ann Rheum Dis 2010;69:964-975
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BeSt study
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BeSt study (Treatment Strategies) Behandel-Strategien
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.
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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 (DAS2.4) was achieved Regular step of tapering
medication if low disease activity was sustained
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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
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4-year follow-up
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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 DAS2.4 was achieved by 81% of patients overall
(p=0.10)
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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
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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
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7-year follow up
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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
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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
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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
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Can we stop biologic therapy in patients who have responded
well ?
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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.
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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
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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): 12861291.T TakeuchiT
Mimori et al
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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 24 weeks by infliximab treatment, the drug
was discontinued. Fifty-six patients (55%) continued to have
DAS28
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