Role of Biologics in Early RA
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Role of Biologics
In Treatment of EarlyRheumatoid Arthritis
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Rheumatoid arthritis (RA) affects
between 0.5% to 1% of the
world's population.
RA can cause chronic pain,
dysfunction, and disability,particularly if it is not treated
early.MacGregor A, Silman AJ. Rheumatology. 3rd ed.
Philadelphia: Elsevier Science, 2003.
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The American College of Rheumatology Criteria for
Rheumatoid Arthritis Classification. 1988
1. Prolonged morning stiffness at least 1 hour induration
2. Arthritis in at least 3 joints
3. Arthritis involving the hand joints
4. Symmetrical arthritis5. The presence of rheumatoid nodules
6. A positive test for rheumatoid factor, withsignificantly increased titers in the serum
7. Radiographic changes typical of rheumatoid arthritisArnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of
rheumatoid arthritis. Arthritis Rheum. 1988;31:315-324.
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New Rheumatoid Arthritis Criteria
Released byACR / EULAR Panel
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Joint Involvement Serology Duration of synovitis Acute phase reactants
1 medium-large joint (0
points)
Not positive foreither RF or anti– CCP
(0 points)
Less than 6 weeks (0points) Neither CRP
nor ESR is abnormal (
Neither CRP noESR is abnorma(0 points)
2-10 medium-large
joints (1 point)
One of these 2 testsare positive at low
titer ( > the upperlimit of normal butnot higher than 3times the upper limitof normal (2 points)
1-3 small joints (2points)
6 weeks or longer(1 point)
Abnormal CRor abnormal
ESR (1 point)
4-10 small joints (3
points)
At least 1test ispositive at hightiter (> 3 times the
upper limit of normal ( oints)
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Why Early Arthritis?
Joint erosions occur in 67% of patients within 2 years of diseaseonset.
50% of RA patients are disabledwithin 10 years of the onset of disease.
Active/ Severe disease is associatedwith premature mortality from
cardiac disease
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Factors suggesting poor
prognosis1. Early age at onset.2. Young female
3 . Swelling >20 joints4 . Extra-articular disease
5.Radiological detection of erosions
6.Elevated ESR / CRP7 .Elevated platelet count
8 . High titre rheumatoid factor
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Criteria for remission1) Duration of morning stiffness not exceeding 15 minutes.
2) No fatigue.
3) No symptoms of joint pain.
4) No joint tenderness or pain on motion.
5) No soft tissue swelling in joints or tendon sheaths.
6) ESR < 30 (female) and <20 (male)
NB Require 5 or more for at least 2 consecutive months. There must be no clinicalmanifestation of active vasculitis, pericarditis, pleuritis, or myositis or unexplainedrecent weight loss or fever attributable to rheumatoid arthritis.
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`` Radiographic joint damage occurs early
and it is persistent and progressive,especially in the first 2 years of disease.
Fuchs HA, Kaye JJ, Callahan LF, Nance EP, Pincus T. Evidence of significant radiographic damage in rheumatoid arthritis within the
first 2 years of disease. J Rheumatol. 1989;16:585-591.
Bukhari MA, Wiles NJ, Lunt M, et al. Influence of disease-modifying therapy on radiographic outcome in inflammatory polyarthritis at
five years: results from a large observational inception study. Arthritis Rheum. 2003;48:46-53.
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Early, aggressive, effective
treatment significantly reducesradiographic progression in RA.
Stenger AA, Van Leeuwen MA, Houtman PM, et al. Early effective suppression of
inflammation in rheumatoid arthritis reduces radiographic progression. Br J Rheumatol.
1998;37:1157-1163.
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If patients with very early RA were
treated with disease-modifying
antirheumatic drug (DMARD)
earlier they will have better clinical
outcomes than those treated later.
Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very
early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis.
Rheumatology (Oxford). 2004.van Aken J., Lard LR, le Cessie S., Hazes JM, Breedveld FC, Huizinga TW. Radiological outcome after
four years of early versus delayed treatment strategy in patients with recent onset rheumatoid arthritis.
Ann Rheum Dis. 2004;63:
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Recent clinical trials have shown that
effective, aggressive therapy with
traditional DMARDs may well control
clinical symptoms but may not slow
radiographic progression
The combination of an anti-tumor
necrosis factor-alpha (TNF-a) and MTXhas been particularly effective.
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MRI, Ultrasonography can use
for early detection of joint
erosion in RA.
Ostergaard M, Peterfy C, Conaghan P, et al. OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging Studies. Core set
of MRI acquisitions, joint pathology definitions, and the OMERACT RA-MRI scoring system. J Rheumatol. 2003;30:1385-
1386
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Structural Damage May Occur
Before Visible Radiographically
MRI can demonstrate bone edema, a precursor to erosion, within 4 wk from onset
of symptoms*
* Wakefield RJ, et al. Br J Rheumatol . 1998;37(suppl):105.Images compliments of: O. Troum, MD, J. Crues, and Magna Vu.
Distal aspect of the metacarpal on the right
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DAS 28 SCORE
DAS 28 stands for "Disease Activity Score "The following parameters are included in the calculation:
1. Number of joints tender to the touch (TEN)
2. Number of swollen joints (SW)
3. Erythrocyte sedimentation rate (ESR),(CRP)
4. Patient assessment of disease activity.
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It is imperative todiagnose and
effectively treat RA as
early as possible.
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BIOLOGIC AGENTS
T N F inhibitors:
Adalimumab, Infliximab, Etanercept,Golimumab, certolizumab.
IL1 inhibitor :
Anakinra.
Tcell Costimulation Blockade:Abatacept.
B cell deplition:
Rituximab.
IL6 inhibitor:
Tocilizumab.
RANk-L blockade:
Denosumab
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`
Treatment With Anti-TNF-αAgents in Early
Rheumatoid Arthritis
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Etanercept
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(ERA) trial The Etanercept in early Rheumatoid Arthritis (ERA)
1st group : MTX up to a maximum of 20 mg/wk)
2nd group : Etanercept monotherapy 10 mg SQ twice/wk (BIW),
3nd group : Etanercept monotherapy 25 mg SQ) BIW.
Both groups receiving etanercept responded much more rapidlythan the group receiving MTX .
Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000; 1593.
Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes.Arthritis Rheum. 2002;
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RESULTS BY ONE YEAR
there was no statistically
significant difference in the
ACR 20, ACR 50, and ACR 70.
By that time, there was also no
statistically significantdifference in radiographic
progression
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BY 2 YEARS
There was a and clinical significant difference only in
the ACR 20 and radiographic
progression was significantly
less in the group treated with
25 mg BIW etanercept than in
the MTX group
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Patients(early rheumatoid)
treated in the ERA trial withetanercept 25 mg BIW werecompared with patients with
long-standing RA who werealso treated with etanercept
monotherapy at 25 mg BIWwith mean disease duration of
12 years
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In early rheumatoid group
(the HAQ score improved by56%).
In late rheumatoid group
(the HAQ score improved by
39%).
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This is considered as an
approval that thetreatment of the disease
early by the samebiologic is more better
than if it is treated late
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Infliximab
Th A ti t ll d St d f P ti t i i
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The Active-controlled Study of Patients receiving
Infliximab for treatment of Rheumatoid
arthritis of Early onset (ASPIRE)
To compare the efficacy of combination
therapy with MTX and infliximab withMTX monotherapy in patients with early
RA.
Clair EW, et al. Arthritis Rheum. 2004;50:3432-3443.
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Patients with disease duration of 7 months
were randomized into 3 groups:
1stgroup : MTX plus placebo.
2nd group : MTX plus 3 mg / kg infliximab
3rd group : MTX plus 6 mg / kg infliximab.
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31%of the patients in the 6 mg/kg group
reached DAS remission versus 15% of the MTX monotherapy group
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The ASPIRE study was the first to
conclusively show that an anti-
TNF-a combination withaggressively dosed MTX is
superior to aggressively dosed
MTX alone in early RA patients
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This trial was also the first study
conclusively showing that an aggressivedose of MTX combined with an effective
dose of an anti-TNF-a significantly slows
radiographic progression whencompared with aggressively dosed MTX
monotherapy in early RA.
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Adalimumab
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(PREMIER) STUDY
controlled study of 799 patients with
active, early RA (mean duration
0.7 year)
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This study compared
1-Aggressively dosed MTXmonotherapy (1st group ).
2-Adalimumab monotherapy (2nd
group).3-Combination of aggressively dosed
MTX and adalimumab (3rd group).
Breedveld FC, Kavanaugh A, Cohen SB. Early treatment of rheumatoid arthritis (RA)with adalimumab (Humira) plus methotrexate vs. adalimumab alone or methotrexate alone: The PREMIER
Study. Proceeding of the American College of Rheumatology, San Antonio, USA; 2004.
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AFTER ONE YEAR
1ST
GROUP 2nd
GROUP 3rd
GROUP
ACR20 63% 54% 73%
ACR50 46% 52A% 62%
ACR70 28% 26% 42%
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1ST
GROUP
2ndg
GROUP
3rd
GROUP
DASSCORE
21% 23% 43%
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1ST GROUP
2nd GROUP
3rd GROUP
RADIOGRPHICPRGRESSI
ON
10.4 5.5 1.9
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This study demonstrated that effectiveness
of MTX combined with an anti-TNF-α
versus either mono-therapy with respectto clinical, functional, and radiographic
outcomes.
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There's clearly substantial radiographic progression with
methotrexate monotherapy vs either of the infliximab orthe adalimumab when given in combination with
methotrexate.
This strategy of adding a TNF inhibitor here is superior in terms of
inhibiting radiographic progression to methotrexate monotherapy
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Golimumab
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Golimumab is a human
monoclonal antibody toTNF-alpha that is under
development at a dose of 100 mg administered
subcutaneously every 4weeks..
k l h d b
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16-week results had been
presented evaluating golimumab
in patients with active RA despitemethotrexate and haddemonstrated statistical
superiority for all doses (50-100mg every 2-4 weeks) compared
with placebo. Zhou H, Xu Z, Rahman MU, et al. Exposure-efficacy assessment of golimumab in
patients with active rheumatoid arthritis despite methotrexate therapy: application of
population pharmacokinetic/pharmacodynamic modeling. Program and abstracts of
the American College of Rheumatology 70th Annual Meeting; November 11-15, 2006;
Washington, DC. Presentation 966.
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Certolizumab
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RAPID 1 involved 982 patients,
1- 393 randomized to
certolizumab 200 mg plus
methotrexate,2- 390 to certolizumab 400
mg plus methotrexate,3- 199 to placebo plus
methotrexate.
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Patients in the certolizumab arms
reported significantly improved
health-related quality of lifecompared with the placebo
group, beginning at week 12 and
continuing through week 52 of
the study.
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Anakinra
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In a monotherapy trial of
anakinra in 472 patients withactive RA, patients received
either placebo or anakinra atdoses of 30, 75, or 150 mg/day
for 24 weeks Baumgartner SW, Fleischmann RM, Moreland LW, Schiff MH, Markenson J, Whitmore JB.Etanercept (Enbrel) in patients with rheumatoid arthritis with recent onset versus establisheddisease: improvement in disability. J Rheumatol. 2004;31:1532-1537.
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RESULTS AFTER 24Ws
ANAKINRA(30mg)
ANAKINRA(75mg)
ANAKINRA(150mg)
PLACEBO
ACR20 30% 34% 43% 27%
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Abatacept
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Abatacept inhibitsprogression of structural
damage in rheumatoidarthritis: results from the
long-term extension of theAIM trial.Kremer etal.ACR,2005
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Rituximab
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This was a trial that was done with over 500patients with rituximab. The patients had had an
inadequate response to methotrexate,
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Here we have ACR20 responses in the 57%
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p 57in the 1000 mg group
and 59% in the 500 mg group.
So really no difference in terms of themilligram dosage effects at ACR20, 50, or 70levels.
Then the remission was achieved in 9% atweek 48 in the 1000 mg group
and 11% with the 500 mg arm. It looks like both doses of rituximab can
work very well in a methotrexate
inadequate response population.
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Tocilizumab
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A trial of 164 patients with RA patientswere randomized to receive either:
1- tocilizumab (4 mg/kg body weight)1stgr
2-(8 mg/kg body weight)2nd gr
3-(placebo)3rd gr
Tocilizumab was administered IV every 4weeks for a total of 3 months.
Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor
antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:1761-1769.
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At 3 months
1st gr 2ndgr 3rdgr
ACR20 57%(4mg)
78%(8mg)
11%(placebo)
Receptor Activator for Nuclear Factor κ B Ligand
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Conclusion
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The initial challenge in treating
RA is
1-Early identifying patients
2-Early treating them.
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Current evidence strongly suggests that:
The combination of MTX and a
TNF-α
inhibitor May be the mosteffective combination that it is
significantly improve the clinical,
radiographic, and functional
outcomes of patients with early RA.
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