Role of Biologics in Early RA

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Role of Biologics

In Treatment of EarlyRheumatoid Arthritis



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.



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.



New Rheumatoid Arthritis Criteria

Released byACR / EULAR Panel



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)



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



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



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.



`` 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.



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.



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:



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.



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



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



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.



It is imperative todiagnose and

effectively treat RA as

early as possible.



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



`

Treatment With Anti-TNF-αAgents in Early

Rheumatoid Arthritis



Etanercept



(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;



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



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



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



In early rheumatoid group

(the HAQ score improved by56%).

In late rheumatoid group

(the HAQ score improved by

39%).



This is considered as an

approval that thetreatment of the disease

early by the samebiologic is more better

than if it is treated late



Infliximab

Th A ti t ll d St d f P ti t i i



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.



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.





31%of the patients in the 6 mg/kg group

reached DAS remission versus 15% of the MTX monotherapy group



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



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.



Adalimumab



(PREMIER) STUDY

controlled study of 799 patients with

active, early RA (mean duration

0.7 year)



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.



AFTER ONE YEAR

1ST

GROUP 2nd

GROUP 3rd

GROUP

ACR20 63% 54% 73%

ACR50 46% 52A% 62%

ACR70 28% 26% 42%



1ST

GROUP

2ndg

GROUP

3rd

GROUP

DASSCORE

21% 23% 43%



1ST GROUP

2nd GROUP

3rd GROUP

RADIOGRPHICPRGRESSI

ON

10.4 5.5 1.9



This study demonstrated that effectiveness

of MTX combined with an anti-TNF-α

versus either mono-therapy with respectto clinical, functional, and radiographic

outcomes.



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



Golimumab



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



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.



Certolizumab



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.



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.





Anakinra



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.



RESULTS AFTER 24Ws

ANAKINRA(30mg)

ANAKINRA(75mg)

ANAKINRA(150mg)

PLACEBO

ACR20 30% 34% 43% 27%





Abatacept



Abatacept inhibitsprogression of structural

damage in rheumatoidarthritis: results from the

long-term extension of theAIM trial.Kremer etal.ACR,2005







Rituximab



This was a trial that was done with over 500patients with rituximab. The patients had had an

inadequate response to methotrexate,



Here we have ACR20 responses in the 57%



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.



Tocilizumab



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.



At 3 months

1st gr 2ndgr 3rdgr

ACR20 57%(4mg)

78%(8mg)

11%(placebo)

Receptor Activator for Nuclear Factor κ B Ligand





Conclusion



The initial challenge in treating

RA is

1-Early identifying patients

2-Early treating them.



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.







Thank you

Documents

Role of Biologics in Early RA