1. Findings of the Rapid 1 trial.
Edward Keystone, Desiree van der Heijde, David Mason, Jr.,
et al
Arthritis&Rheumatism 2008; 58; 11
______________________________
Elena Villagran, MD
2. Novel TNF- α inhibitor
Fab’ antigen-binding
domain of a humanized
anti-TNF-α monoclonal
antibody
Does not contain Fc
region
Pegylated
3. To evaluate the efficacy and safety of two
dosage regimens of subcutaneous lyophilized
certolizumab pegol (CZP) as adjunctive
therapy to methotrexate (MTX) in patients with
active rheumatoid arthritis (RA) with an
inadequate response to MTX alone.
52-week , phase III, multicenter, randomized,
placebo-controlled, parallel-group trial.
Edward Keystone et al. Arthritis & Rheumatism 2008;11;3319-3329.
4. Adults with RA diagnosis for ≥6 months but
<15 years
Active disease (≥9 tender and 9 swollen joints)
at baseline
ESR ≥30 mm/hr or C-reactive protein >15
mg/L
On MTX for ≥6 months, at stable dosage (≥10
mg/wk) for ≥2 months prior to baseline
Edward Keystone et al. Arthritis & Rheumatism 2008;11;3319-3329.
5. Diagnosis of any other inflammatory or non-
inflammatory arthritis
History of tuberculosis (TB) or chest x-ray
showing active or latent TB
History of severe hypersensitivity or
anaphylactic reaction to biologic therapy
Prior failure to respond to anti-TNF therapy
Edward Keystone et al. Arthritis & Rheumatism 2008;11;3319-3329.
6. 982 patients were randomized 2:2:1 into 3
treatment groups :
CZP 200 mg (n=392) every 2 weeks after an initial
starting dose of CZP 400 mg at Weeks 0, 2, and 4
plus weekly MTX
CZP 400 mg (n=390) every 2 weeks beginning at
Week 0 plus weekly MTX
Placebo (n=199) every 2 weeks plus weekly MTX
Edward Keystone et al. Arthritis & Rheumatism 2008;11;3319-3329.
7.
8. Response rate at week 24 according to the
American College of Rheumatology 20%
criteria for improvement (ACR 20)
Mean change from baseline in the modified
total Sharp score (mTSS) at week 52
Edward Keystone et al. Arthritis & Rheumatism 2008;11;3319-3329.
9. ACR20 responder rate at wk 52
Change from baseline in mTSS at week 24
ACR50(50% improvement) and ACR70 (70%
improvement) responder rates at week 24&52
Change from baseline in the disability Index (DI)
of the Health Assessment Questionnaire (HAQ) at
weeks 24&52
Edward Keystone et al. Arthritis & Rheumatism 2008;11;3319-3329
10. Mean change from baseline in:
Erosion and joint space narrowing scores
Swollen (n=66) and tender (n=68) joint counts
Physician and patient global assessments of disease
activity
Patient assessment of arthritis pain
Physical function (measured by HAQ-DI)
Disease Activity Score 28-joint assessment
Level of acute-phase reactant (ESR, CRP)
Edward Keystone et al. Arthritis & Rheumatism 2008;11;3319-3329.
11. Patients were followed up at Weeks 1 and 2,
then every 2 weeks until Week 16, and then
every 4 weeks until Week 52
Radiographs of the hands and feet taken at
baseline, Week 24&52 (or at early withdrawal)
Safety assessments: vital signs, physical
examination, laboratory testing, anti-CZP
antibodies.
Adverse events (AEs) were monitored at each
visit.
12. At week 24, ACR20
response rates for the
groups taking 200mg
and 400mg of CZP
plus MTX were 58.8%
and 60.8%,
respectively,
compared with 13.6%
for the placebo plus
MTX group(p<0.001)
13. At week 1, significantly more
patients in CZP 200 mg and
400 mg groups achieved an
ACR20 response than did in
placebo group (P<0.001):
responders rates were 22.9%
and 22.3% versus 5.6%
respectively. The ACR20
response rate peaked at week
12 and was sustained to week
52.
14. At week 52 the mean
change from baseline in
the mTSS was smaller in
patients treated with
CZP 200mg and 400mg
(0.4 and 0.2 Sharp units
respectively) than in
placebo-treated patients
(2.8 Sharp units)
(P<0.001)
15.
16. Treatment with certolizumab pegol 200
or 400 mg as add-on therapy to MTX
significantly reduced signs and
symptoms of RA, inhibited the
progression of structural joint damage,
and improved physical function as
compared with placebo plus MTX
treatment in patients with active RA
with an incomplete response to MTX.
Editor's Notes
The most common chronic inflammatory arthritis , affecting 1% of Northern American population. Women are predominantly affected, at a ratio of 3:1Symmetrical polyarthritis affecting small and large joints. Typical joints involved in classic RA include MCP and PIP, and wrists; DIP spared. Other joints : high cervical spine, elbows, knees, hips, MTP joints and ankles: thoracic and lumbar spine usually spared. Morning stiffness for 30 minutes or more
RF are auto antibodies to the Fc region of immunoglobulin's. RF binds to immunoglobulin's to form immune complexes. IgG-Rf complexes are small, cannot efficiently fix complement, and therefore escape clearance. They cross endothelium leaving the vasculature and access tissue macrophages. These small IgG-RF complexes are able to bind to CD16 receptor of macrophages, activating them with release of TNF-alfa, IL-1, and other inflammatory cytokines.The TNF-alfa acts on synovial fibroblasts to express vascular cell adhesion molecule(VCAM-1), decay accelerating factor(DAF), complement receptor 2(CR-2) and a morphology characteristics of follicular dendrite cells.This stromal cell differentiation creates environment that can support the survival and differentiation of B-cells. B-cells accumulate and survive within the synovium. Activation and differentiation occurs with the help of the helper T-cells.Some plasma cells produce the rheumatoid factor. IgG-Rf and IgM-Rf immune complexes form large complexes within the synovium. These large immune complexes can activate complement and also may crosslink the CD64, CD32, and CD 16 receptors amplifying the inflammation already initiated by small IgG-Rf complexes binding to the CD 16 receptors.The development of lesions in rheumatoid arthritis appears to include both cell-mediated and humoral responses. CD4+ T-cells, activated B-lymphocytes, and plasma cells, as well as well-formed lymphoid follicles with germinal centers (in more severe cases), are present in the synovium of patients diagnosed with RA. T-cells are the dominant cell type in the synovial filtrate of patients with RA. Cytokine secretion by activated T-cells leads to an inflamed synovium and the formation of pannus (Abbas et al., 1994). Numerous cytokines have been detected in the synovial fluid of patients with RA; these include interleukin-1 (IL-1), IL-8, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma). These cytokines activate synovial cells to produce hydrolytic enzymes, including collagenase, that cause destruction of the cartilage, ligaments, and tendons on the joints. These cytokines are presumably produced as a result of local activation of T-cells and macrophages.Two clinically important cytokines released in the synovium are IL-1 and TNF-alpha. Both cytokines increase the production of cyclo-oxygenase-2 (COX-2), nitric oxide, adhesion molecules, IL-6, chemokines, and collagenases. Both IL-1 and TNF-alpha stimulate the production of one other. IL-1 contributes to increased osteoclast activation and angiogenesis, and TNF-alpha increases apoptosis. The actions of these and other cytokines lead to the clinical manifestations of the disease. For example, IL-2 activates monocytes and macrophages, which leads to inflammation; it induces fibroblast proliferation, which causes synovial pannus formation; it activates chondrocytes, which leads to cartilage destruction; and it activates osteoclasts, which causes bone resorption.Rheumatoid arthritis not only involves TH1 cells responding to self-antigens, but it also involves antibodies . Rheumatoid factors are anti-immunoglobulin antibodies. In RA, the rheumatoid factors are usually IgM anti-IgG auto antibodies that react with the Fc fragment of altered IgG (after combination with antigen or aggregation) (Bach, 1982). The fact that rheumatoid factors have been isolated from the joints of patients with RA provides evidence for a T-cell dependent, antigen-driven B-cell response against the Fc portion of IgG, and the subsequent formation of IgM:IgG immune complexes leads to tissue damage (Janeway et al., 2001). However, the presence of rheumatoid factors is not specific for RA since they are also present in 5% of normal subjects (Bach, 1982).
