RA Treatment Highlights

The treatment of RA has seen a number of targeted biological therapies introduced in the last 7 years beginning with TNF antagonists, etanercept, infliximab, and adalimumab, the IL1-anagonsist anakinra, and most recently with the approval of the T-cell costimulatory blocking agent, abatacept and rituximab, a selective B cell depleting agent.  As agents have been incorporated into the treatment armamentarium of patients with RA and other inflammatory diseases, the questions that come up regarding their use change from ones of clinical efficacy to focus more on aspects related to safety, administration, and insights on mechanism of action for existing compounds.  Additional agents are in development that have similar mechanisms of action and distinctly novel mechanisms of action.  ACR 2007 had a number of studies presented on several of these compounds, some of which have been selected for review below.  Because of the large number of abstracts presented at ACR, only a selection of these studies could be included for review.

TNF Antagonists

• Abstract 693: [18f] FDG-PET Changes after 2 Weeks of Infliximab Treatment Correlate with Long-Term Clinical Outcome in Rheumatoid Arthritis Patients
• Abstract L17: Remission Rates in Subjects With Active Early Rheumatoid Arthritis - 1 Year Results of the COMET Trial: Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis
• Abstract 726: Efficacy and Safety of Etanercept 100 mg in Patients with Rheumatoid Arthritis who are Suboptimal Responders to Etanercept 50 mg
• Abstract 268: Anti-TNF Treatment with Adalimumab Reduces Hand Bone Loss in Early Rheumatoid Arthritis (RA): Explorative Analyses from the Premier Study

Certolizumab pegol

TNF inhibition is an effective therapy for patients with rheumatoid arthritis and other forms of inflammatory disease including psoriasis, psoriatic arthritis, and ankylosing spondylitis.  Currently available therapies include a soluble p75 TNF receptor:Fc construct, etanercept, a chimeric monoclonal antibody antibody, infliximab, and a fully human monoclonal antibody, adalimumab.  Certolizumab pegol (CZP) is a novel TNF inhibitor which is an antigen-binding domain of a humanized TNF antibody coupled to polyethylene glycol (PEG) to increase half-life, and thus is Fc-domain-free.  Two major phase III randomized placebo-controlled studies were presented at ACR 2007 with this compound in patients with rheumatoid arthritis that have were also presented at EULAR. The RAPID1 Study (Abstract 700) was a 52 week Phase III study of a lyophilized formulation of certolizumab in RA patients on background MTX.  The RAPID 2 Study (Abstract 696) was a 52 week Phase III study using a liquid formulation of the drug also in RA patients on background MTX.  In both studies patients received 400 mg weekly SQ or placebo x 3 doses.  Patients receiving drug were then randomized to receive 400 mg sq q2wk or 200 mg sq q 2wk, and patients on placebo continued placebo. New data presented at ACR included radiographic.

• Abstract 696: Liquid Formulation Certolizumab Pegol with Methotrexate Decreases Progression of Structural Joint Damage in Rheumatoid Arthritis Patients: The RAPID 2 Study
• Abstract 700: The Anti-TNF Certolizumab Pegol in Combination with Methotrexate is Significantly More Effective than Methotrexate Alone in the Treatment of Patients with Active Rheumatoid Arthritis: 1-Year Results from the RAPID 1 Study

Abatacept

• Abstract 699:Long-Term Efficacy and Safety of Abatacept through 3 Years of Treatment in Rheumatoid Arthritis Patients in the AIM and ATTAIN Trials

Rituximab

• Abstract 2088: Repeated Treatment Courses of Rituximab Produce Sustained Efficacy in Patients with Rheumatoid Arthritis and an Inadequate Response or Intolerance to One or More TNF Inhibitors
• Abstract 261: Immunoglobulin Levels and Infection Rates in Patients with Rheumatoid Arthritis (RA) Treated With Repeated Courses of Rituximab

Ofatumumab

• Abstract 2086: Ofatumumab, a Human CD20 Monoclonal Antibody, in the Treatment of Rheumatoid Arthritis: Early Results from an Ongoing, Double-Blind, Randomized, Placebo Controlled Clinical Trial

Ocrelizumab

• Abstract 695: Ocrelizumab, a Novel Humanized Anti-CD20 Antibody: Week 72 Results from a Phase I/II Clinical Trial in Patients with Rheumatoid Arthritis

Denosumab

• Abstract 698: Denosumab Inhibits RANKL, Reducing Progression of the Total Sharp Score and Bone Erosions in Patients With Rheumatoid Arthritis: 12-month X-Ray Results

Tocilizumab

Interleukin-6 is a cytokine involved in RA pathogenesis and is involved in the activation of many of the cells and also affect levels of inflammatory markers such as C-reactive protein and ESR.  Tocilizumab (previously known as MRA) is a humanized monoclonal antibody directed against the IL-6 receptor. Targeted blockade of IL-6 using this antibody represents a new approach to treatment of RA.  Studies have been published demonstrating efficacy of this compound (1. Maini RN, Taylor PC, Szechinski J, Pavelka K, Bröll J, Balint G, Emery P, Raemen F, Petersen J, Smolen J, Thomson D, Kishimoto T; CHARISMA Study Group.Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum. 2006 Sep;54(9):2817-29.   2 Nishimoto N, Hashimoto J, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Murata N, van der Heijde D, Kishimoto T. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007 Sep;66(9):1162-7). We have previously reviewed studies presented at ACR 2006 of this medication in RA and JRA.  Prior studies from Japan used a background of methotrexate of only 8 mg/week thus making the extrapolation of results to populations in the US and EU in which patients typically receive higher doses of MTX background therapy were needed.  At EULAR2007, results from OPTION, a large multicentered international phase III study were presented and summarized. At ACR an additional study was presented (TOWARD, Late Breaking 15).

• Abstract 2089: Targeted Inhibition of the IL-6 Receptor with Tocilizumab Effectively Reduces Disease Activity in Patients with Rheumatoid Arthritis
• Abstract L15: IL-6 Receptor Inhibition with Tocilizumab Reduces Disease Activity in Patients with Rheumatoid Arthritis with Inadequate Response to a Range of DMARDs: The TOWARD Study

RA Treatment: Safety

Is TNF Inhibitor Use Associated with Adverse Maternal-Fetal Outcomes?

Although TNF inhibitor use during pregnancy does not appear to lead to adverse outcomes in animal models, human data are limited and current recommendation mandate discontinuation during pregnancy, delivery, and breast feeding.  Two abstracts presented as podium presentations addressed the issue of fetal outcomes associated with TNF inhibitor use, with seemingly discordant conclusions.

• Abstract 667: A Safety Assessment of TNF Antagonists during Pregnancy: A Review of the FDA Database
• Abstract 730: Pregnancy Outcome after Exposure to Biologics: Results from the German Biologics Register RABBIT

Other Safety Abstracts

• Abstract 1343: Rheumatoid Arthritis, Interstitial Lung Disease, Mortality, and Anti-TNF Therapy: Results from the BSR Biologics Register (BSRBR)
• Abstract 1344: Are Cancers Occurring in RA Patients Treated with TNF Antagonists Particularly Aggressive?

 

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