ACR Highlights - Day 1 - CME
Accreditation Statement: The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Credit Designation: The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation.
There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.
The Johns Hopkins University School of Medicine takes responsibility for the content, quality and scientific integrity of this CME activity
Educational Goal: To help address the unmet needs between current knowledge and its application in patient care, the Highlights from the 71st Annual ACR Meeting: A Continuing Education Series seeks to provide rheumatologists and to other related healthcare professionals with the latest clinical information and data from the 71st Annual American College of Rheumatology Meeting.
Learning Objectives: At the conclusion of this activity, participants should be able to:
- Discuss key data being presented at the annual ACR meeting in a manner that is practical and clinically relevant.
- Assess how biologics can be incorporated into appropriate therapeutic strategies based on their different mechanisms of actions, response rates, frequency of administrations and safety and tolerability profiles.
- Recognize the long-term implications of biologic therapy on joint stability and mobility, cardiovascular complications and other risk factors.
Release Date: November 27, 2007
Expiration Date: November 27, 2008
Estimated time for completion: 30 minutes
Target Audience: This activity is intended for rheumatologists and relatedhealthcare professionals. There are no prerequisites for participants.
Faculty and Qualifications:
- Alan Baer, MD, Associate Professor of Medicine and Director, Johns Hopkins University Clinical Practice at Good Samaritan Hospital, Chief of Rheumatology at Good Samaritan Hospital
- Jon T. Giles, MD, Assistant Professor of Medicine, Division of Rheumatology, Department of Medicine, Johns Hopkins University
- Vicky Ruffing, RN, Nurse Manager, Johns Hopkins Arthritis Center
Disclosure Statements: As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a provider has with the manufacturer(s) of any commercial product(s) discussed of any commercial product(s) discussed in an educational presentation. The presenting faculty reported the following:
- Alan Baer, MD - Dr. Baer has no financial relationships to disclose.
- Jon T. Giles, MD – Dr. Giles discloses the following: Grants/Research Support: Roche, Centocor; Consultant: Abbott Laboratories; Honorarium: Prous Science, Amgen.
- Vicky Ruffing, RN – Ms. Ruffing discloses the following:Consultant for Roche, Amgen, Genentech, BMS, and Abbott
Off-Label Statement: No faculty member has indicated that their presentation will include information on off-label products.
Disclaimer: The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combination of drugs, including indications, contradictions, warnings and adverse effects before administering pharmacologic therapy to patients.
Method of Participation: In order to receive your certificate follow the link to the post-test, achieve a score of at least 70 percent and complete the program evaluation. Upon successful completion follow the directions to print your certificate.This activity is designed to be completed within the time designated; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period.
INTRODUCTION: The Impact of Rheumatic Diseases
Rheumatic diseases cause significant disability and are the main reason people over the age of 65 see a health care provider. Arthritis and chronic joint conditions affect 1 in 3, or 70 million, adults in the United States. Arthritis alone results in approximately $51 billion in direct medical costs and $86 billion in total costs annually. (1,2)
The ACR/ARHP annual scientific meeting is the largest world meeting of physicians, allied health care professionals, and researchers focused on improving outcomes for people with rheumatic diseases. This issue highlights key information about the treatment of rheumatoid arthritis (RA) presented on Thursday, November 8, 2007.
Summary of New Treatments for Rheumatoid Arthritis
Targeted immunomodulating therapies have revolutionized RA treatment. Despite demonstrated efficacy, a significant subset of RA patients either do not respond fully or are unable to tolerate the available therapies, creating a need for agents with novel mechanisms. Several currently available agents work by inhibiting tumor necrosis factor alpha (TNF-α), an important proinflammatory cytokine in RA. Certolizumab pegol (CZP) is the first PEGylated, Fc-free low molecular weight anti-TNF antibody to be studied in RA. It is designed to have a long half-life (14 days) and selectively target TNF-α with high affinity. Denosumab is a novel monoclonal
antibody targeted at the RANK ligand (RANKL), an important mediator of bone erosion in RA. Recently, B-cell depletion has been shown to be an effective strategy for RA treatment. Ocrelizumab is a humanized monoclonal antibody directed at the CD20 site on B-cells.
Anti-TNF Agents
Currently available anti-TNF-α monoclonal antibodies are complexed to the Fc portion of IgG immunoglobulin. This process may affect the uptake of the agent into tissues and significantly adds to cost. PEGylation eliminates the Fc portion, potentially making the delivery of the TNF inhibitor to inflamed joints more rapid and less costly to manufacture.
Certolizumab Pegol in Combination With MTX: 1-Year Results From the RAPID 1 Study (3)
Dr. Ed Keystone presented results of the RAPID 1 study, a phase III multicenter, double-blind, placebo-controlled, parallel-group study evaluating the efficacy and tolerability of a lyophilized form of CZP as add-on therapy to methotrexate (MTX) in patients with active RA refractory to MTX alone. Patients were randomized to treatment with CZP (three 400-mg doses every 2 weeks, followed by doses of 200 mg or 400 mg every 2 weeks) or placebo, with MTX therapy continued as usual. The average MTX dose was 13 mg. Patients who withdrew for any reason were considered nonresponders from that point forward. A total of 982 adult patients were randomized to treatment (intent-to-treat population [ITT]): CZP 200 mg, n = 393; 400 mg, n = 390; placebo, n = 199. Of these, 572 completed the study (n = 255, 274, and 43, respectively). The following withdrew due to lack of efficacy: 24.9%, 19%, and 70.9% for CZP 200 mg, 400 mg, and placebo respectively. At week 24, the ACR20 responder rates were 58.8%, 60.8%, and 13.6%; and at week 52 were 53.1%, 54.9%, and 13.1%, respectively; all values were P<0.001. There was rapid onset of efficacy, with 30% of patients achieving ACR20 at 1 week and 50% at 2 weeks after initiation of CZP treatment. The effects of the 200-mg and 400-mg doses of CZP were virtually identical. Both doses were well tolerated with a low incidence of discontinuation due to adverse events (AEs). CZP is a promising new agent that, when added to MTX in patients with MTX-refractory RA, appears to have a rapid onset of effect that is sustained for at least 1 year.
Certolizumab Pegol With MTX Decreases Progression of Structural Joint Damage in RA: The RAPID 2 Study (4)
Dr. Desire van der Heijde presented the results of a phase III, double-blind, randomized, placebo-controlled study conducted to assess the efficacy of 2 doses of a liquid formulation CZP plus MTX in patients with RA and incomplete MTX response. Inhibition of radiographic progression at week 24 was the primary efficacy endpoint. Patients received MTX with CZP 400 mg at baseline and at weeks 2 and 4, followed by either 200 mg or 400 mg every 2 weeks or placebo. Patients who did not achieve an ACR20 response at both weeks 12 and 14 could withdraw at week 16 and enter an open-label, follow-up study on active treatment. For patients who withdrew prior to study end, linear extrapolation was used to determine radiographic progression. In 619 patients randomized, the mean age was 52 years and mean disease duration 6 years. Groups were comparable at baseline with a mean DAS28 score of 6.8. Patients on placebo, CZP 200 mg, or CZP 400 mg every 2 weeks had a mean total Sharp score (mTSS) at baseline of 47.2, 40.2, and 48.2 Sharp units, and mean estimated yearly progression of 9.3, 7.5, and 8.2 Sharp units/year, respectively. In the placebo group, 87% of patients withdrew at week 16 due to lack of efficacy and entered the open-label treatment phase compared with 19.7% in the CZP group. The change in mTSS from baseline based on last observation carried forward (LOCF) was significantly lower in patients receiving CZP + MTX compared with those receiving placebo + MTX at 24 weeks (1.2 ± 4.1; 0.2 ± 2.7 [P = .003]; -0.4 ± 2.1 [P < .001]). The mean change from baseline in mTSS in the 400 mg group of -0.4 Sharp units (95% CI: -0.7, -0.1) suggests joint repair. There were no significant differences between the 2 CZP groups. CZP plus MTX demonstrated effective disease modification in these patients with active RA. These results are consistent with those seen for the lyophilized CZP preparation.
B-cell Depletion
Fully humanized monoclonal antibody therapeutics have putative advantages over those with nonhuman components because the potential for infusion reaction and the development of neutralizing antibody may be reduced. Ocrelizumab has been developed as a “second-generation anti-CD20.”
Ocrelizumab, a Novel Humanized Anti-CD20 Antibody for RA: Results of the ACTION Study (5)
Dr. Mark Genovese presented the results of a Phase I/II study evaluating the efficacy and safety of ocrelizumab in 237 patients with moderate to severe RA who were rheumatoid factorpositive (RF+) with inadequate response to at least MTX. Patients remained on a stable dose of MTX (10-25 mg/week) and were randomized to a single course of ocrelizumab (10, 50, 200, 500, or 1000 mg) or placebo by intravenous (IV) infusion on days 1 and 15. No IV corticosteroids were given before ocrelizumab infusions. There were 196 ocrelizumab and 41 placebo-treated patients included in the ITT population. Demographic characteristics and prior use of TNF inhibitors (47%) were similar among groups. The most frequent AEs with ocrelizumab were infusion-associated mild to moderate headaches, nausea, chills, pyrexia, and dizziness. AEs were more common following the first infusion and were similar among all ocrelizumab dose groups and similar to placebo after the second infusion. Rates of serious AEs and infection-related AEs were similar for ocrelizumab and placebo. B-cell depletion was observed with all doses of ocrelizumab, with earlier B-cell repletion at lower doses. Clinical activity at 24 weeks based on ACR20, -50, and -70 and moderate/good EULAR scores was observed at all dose levels. Efficacy was best with doses of 200 mg and higher, and these doses were associated with lower immunogenicity based on development of human antihuman drug antibodies (HAHAs). Although still early in clinical evaluation, ocrelizumab plus MTX appears to be well tolerated, and doses of 200 mg and higher may prove clinically efficacious in subsequent clinical testing in patients with moderate to severe RA. Ocrelizumab may offer advantages over rituximab based on its low immunogenicity.
RANK-Ligand Inhibition
Preventing articular damage and deformity is a primary goal of RA therapy. Despite reduction in joint symptoms with current therapeutics, some RA patients continue to demonstrate progression of bony erosion over time, making the use of agents that selectively inhibit bone erosion compelling.
Denosumab Inhibits RANKL, Reducing Bone Erosions in Patients With RA (6)
Dr. Desire van der Heijde presented 12-month results of an ongoing Phase II, double-blind, placebo-controlled study evaluating the efficacy of denosumab, a fully human monoclonal antibody to RANKL, added to MTX therapy in patients with active RA. Patients were allowed to receive bisphosphonates. A total of 227 patients received subcutaneous injections of denosumab 60 mg (n = 73), 180 mg (n = 76), or placebo (n = 78) every 6 months. There was a smaller increase (worsening) in mean van der Heijde-modified TSS from baseline in the denosumab 60-mg group (0.85 ± 2.52, P = .03) and 180 mg group (0.97 ± 2.70, P = .18) compared to placebo (1.87 ± 5.06). The increase in the mean erosion score was smaller than placebo for both the 60-mg and 180-mg groups (mean reduction, 75% and 86% [P < .05], respectively). There was no detectable difference between either denosumab group or placebo for joint space narrowing. AEs were similar across the denosumab and placebo groups. Based on this early data, denosumab appears to reduce progression of TSS and bone erosions with good tolerability. As denosumab has no demonstrated efficacy in reducing the signs and symptoms of RA (ie, joint swelling and tenderness), additional studies are needed to determine the optimal effective and safe dose and how the agent may be combined with other disease modifying agents (including biologics).
Summary Of Current Rheumatoid Arthritis Therapies
Increasing the dose of certain biologic antirheumatic therapies can result in additional clinical benefits (eg, infliximab). However, the clinical efficacy of higher doses of etanercept has not been evaluated in RA patients.
Efficacy and Safety of Etanercept 100 mg in Suboptimal Responders to Etanercept 50 mg (7)
Dr. Michael Weinblatt presented results of a multicenter, double-blind active control study evaluating the efficacy and safety of etanercept (ETN) 100 mg/week (QW) in suboptimal responders (≥ 5 tender and swollen joints after at least 6 months) to ETN 50 mg/week and MTX ≥ 15 mg/week. Patients were randomized to ETN 50 mg QW (n = 40) or ETN 100 mg QW (given as 50 mg twice weekly) (n = 160) for 12 weeks. After 12 weeks, patients meeting predefined response criteria (EULAR, DAS28) began 12 weeks of open-label ETN: responders received
ETN 50 mg, partial responders received ETN 100 mg through week 24, and nonresponders to ETN 100 mg were discontinued. A total of 215 patients enrolled, 201 were randomized, 200 received ≥ 1 dose ETN, 187 completed 12 weeks, and 102 completed the entire 24-week study; 75 who discontinued were nonresponders to 100 mg at week 12. The mean age was 53 years and the mean disease duration was 10 years. Mean baseline MTX doses were 18 mg in the 50-mg group and 17 mg in the 100-mg group. At week 12, the percentage of good to moderate DAS28 responders (the primary endpoint) was higher in the 100-mg group than in the 50-mg group (46% vs 35%, P = NS). Median serum ETN concentrations at week 12 were reflective of the dosing (2343 ng/mL for the 50-mg group and 6596 ng/mL for the 100-mg group), but were not predictive of clinical response. ETN was generally well tolerated; 34.4% of ETN 100 mg and 37.5% of ETN 50 mg had AEs. Only 4.4% and 1.9% in the ETN 100-mg group had serious AEs or serious infections, compared to none in the ETN 50-mg group. This interpretation was limited by the small number of events. Increasing the ETN dose from 50 to 100 mg/week in patients on chronic ETN with MTX did not produce a statistically significant improvement in RA activity. In addition, more information on the potential for AEs is needed.
Managing Osteoporosis In Rheumatoid Arthritis
Secondary osteoporosis is a well-known consequence of corticosteroid use, contributing to fracture in up to 50% of long-term users. Antiresorptive therapy with a bisphosphonate is currently recommended for the prevention of glucocorticoid-induced osteoporosis but may not be optimal compared to newer bone-anabolic agents in patients at the highest risk for fracture.
Teriparatide Versus Alendronate in the Treatment of Glucocorticoid-Induced Osteoporosis (8)
Dr. Kenneth Saag reported the first data comparing the efficacy of teriparatide, an anabolic bone-building agent, with that of alendronate in an 18-month randomized controlled trial in 428 patients with RA on a dose equivalent of prednisone ≥ 5 mg/day for at least 3 months and either low bone mineral density or antecedent fractures. Patients were randomized to teriparatide 20 μg injected subcutaneously once daily (n = 214) or alendronate 10 mg orally once daily (n = 214). The primary objective was to determine whether the increase in lumbar spine bone density with teriparatide exceeded that obtained with alendronate. The study population was 81% women with a mean age of 57 years, and a median (25th, 75th interquartile range) glucocorticoid daily dose and use duration of 7.5 (5.0, 10.0) mg and 1.3 (0.3, 5.5) years. Baseline lumbar spine T-scores were -2.5 ± 1.0. A total of 208 (49%) randomized subjects (100 alendronate; 108 teriparatide) had a prevalent fracture. Both treatments significantly increased bone density at the lumbar spine, total hip and femoral neck, with greater increases in the teriparatide group than alendronate. Fewer new vertebral fractures occurred with teriparatide (1/171, 0.6%) than with alendronate (10/165, 6.1%) (P = .004), but the incidence of nonvertebral fractures was not significantly different between alendronate (8/214, 3.7%) and teriparatide (12/214, 5.6%). These results indicate that teriparatide is more effective than alendronate in improving bone mass density and reducing vertebral fractures in high-risk patients with glucocorticoid-induced osteoporosis. Further investigation is needed to evaluate the safety and efficacy of teriparatide in lower risk patients.
Efficacy and Safety of Zoledronic Acid 5 mg in Preventing Fractures (9)
Limited gastrointestinal absorption and generally poor adherence to therapy are the major barriers to effective treatment with oral bisphosphonates. Intravenous and injected alternatives are therefore potentially preferable.
Dr. Lyles and colleagues presented results of the HORIZON-RFT study evaluating the effects of zoledronic acid (ZOL) 5 mg IV once a year (n = 1054) versus placebo (n = 1057) on the risk for future fracture and mortality in 2111 men and women ≥ 50 years of age with previous hip fracture. Patients received loading doses of vitamin D2 or D3 and daily supplements of vitamin D and calcium. Seventy-six percent of patients were women, with a mean age of 76 years; only 42% had a T-score less than -2.5. Clinical fractures occurred in 231 patients (91 ZOL, 139 placebo) for a 2-year cumulative event rate of 8.59% versus 13.88%, respectively. This corresponded to a relative risk reduction of 35% (HR = 0.65, 95% CI: 0.50-0.84; P = .0012). ZOL was also associated with a statistically significant reduction in the risk for clinical vertebral fractures by 46% (HR = 0.54, 95% CI: 0.32-0.92; P = .0210); nonvertebral fractures by 27% (HR = 0.73; 95% CI: 0.55-0.98; P = .0338); and hip fractures by 30% (HR = 0.70, 95% CI: 0.411-1.19; P = .1815, NS). This was the first study to show a lower incidence of total mortality, reduced by 28% with bisphosphonates, 9.58% versus 13.24% with placebo (HR = 0.82; 95% CI: 0.56-0.93, P = .0117). The overall incidence of AEs and serious AEs was comparable between groups, specifically cardiovascular events and renal function, and there were no cases of osteonecrosis of the jaw seen with ZOL.
Summary
In summary, there are several promising new agents in later stages of clinical development that will provide additional treatment options for patients with RA and associated disorders. In addition, there is increasing knowledge about dosing and monitoring of currently available agents that may lead to improved patient outcomes.
Outcomes:
References
- 109th Congress Pending Legislation: Arthritis Prevention, Control, and Cure Act of 2005 (H.R. 583, S. 424). http://olpa.od.nih.gov/legislation/109/pendinglegislation/arthritis.asp. Accessed November 2007.
- National Center for Chronic Disease Prevention and Health Promotion. Arthritis. http://www.cdc.gov/arthritis/. Accessed November 8, 2007.
- Keystone E, Mason D, Combe B. 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 (platform presentation 700). Paper presented at: The Annual Meeting of the ACR/ARHP; November 8, 2007; Boston, MA.
- Landewé RB, Strand V, Smolen J, van der Heijde D. Liquid formulation certolizumab pegol with methotrexate decreases progression of structural joint damage in rheumatoid arthritis patients: the RAPID 2 study (platform presentation 696). Paper presented at: The Annual Meeting of the ACR/ARHP; November 8, 2007; Boston, MA.
- Genovese M, Kaine J, Lowenstein M, et al. Ocrelizumab, a novel humanized anti-CD20 antibody: week 72 results from a phase I/II clinical trial in patients with rheumatoid arthritis (platform presentation 695). Paper presented at: The Annual Meeting of the ACR/ARHP; November 8, 2007; Boston, MA.
- van der Heijde D, Cohen S, Sharp JT, et al. Denosumab inhibits RANKL, reducing progression of the total Sharp score and bone erosions in patients with rheumatoid arthritis: 12-month X-ray results (platform presentation 698). Paper presented at: The Annual Meeting of the ACR/ARHP; November 8, 2007; Boston, MA.
- Weinblatt ME, Schiff MH, Ruderman EM, et al. Efficacy and safety of etanercept 100 mg in patients with rheumatoid arthritis who are suboptimal responders to etanercept 50 mg (platform presentation 726). Paper presented at: The Annual Meeting of the ACR/ARHP; November 8, 2007; Boston, MA.
- Saag KG, Shane E, Boonen S, et al. Active-comparator trial of teriparatide versus alendronate in the treatment of glucocorticoid-induced osteoporosis (platform presentation 665). Paper presented at: The Annual Meeting of the ACR/ARHP; November 8, 2007; Boston, MA.
- Lyles K, Colon-Emeric C, Magaziner J, et al. Efficacy and safety of zoledronic acid 5 mg in preventing fractures in men and women with prevalent hip fracture: the HORIZION-recurrent fracture trial (platform presentation 666). Paper presented at: The Annual Meeting of the ACR/ARHP; November 8, 2007; Boston, MA.
