2007 ACR CME Activity - Day Three
CME Information
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 29, 2007
Expiration Date: November 29, 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 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. “Highlights from the 71st Annual American College of Rheumatology Meeting*: A Continuing Education Series” presents practitioners with a practical summary of key data presented at the conference. On Saturday, November 10, key presentations at the ACR annual meeting described insights into the genetic risk factors for rheumatic diseases, new biomarkers for disease activity, the effect of new treatment options for rheumatoid arthritis (RA), how to handle special situations in patients on biologic therapy, and outcomes in patients with systemic lupus erythematosus (SLE).
DAY 3: Insights Into Genetic Risk Factors for Rheumatoid Diseases
The contribution of genetic factors to the risk of the rheumatic diseases is varied and complex. Although imperfectly understood, most rheumatic diseases likely involve many genetic determinants that each make small but significant contributions to risk. Genetic association studies are emerging as powerful ways of identifying novel genetic regions with small contributions to risk that were previously unidentifiable with other methods.
The STAT4 Gene as a Genetic Risk Factor for RA and SLE1
Dr. Elaine Remmers presented results of a candidate gene association study showing a link between single nucleotide polymorphisms (SNPs), or small genetic variations, in the STAT gene region and the risk for RA and SLE. Data from the phase II HapMap, a catalog of common genetic variants that occur in human beings, was used. The STAT1/STAT4 region was fine-mapped with 63 SNPs. The STAT4 gene encodes a protein that plays an important role in the regulation and activation of certain cells of the immune system, such as Th1 and Th17 T-cell pathways. Two North American RA cohorts with a total of 1620 cases and 2635 controls were used for mapping. The most significantly associated SNP was also genotyped in a third RA case-control cohort from Sweden consisting of 1529 RA cases and 881 controls. Three cohorts of SLE patients totaling 1036 cases and 1188 independent controls were also evaluated. All cases studied were of European descent. Four SNPs located in the third intron of STAT4 were strongly associated with disease susceptibility in both RA and SLE. These results indicate that RA and SLE may share mechanistic pathways in patients of European ancestry. Genotyping patients for these STAT4 variants are not likely to be used diagnostically but may represent an area of focus for new therapeutic targets for RA and SLE.
DAY 3: Updates on Diagnosis and Monitoring of SLE
Activation of the type I interferon pathway is more common among SLE patients with active disease. Interferon-induced genes and their protein products thus hold promise as markers of disease activity in lupus.
IFN-Regulated Chemokines are Reliable Biomarkers of SLE Disease Activity(2)
The type I interferons (IFN) are strongly implicated in the pathophysiology of SLE and lead to increased cytokine levels. Dr. Jason Bauer presented results of a longitudinal study performed to validate the use of IFN-regulated chemokines as biomarkers of SLE activity. Serum samples for 3 interferon-regulated chemokines (IP-10, MCP-1, and MIP-3B) from 288 SLE patients in the Johns Hopkins SLE cohort were analyzed. Patients were evaluated by the same examining physician at each visit and followed longitudinally for 1 year, which represented 1300 total visits. A normalized chemokine score was created to reflect the combined levels of all 3 chemokines. Detailed clinical information and laboratory results were also available for each visit. Paired, consecutive visits from patients who either experienced a flare of disease activity (increase in SLE Disease Activity Index [SLEDAI] ≥ 3, n = 74) or a reduction of disease activity (decrease in SLEDAI ≥ 3, n = 93). Patients were also divided based on baseline chemokine levels and the incidence of future disease activity was compared. The levels of IP-10, which has a role in migration of Th1 cells, increased with flare (P = 1x10-3) and decreased with remission (P = 3x10-5). The chemokine score was also a highly significant marker of disease activity increasing with flare (P = 2x10-4) and decreasing with remission (P = 4x10-4). In contrast, classic laboratory tests (dsDNA abs, complements, and erythrocyte sedimentation rate [ESR]) did not show the same level of significance (flare, P > .3; remission, P =.01). Baseline chemokine levels also predicted future activity, with patients having high chemokine levels at baseline more likely to have an active future disease course as measured by the SLEDAI (P = 3x10-3). These data strongly suggest that monitoring IFN-regulated chemokines in SLE will be a useful clinical tool to aid physician decision-making. It may also provide a reliable measure of disease activity for use in clinical trials. Further validation studies using samples from independent SLE cohorts are planned to provide the data necessary to effectively translate the results of the current study into a novel laboratory test for SLE.
DAY 3: Updates on Arthritis Treatment Options
Early, aggressive RA therapy has become the standard for preventing accumulated irreversible articular damage. Prior results of the PROMPT study demonstrated the ability of methotrexate to delay clinical RA in patients with early, undifferentiated synovitis (ie, only a few active joints) who were seropositive for anti-CCP antibody.
Loss of Benefit After Methotrexate (MTX) Discontinuation in Undifferentiated Arthritis (3)
The results of the PROMPT study that evaluated the effect of 1 year of treatment with MTX showed a sustained suppressive effect on radiographic progression 18 months after treatment discontinuation. In this double-blind, placebo-controlled, multicenter trial, 110 undifferentiated arthritis (UA) patients were randomized to treatment with MTX 15 mg/week or placebo with the dose increased to MTX 30 mg/week based on 3 monthly calculations of the disease activity score (DAS) (goal DAS ≤ 2.4). In the first year, 53% of placebo patients compared with 20% in the MTX group switched to open-label MTX after fulfilling ACR criteria for RA. In all other patients study medication was discontinued after 12 months. During follow-up, an additional 20% of the patients in the former MTX group started open-label MTX for RA, but no patients in the placebo group started open-label MTX. The radiographic progression over 30 months was scored in chronological order by 2 readers, using the Sharp/van der Heijde score (SHS). Median joint damage progression over 30 months and the percentage of patients showing progression > 2.81 on the Stokes Ankylosing Spondylitis Spinal Score (SDC) were similar for MTX and placebo (P =.415 and P=.249 respectively). Both anti-CCP positive and negative patients showed no differences in radiographic progression between the 2 treatment groups; however, there was more effect in the CCP+ group. Of the patients showing progression after 30 months, 33% in the MTX group progressed during the first year and 67% showed progression only after discontinuation of treatment versus 70% and 30% respectively in the placebo group. The initial effect of one year of MTX to decrease radiographic progression in UA patients was no longer seen 18 months after MTX discontinuation. Therefore, MTX use appears to postpone the progression of UA to RA, but the suppression of joint damage is not sustained after MTX withdrawal. These data suggest that in anti-CCP+ patients, MTX should be started early and continued long term.
Local Treatment for Inflammatory Arthritis: Intra-articular Administration of Recombinant Adeno-associated Vector (AAV) Containing a TNF-α Antagonist Gene (4)
Intra-articular (IA) delivery of immunomodulating gene therapy represents a novel therapeutic strategy, one with potential safety benefits, because therapy is local rather than systemic. Data from 61 patients in a dose escalation arm of a phase I/II clinical study of single and repeat IA injections of AAV2-TNFR:Fc (tgAAC94), an adeno-associated virus vector containing the cDNA for the TNFR:Fc fusion gene, were presented by Dr. Philip Mease. A total of 120 subjects with persistent moderate or severe inflammation in a target joint were enrolled and received a single IA injection of either AAV2-TNFR:Fc (1x1011, 1x1012, or 1x1013 DNase-resistant particles [DRP]/mL joint volume) or placebo, followed by open-label AAV2-TNFR:Fc based on when the target joint met predetermined criteria for re-injection. The primary endpoint was safety and secondary endpoints included an expanded target joint evaluation, patient assessment, and a functional assessment. In the phase 2 portion, 58 subjects (49 with RA, 7 with PsA, and 2 with AS; 32 on TNF-α antagonists) have been enrolled and received a single injection of study drug into the knee (n = 15), ankle (n = 14), wrist (n = 16), MCP (n = 8), or elbow (n = 5). In all subjects, administration site reactions, consisting of mild to moderate increase in tenderness and swelling of the injected joint, sometimes accompanied by erythema or pruritis, were reported in approximately 10% of subjects. The incidence of adverse events (AEs) was higher with higher doses and varied by the joint injected—for example 4.2% of MCP injections and 14% of wrist injections were associated with AEs. Two patients developed serious AEs:
- One case of culture negative septic arthritis, 15 weeks after injection of study agent that the investigator considered probably related to the study agent.
- One fatal case of disseminated histoplasmosis, in a patient also receiving adalimumab, methotrexate (MTX), and prednisone, ultimately died due to multiorgan failure and retroperitoneal hemorrhage; this was considered as probably unrelated to the study agent. There was evidence of AAV in the injected knee joint but barely detectable systemic levels. The study is currently on clinical hold pending further review of this case. Based on efficacy analyses, there was a trend toward decreased joint swelling and tenderness with the study agent.
Although this news is promising, more data on long-term efficacy and safety of this and similar therapeutics is required before widespread use of intra-articular gene therapy strategies can be expected.
Remission Rates in Subjects With Active Early Rheumatoid Arthritis—1 Year Results of the COMET Trial (5)
Dr. Paul Emery presented results of the COMET trial, a multicenter, randomized, double-blind trial of etanercept plus MTX (n = 274) versus MTX alone (n = 268) in patients with active early RA. This was the first major RA trial with etanercept to use clinical remission as a primary endpoint, as measured by disease activity score (DAS28 < 2.6). At baseline, the mean disease duration was 7 months, DAS28 was 6.5, and 22% of patients had prior disease-modifying anti-rheumatic drug (DMARD) use. At week 52, half (50%) of patients in the combination therapy group achieved the primary endpoint of clinical remission (DAS28 <2.6) versus 28% of patients treated with MTX alone (P < .001). The proportion of patients achieving DAS remission and low disease activity (DAS ≤3.2) was significantly greater in the combination therapy group by week 2 and at all timepoints thereafter. The results of the secondary endpoints in the combination and MTX-only groups, respectively were:
- ACR20: 86% versus 67%, P < .001
- ACR50: 71% versus 49%, P < .001
- ACR70: 48% versus 28%, P < .001
The most common AEs were injection site reaction, infection, and headache. There were no differences in rates of serious infections or malignancies among patients in the etanercept plus MTX group compared with the MTX-only group. There were no cases of tuberculosis (TB) or demyelinating disease reported. These results suggest that clinical remission is an achievable goal in many patients with early RA yet still remains elusive for a substantial number. Early, aggressive initial therapy with combination regimens may become the standard for RA patients with the greatest risk for progressive disease. However, more research is needed to distinguish the subgroup of patients who will benefit the most from early, initial combination therapy.
Tocilizumab-Targeted Inhibition of the IL-6 Receptor Reduces Disease Activity in RA (6)
IL-6 is a highly inflammatory cytokine with a pivotal role in the RA disease process. Targeted inhibition of IL-6 is a promising strategy for treating synovitis and reducing articular damage in RA. Dr. Andre Beaulieu presented results of the OPTION Study, evaluating the efficacy and safety of tocilizumab (TCZ), a novel humanized antihuman IL-6 receptor antibody, in patients with moderate to severe active RA despite treatment with MTX. In this double-blind, placebo-controlled phase III study, 623 patients were randomized to either 8 mg/kg TCZ, 4 mg/kg TCZ, or placebo given intravenously every 4 weeks. All groups received a stable dose of MTX 10-25 mg weekly, but no other DMARDs were allowed. On average, patients had high disease activity at baseline, with a mean DAS28 of 6.8. A significantly higher proportion of TCZ-treated patients had improvement in the primary endpoint of ACR20 at 24 weeks (TCZ 8 mg/kg 59%; TCZ 4 mg/kg 48%; placebo 27%; P < .0001). Significantly more patients also achieved ACR50 and ACR70 response by 24 weeks with TCZ 8 mg/kg and TCZ 4 mg/kg versus placebo (ACR50: 44% and 32% vs 11%, respectively; ACR70: 22% and 12% vs 2%, respectively, P < .0001). A total of 21 patients achieved ACR90 response, 11 (5.4%) with TCZ 8 mg/kg and 10 (4.7%) with TCZ 4 mg/kg, compared with none for placebo. There were also highly significant differences (P < .0001) for many individual components (swollen joint count [SJC], tender joint count [TJC], ESR with TCZ 4 mg/kg; TJC, SJC, patient’s global assessment of disease activity, patient’s assessment of pain, ESR, and c-reactive protein (CRP) with TCZ 8 mg/kg. There was a rapid response to TCZ, with 20% of patients achieving ACR20 by 2 weeks and 40% by 4 weeks; in addition, the Health Assessment Questionnaire (HAQ) score had improved by 4 weeks. CRP dropped by 2 weeks and normalized in patients on 8 mg/kg TCZ. There was a similar overall incidence of AEs in all groups. There were 41 serious AEs in approximately 6% of patients in each group; 15 were considered related to study treatment and 11 led to discontinuation. Serious infections were observed with a higher frequency in patients treated with TCZ (2.9% in the TCZ 8 mg/kg group, 1.4% in the TCZ 4 mg/kg group, and 1% in the placebo group). This large phase 3 study provides evidence that IL-6 plays a fundamental role in the pathogenesis of RA and suggests that, at least in the short term, IL-6 inhibition is safe and efficacious in combination with background MTX for the treatment of RA patients with inadequate responses to prior MTX monotherapy.
How to Manage Biologics in Special Circumstances7
In a special symposium, Dr. Peter Taylor reviewed the latest published evidence regarding the use of biologics in special situations. The highlights of the recommendations for managing therapy in these circumstances are:
- There is evidence associating biologic therapies with an increased incidence of postoperative infection. Current recommendations are to stop these agents 2 to 5 half-lives prior to surgery and resume therapy after wound healing with no signs of infection. When making clinical decisions, it is important to consider the septic risks of the surgical procedure.
- Use of biologic agents may be associated with an increased risk of infection. If a moderate to severe infection develops in a patient taking one of these agents, it is recommended that the agent be discontinued and appropriate antibiotic or antiviral therapy be intiated.
Consideration of whether the biologic agent can be restarted can begin after the infection resolves. In this situation, it is important to consider the severity of the infection when making clinical decisions; for example, biologic agents most likely do not need to be discontinued in patients with a mild upper respiratory infection.
- Current evidence suggests that biologic agents should be avoided in patients with HIV or HBV infection and they should be used cautiously in patients with HCV infection. It is prudent to test serology prior to beginning treatment with a biologic agent.
- Based on current evidence, live or attenuated vaccines should be avoided in patients on biologic therapies; however, inactivated vaccines are safe and should be encouraged.
DAY 3: Outcomes in SLE
Outcomes After Acute Myocardial Infarction in SLE (8)
The risk for adverse outcomes after acute myocardial infarction (AMI) among patients with SLE is not well known. Dr. Mansi Shah and colleagues analyzed the risk for prolonged hospitalization and in-hospital mortality following AMI in the1993-2002 US Nationwide Inpatient Sample (NIS), a national hospital discharge database for SLE, diabetes mellitus (DM), and SLE/DM groups compared to controls. A total of 906,638 patients hospitalized for AMI (30.2% females) were included. For the SLE (n = 2192), DM (n = 236,016), SLE/DM (n = 474), and control (n = 667,956) groups, the in-hospital mortality rates were 8.3%, 6.2%, 5.7%, and 4.7%, respectively. All 3 groups had higher adverse outcome risk ratios compared to control group based on multivariate analysis. The adjusted odds ratio (OR) for prolonged hospitalization was higher for those with SLE (OR = 1.48, 95% CI: 1.32-1.79) compared to those with DM (OR = 1.30, 95% CI: 1.28-1.32). A similar pattern was observed for multivariate-adjusted hazard ratios (HR) for in-hospital mortality (HR for SLE = 1.65, 95% CI: 1.33-2.04; HR for DM = 1.11, 95% CI: 1.07-1.14). SLE appears to increase the risk of poor outcomes after AMI, exceeding the magnitude of risk seen in patients with diabetes.
Outcomes / Post Test
Posttest and Evaluation for Day Three of ACR HighlightsReferences
- Remmers EF, Plenge RM, Lee AT, et al. Case-control association studies identify a variant form of the signal transducer and activator of transcription 4 gene (STAT4) as a genetic risk factor for rheumatoid arthritis and systemic lupus erythematosus. (Platform presentation 2055.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 10, 2007; Boston, MA.
- Bauer JW, Petri M, Batliwalla FM, et al. IFN-regulated chemokines are reliable biomarkers of systemic lupus erythematosus disease activity. (Platform presentation 2056/) Paper presented at: The Annual Meeting of the ACR/ARHP; November 10, 2007; Boston, MA.
- Visser K, van Dongen H, van Aken J, et al. Loss of radiographic benefit after discontinuation of treatment with methotrexate in patients with undifferentiated arthritis. (Platform presentation 2087.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 10, 2007; Boston, MA.
- Mease P, Wei N, Fudman E, et al. Local treatment for inflammatory arthritis: a phase 1/2 clinical study of intra-articular administration of a recombinant adeno-associated vector containing a TNF-α antagonist gene. (Platform presentation 2084.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 10, 2007; Boston, MA.
- Emery P, Breedveld F, Hall S, et al. 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. (Platform presentation L17.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 10, 2007; Boston, MA.
- Beaulieu AD, Rubbert-Roth A, Woodworth T, et al. Targeted inhibition of the IL-6 receptor with tocilizumab effectively reduces disease activity in patients with rheumatoid arthritis. (Platform presentation 2089.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 10, 2007; Boston, MA.
- Taylor P, Symmons D, Keystone E. Issues in biologics therapy. (Platform presentation.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 10, 2007; Boston, MA.
- Shah M, Shah A, Krishnan E, et al. Outcomes after acute myocardial infarction in systemic lupus erythematosus. (Platform presentation 2156.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 10, 2007; Boston, MA.
