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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

ABSTRACTS in PERSPECTIVE based on presentations from the 10th Annual European Congress of Rheumatology (EULAR)

Copenhagen, Denmark / June 10-13, 2009

EDITORIAL OVERVIEW:

Alfred A. Cividino, MD, FRCPC,

Clinical Professor of Medicine, Division of Rheumatology, McMaster University, Hamilton, Ontario

If inflammation over time equals joint damage, then timely control of rheumatoid arthritis (RA) should minimize joint damage. Structural joint damage also occurs early on—clearly an argument in favour of early appropriate intervention in RA.

Several measures of disease activity are available to assess the effects of therapeutic intervention including the Disease Activity Score (DAS), the American College of Rheumatology (ACR) response rate, the Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI). Core components of each of these indices differ, but the DAS, ACR and the SDAI all require some measure of an acute-phase response (APR), which is not usually available during the initial patient visit. The development of a simplified, patient-centred assessment score could thus prove very useful in daily clinical practice.

As presented by Dr. Theodore Pincus, Clinical Professor of Medicine, Division of Rheumatology, New York University School of Medicine, routine assessment of patient index data (RAPID3) responses were compared to DAS28 responses attained in two abatacept trials, AIM (Abatacept in Inadequate Responders to Methotrexate) and ATTAIN (Abatacept Trial in the Treatment of Anti-TNF Inadequate RA Responders). In AIM, 27% of patients in the active therapy arm achieved a good DAS28 response, while in ATTAIN, 17% achieved the same good response. Using the RAPID3 scoring system, 35% of AIM patients and 24% of ATTAIN patients were judged to have a good response. Moderate and poor responses as assessed by DAS28 and by RAPID3 were also relatively similar, suggesting that the RAPID3 criteria may serve clinicians well in routine clinical care.

It may not be widely appreciated that RA patients have a cardiovascular disease (CVD) risk that is roughly equal to that of patients with type 2 diabetes. In recognition of this risk, EULAR recommendations have been made for primary prevention of CVD in patients with inflammatory arthritis including RA, ankylosing spondylitis (AS) and psoriatic arthritis (PsA), starting with an annual assessment of traditional risk factors.

EULAR also recommends physicians use the Systematic Coronary Risk Evaluation (SCORE) algorithm adapted for RA patients to determine a patient’s 10-year CV risk and to treat patients to guideline targets if their 10-year CVD risk is =10%. Adequate control of disease activity is also mandatory to reduce CV risk. Disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) as well as antitumour necrosis factor (anti-TNF) agents have dramatically improved disease control in RA and with it, patient outcomes. Nevertheless, approximately 20% of patients do not achieve an adequate response to MTX, while approximately one-third of patients do not respond well to the anti-TNFs.

IL-6 Inhibition

In the biologic arena, beyond TNF inhibitors, a new option is tocilizumab (TCZ), a humanized monoclonal antibody to the IL-6 receptor. As presented by Prof. Josef Smolen, Professor of Medicine, Medical University of Vienna, Austria, an interim analysis of extension trial data out to 2.5 years confirms that efficacy is sustained beyond early study findings. For this particular analysis, three patient groups were evaluated: those on TCZ 8 mg/kg monotherapy; those who had an inadequate response to anti-TNFs (anti-TNF-IR) and those who had an inadequate response to DMARDs (DMARD-IR). A total of 2583 subjects were included in the extension trial, receiving TCZ 8 mg/kg.

At 108 weeks, 16.7% of patients in the TCZ monotherapy group, 10.9% of the anti-TNF-IR group and 16.9% in the DMARD-IR group who had achieved an ACR70 response for 24 consecutive weeks were still in major clinical remission. Some 13.6% of patients in the monotherapy group, 5.8% of patients in the anti-TNF-IR group and 10.6% of the DMARD-IR group also maintained an ACR70 for 48 consecutive weeks. The proportion of patients who achieved a DAS28 =3.2, a DAS28 remission (<2.6) and a EULAR good response in the initial clinical trials out to 24 weeks was maintained out to week 108.

In a separate post-hoc analysis, Prof. Graeme Jones, Professor of Rheumatology and Epidemiology, University of Tasmania, Hobart, Australia, and colleagues evaluated TCZ 8 mg/kg in MTX- and other DMARD-naive patients (two-thirds were truly MTX-naive). At 24 weeks, roughly 70% of all three patient groups—the intent-to-treat (ITT), the MTXnaive and DMARD-naive—had achieved an ACR20, compared to slightly over 50% in the placebo (MTX) groups.

Approximately 45% of TCZ patients in all three groups achieved an ACR50 compared with approximately 33% in the MTX group, while approximately 30% of TCZ patients in all three groups achieved an ACR70 compared with approximately 15% of MTX recipients. A greater proportion of all three TCZ groups achieved both a DAS28 remission and EULAR good response.

Inhibition of radiographic progression is a major driver of all RA therapy, as function is maintained with minimal radiographic progression. In the LITHE (TociLIzumab Safety and THE Prevention of Structural Joint Damage) study, patients received TCZ 4 mg/kg or 8 mg/kg plus MTX or MTX alone. As reported by Dr. Joel Kremer, Albany Medical College, New York, 47%, 30% and 8% of patients in the 8 mg/kg arm, the 4 mg/kg arm and the MTX arm had achieved a DAS28 remission, respectively, at week 52, while 64%, 45% and 19% had achieved a low DAS28, respectively. DAS28 remission rates also increased from week 24 to 52, suggesting that the magnitude of benefit with TCZ increases over time, a novel feature among the biologics.

Again at week 52, the 8 mg/kg dose was associated with a 74% inhibition of radiographic progression and even those on 4 mg/kg had minimal or no evidence of radiographic progression at study end point. In longer-term follow-up of patients who had received TCZ for a mean of 1.5 years, there were no new safety signals that emerged; the withdrawal rate attributable to adverse events was 6.5 per 100 patientyears. Serious infections were the most frequently reported serious adverse event, occurring at an overall rate of 4.3 per 100 patient-years. Continued exposure to TCZ was not associated with an increasing risk for serious infection, malignancy or other serious adverse events.

APR Changes and Clinical Efficacy

It has been suggested that the efficacy of TCZ may have been overestimated in clinical trials because it potently inhibits IL-6, thereby rapidly reducing C-reactive protein (CRP) on initiation of treatment. To answer this question, Dr. Daniel Aletaha, Associate Professor of Medicine, Medical University of Vienna, re-evaluated three pivotal TCZ trials using the SDAI score, which contains a lightly weighted CRP component, and the CDAI score, a purely clinical measure of disease activity.

Changes in both SDAI and CDAI scores from baseline to study end point were all significantly higher in all TCZ groups in all three trials compared with placebo. Approximately 34% of placebo patients received rescue TCZ after 16 weeks. Furthermore, 98% of patients who were in remission according to CDAI criteria were also in remission according to SDAI criteria and of those patients in SDAI remission, 82% were also in CDAI remission. These findings indicate that the efficacy of TCZ is not overestimated on disease activity measurements that contain an APR component, as efficacy was not compromised on either the SDAI or CDAI remission scores, which give little to no weight to changes in APR.

In clinical trials of RA, a higher rate of patients achieve DAS28 remission than ACR70 improvement. In a pooled analysis of TCZ-treated patients, Dr. Edward Keystone, Professor of Medicine, University of Toronto, Ontario, and colleagues sought to determine factors that influence patients achieving a DAS28 remission but not an ACR70 response. According to their analysis of patients receiving TCZ 8 mg/kg, of the 31% that achieved DAS28 remission, 19% obtained an ACR70 response as compared to 3% and 2% of placebo patients, respectively. They observed that most TCZ patients in DAS28 remission experienced at least a 70% improvement in swollen joint count while fewer than half achieved this improvement in tender joint count. To achieve an ACR70 response, 70% improvement is required in both joint counts. Notably, although 54% of TCZ-treated patients did not achieve this magnitude of improvement in both joint counts, those who did achieve a DAS28 remission at week 24 still experienced a substantial clinical benefit with a mean improvement of 64.7 % in ACR scores.

ABSTRACT SAT0116 - Similar Results for Good, Moderate and Poor Responses According to EULAR-DAS28 (EULAR-Disease Activity Score) Response Criteria and Proposed RAPID3 (Routine Assessment of Patient Index Data) Response Criteria in the AIM and ATTAIN Abatacept Clinical Trials

T. Pincus, Y. Yazici, M. Bergman, A. Fischer, P. Hines, R. Maclean, L. C. Rosenblatt

Background: EULAR response criteria in rheumatoid arthritis (RA) clinical trials have been classified as good, moderate and poor, according to change in DAS28 from baseline to endpoint, as well as endpoint DAS28. An index of only 3 patient self-report measures – physical function on a health assessment questionnaire (HAQFN), pain (PAIN) and global estimate (PTGL) – RAPID3 (routine assessment of patient index data), is correlated significantly with DAS28 in clinical trials and clinical care.RAPID3 is calculated in the clinic in 10 seconds, compared to 120 seconds for a DAS28. We analyzed responses according to EULAR-DAS28 improvement criteria compared to proposed RAPID3 improvement criteria in the AIM and ATTAIN abatacept clinical trials.

Objectives: To compare AIM and ATTAIN good, moderate, and poor EULAR-DAS28 responses to proposed RAPID3 good, moderate, and poor responses.

Methods: DAS28 and RAPID3 [HAQ-FN (scored 0-3, converted to 0-10)+pain+patient global on visual analog scales (both 0-10), total=0-30] were computed at baseline and endpoint of AIM and ATTAIN. DAS28 responses were classified as: good=decrease of >1.2 units AND final <3.2; moderate=decrease of >1.2 AND final >3.2, OR decrease of 0.6-1.2 AND final <5.1; poor=decrease of <0.6 OR final >5.1 Proposed RAPID3 responses were classified as: good=decrease of >3.6 units AND final <6; moderate=decrease of >3.6 AND final >6, OR decrease of 1.8-3.6 AND final =12; poor=decrease of <1.8 OR final >12. Numbers and percentages of patients in each trial with good, moderate and poor DAS28 and RAPID3 responses were compared with crosstabulations, kappa and weighted kappa statistics.

Results: In AIM, good responses were seen in 27% and 35% of abatacept patients for DAS28 and RAPID3, respectively, compared to 4% and 16%, respectively, of placebo patients. In ATTAIN, good responses were seen in 17% and 24% of abatacept patients for DAS28 and RAPID3, respectively, compared to 4% and 6% of the placebo patients. Kappa values ranged from 0.29 to 0.48, and weighted kappas from 0.36 to 0.52, indicating fair-to-good agreement between the two indices.

Conclusions: Proposed RAPID3 good, moderate and poor response criteria give similar results to EULARDAS28 response criteria in the AIM and ATTAIN clinical trials. DAS28 should be used in clinical trials because of specificity for RA, while RAPID3 may prove useful in standard clinical care.

Commentary on abstract SAT0116

In RA management, disease activity must be evaluated to determine choice of therapy and assess treatment response. Currently, the DAS28 is the most widely used disease activity index but it is a complex scoring system and physicians must wait for laboratory results—either CRP or erythrocyte sedimentation rate (ESR)—until they can make a complete assessment. The need to carry out a formal 28 TJC and SJC is also time-consuming. RAPID3 includes only three patient self-reported RA measures: physical function, pain and patient global estimate. Instead of the 114 seconds it takes to arrive at the DAS28 score, RAPID3 takes about five seconds and requires no laboratory measure to assess disease activity. In a comparison of EULAR-DAS28 responses and responses based on RAPID3 assessment, Pincus et al. found a high level of agreement in the AIM and ATTAIN cohorts. In AIM, good responses were seen in 27% of patients assessed by DAS28 and 35% on RAPID3; in ATTAIN, good responses on DAS28 were seen in 17% of patients and 24% of patients with RAPID3. This rapid, convenient scoring system could thus prove very useful in the clinical care setting, simplifying disease assessment and helping physicians quickly monitor treatment response.

Questions and answers with Dr. Theodore Pincus, Clinical Professor of Medicine, Division of Rheumatology, New York University School of Medicine, New York

Q: What led you to develop the RAPID3 assessment tool?

A: Simply because in a study we did, we found that it takes 114 seconds on average to do the DAS28 scoring, 106 seconds to assess patients with the CDAI score and at least 94 seconds to do the TJC and SJC formally. Plus you do not necessarily have CRP or ESR results at the time the patient is seen, so we had a problem with that. So we developed cutpoints for RAPID3 responses to classify good, moderate and poor responses to therapy. Our results showed the proposed RAPID3 criteria give similar results to EULAR-DAS28 in the active therapy arms in AIM and ATTAIN as well as in placebo patients.

Q: Do you think the RAPID3 response criteria should replace DAS28?

A: No. DAS28 should still be used in clinical trials because of its specificity for RA. But if physicians, especially primary care physicians, want to use the RAPID3 response criteria, it is a much quicker way to assess disease activity than DAS28; it can be done in a single visit, and I think it could prove very useful in the course of standard patient care.

ABSTRACT OP-0029 - EULAR Recommendations: Cardiovascular Risk Management in Patients with Rheumatoid Arthritis and Other Types of Inflammatory Arthritis: A EULAR Task Force

M. J. L. Peters, D. P. M. Symmons, D. W. McCaery, M. T. Nurmohamed

Objectives: To develop evidence-based EULAR recommendations for cardiovascular risk management (CV-RM) in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA).

Methods: The multidisciplinary steering committee, comprising 18 members including rheumatologists, cardiologists, internists, and epidemiologists, representing 9 European countries, formulated 9 evidence and expert opinion based recommendations for CV-RM.

Results:

1. RA should be considered as a high-risk condition for CV disease. This also applies for AS and PsA, although the evidence is more limited. The increased risk appears to be due to both an increased prevalence of traditional risk factors and the inflammatory burden.

2. Adequate control of disease activity is necessary to lower the CV risk (best evidence for anti-TNF treatment and MTX treatment).

3. CV risk assessment using National Guidelines is recommended for all RA patients on an annual basis and should be considered for all AS and PsA patients on an annual basis. Risk assessments should be repeated when anti-rheumatic treatment has been changed (in absence of National Guidelines the SCORE function model is advised).

4. Risk score models should be adapted for RA patients by introducing a 1.5 multiplication factor that should be used when a RA patient meets 2 of the following 3 criteria: disease duration of more than 10 years; RF or anti-CCP positivity; presence of certain extra-articular manifestations.

5. TC/HDL cholesterol should be used when the SCORE model is used.

6. Intervention with lipid lowering agents and antihypertensive drugs should be carried out according to national guidelines.

7. Statins, ACE-inhibitors and/or AT-II blockers are preferred treatment options due to their potential pleiotropic effects.

8. The role of coxibs and most NSAIDs regarding the CV risk is not well established and needs further investigation. Hence, they should be prescribed cautiously.

9. Corticosteroids: use the lowest dose possible.

Conclusions: Rheumatologists should consider yearly assessment of the CV risk profile for cardiovascular risk management in patients with inflammatory arthritis according to the evidence-based EULAR recommendations.

Commentary on abstract OP-0029

A study investigating the prevalence of CVD and underlying risk factors in RA patients indicated that patients with a disease duration of >12 years have the same CV risk (13%) as patients with type 2 diabetes (12%) based on the Hoorn observational study in the general population (Dekker et al. Circulation 2005;112(5):666-73). Underlying chronic inflammation in part increases patients’ susceptibility to ongoing atherosclerosis; consequently, RA, AS and PsA should be considered new risk factors for CVD. Generally speaking, CV risk management starts with an assessment of a patient’s CV risk profile including blood pressure, lipids and glucose levels. Their 10-year CV risk should be determined using the SCORE system and abnormalities should be treated to recommended targets if that 10-year CV risk is =10%. As task force members indicated, recommendations are for primary prevention only, as RA patients who require prevention of recurrent CVD events should be managed according to existing guidelines for secondary prevention. Nevertheless, the task force felt it was important that all RA, AS and PsA patients be assessed for CV risk on an annual basis and disease activity controlled as fully as possible to reduce this risk.

Questions and answers with Dr. Michael Nurmohamed, Jan van Breemen Institute and VU University Medical Center, Amsterdam, The Netherlands

Q: What was the rationale for multiplying risk score models by 1.5 when assessing CV risk in RA patients?

A: When you look at CV risk in RA, it is approximately double that for a control group in the general population, and approximately 50% of that increased risk is explained by traditional CV risk factors and approximately half for RA itself. If we [multiplied] the risk by 2, however, hypertension qualified too much in our model, which is why we recommend you multiply their risk by only 1.5.

Q: Did you address the use of low-dose ASA in RA patients?

A: Yes, and as is the case for other groups in Europe, we do not recommend ASA for primary risk prevention for patients with RA.

Q: Why did you decide to use the SCORE system rather than Framingham, which is widely used in North America?

A: We used SCORE instead of Framingham because Framingham is based on US citizen data, and SCORE is based on a large European cohort that has been followed now for at least 10 years.

Q: It may be argued that in order to have a successful prevention strategy, using a disease duration of over 10 years in the algorithm may make it too late to change CV risk. Could you tell us why you used disease duration in excess of 10 years?

A: The literature is actually based on patients with established RA so we adapted the SCORE model for patients whose disease had been present for more than 10 years. It suggests that patients with lower levels of disease duration probably would not qualify for risk intervention although we still think everybody should be screened for CV risk.

ABSTRACT FRI0133 - Efficacy of Tocilizumab (TCZ) in Rheumatoid Arthritis (RA): Interim Analysis of Long-term Extension Trials of up to 2.5 Years

J. S. Smolen, R. H. E. Alten, J. Gomez-Reino, W. Rizzo, C. Davies, E. Alecock, R. van Vollenhoven

Background: Randomized controlled trials of 6-12 months’ duration have demonstrated the efficacy and safety of tocilizumab (TCZ) in RA pts.

Objectives: To assess the longer-term efficacy of TCZ in 2 ongoing, open-label, long-term extension studies of up to 2.5 years (clinical cutoff date, March 10, 2008).

Methods: Of 2733 pts (including DMARD-IR and anti-TNF-IR pts) completing four 24-wk controlled studies of TCZ as monotherapy or with DMARDs, 2583 transitioned into 2 ongoing extension studies (GROWTH95; GROWTH96) of TCZ 8 mg/kg every 4 wks. Pts who received =1 dose TCZ in an extension study were included as 3 groups: DMARD-IR, anti-TNF-IR, and monotherapy (predominantly MTX-naive). Data were summarized every 12 wks from initial TCZ exposure to the clinical cutoff date and analyzed for ACR50/70, DAS28 remission (DAS28 <2.6), and low disease activity (LDAS; DAS28 =3.2). Proportions of pts with HAQ-DI=0, =1SJC, and =1TJC were also determined at 96 wks. LOCF was used for TJC and SJC; no imputation was used for missing HAQ-DI, VAS assessments, or CRP.

Results: During the 132-wk observation, proportions of DMARD-IR pts achieving ACR50/70 and maintaining ACR70 responses for 24 consecutive wks increased (Table). A similar pattern of response was seen with dosing continuation in the other groups (anti-TNF-IR, monotherapy; not shown). Similarly, proportions of pts achieving LDAS and DAS28 remission consistently increased or were maintained in all 3 groups. At 96 wks the proportions of pts in the DMARD-IR, anti-TNF-IR, and monotherapy groups with HAQ=0 were 17%, 9%, and 25%, respectively; the proportions with =1 SJC were 46%, 30%, and 49%, respectively; and the proportions with =1
d 33%, respectively.

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Conclusion: Longer-term treatment with TCZ for up to 132 wk yielded RA efficacy outcomes at maintained proportions of pts (albeit with decreasing pt numbers). These results support TCZ as an effective long-term treatment for RA pts.

Commentary on abstract FRI0133

The efficacy of TCZ has previously been tested in several trials lasting 24 weeks. For this analysis, longterm responses were evaluated for three groups: those on TCZ 8 mg/kg monotherapy (AMBITION trial); those who had an inadequate response to anti-TNF agents (anti-TNF-IR) (RADIATE trial) and those who had an inadequate response to DMARDs (DMARD-IR) (TOWARD and OPTION trials). 2583 patients were included in the extension trials and responses were reported for TCZ 8 mg/kg only. Responses were maintained in all three patient groups for up to 2.5 years. At 108 weeks, 16.7% of patients in the TCZ monotherapy group, 10.9% of the anti-TNF-IR group, and 16.9% in the DMARD-IR group who had achieved an ACR70 response for 24 consecutive weeks were still in major clinical remission. At the same time point, 13.6% of patients in the monotherapy group, 5.8% of patients in the anti-TNF-IR group and 10.6% of patients in the DMARD-IR group also maintained an ACR70 for 48 consecutive weeks. The proportion of patients who had achieved a DAS28 remission (<2.6) was also maintained in all three groups, as was the proportion of patients in low disease activity (DAS=3.2) and in good EULAR response. Only 3% of patients withdrew from therapy because of lack of response during the extension phase trials.

Questions and answers with Prof. Josef Smolen, Professor of Medicine, Medical University of Vienna, Austria

Q: What do you think are the most important findings from this long-term analysis?

A: For us, a major finding is that patients who did not receive TCZ during the first part of the study (i.e.placebo controls) responded as well as those who did receive TCZ once placebo controls were switched to active therapy, so responses in placebo controls who later got TCZ were similar to the active therapy group. The other aspect is that responses and response rates were maintained over time, so those who started on TCZ and who had a good response to it at six months appeared to maintain that response.

Q: How do you believe TCZ can contribute in the management of RA?

A: Every biological agent we get can capture an additional fraction of patients who will respond well to treatment and minimize further progression of disease, so that is the most important thing about having TCZ. For example, approximately 11% of patients with an inadequate response to anti-TNFs prior to receiving TCZ still had a 70% improvement in ACR at 108 weeks. So it seems that blocking IL-6, at least in most patients, is not overridden by TNF and vice-versa—blocking TNF is not overridden by blocking IL-6. This means that drugs with a different mechanism of action enhance our ability to control disease activity.

Q: Do you see TCZ being used earlier in the management of RA—for example, prior to DMARD therapy?

A: TCZ will likely first be used in patients who have experienced TNF inhibitors because we need to have more experience with the drug itself before we explore other options. But in Europe, TCZ is already licensed for all indications—as a first-line biologic, as monotherapy, even prior to the use of DMARDs, so it can really be used in any patient.

ABSTRACT FRI0252 - Efficacy of Tocilizumab (TCZ) vs Methotrexate (MTX) Monotherapy in Patients with Rheumatoid Arthritis (RA) with no Prior MTX or DMARD Exposure

G. Jones, J. J. Gomez-Reino, M. B. Lowenstein, J. Tornero, A. Sebba, E. Alecock, E. Guarin, M. Genovese

Background: The AMBITION study showed that TCZ monotherapy was clinically superior to MTX monotherapy with a well-defined and manageable safety profile in patients (pts) with active RA who had not failed previous MTX or biologic treatment.

Objectives: To compare efficacy of TCZ and MTX monotherapies in MTX-naive and DMARD-naive pts.

Methods: This was a post hoc analysis of the AMBITION study, in which 570 ITT pts were randomized to TCZ 8 mg/kg IV every 4 weeks (wks) or an initial dose of MTX 7.5 mg/wk, titrated up to 20 mg/wk within 8 wks, for 24 wks. The study included pts who might have been exposed to MTX (not within the last 6 months before study entry) but had not failed prior MTX, other DMARDs, or biologic therapy. In this analysis, MTXnaive pts were defined as never having been exposed to MTX and DMARD-naive pts as never having been exposed to MTX or any traditional DMARD; pts in these groups were not mutually exclusive. Data for the ITT population, MTX-naive, and DMARD-naive pts of the AMBITION study were analyzed at 24 wks for ACR20, ACR50, and ACR70 responses, DAS28 remission (DAS28 <2.6), and EULAR Good response.

Results: In the ITT population, 67% of pts were MTX naive and 43% DMARD naive. Baseline demographics and RA characteristics (RF+, steroid use, DAS28) of MTX- and DMARD-naive pts were well balanced between treatment groups and consistent with the ITT population; of note, RA duration was shorter in MTX- and DMARD-naive vs ITT. Post hoc analysis showed that pts in the MTX- and DMARD-naive populations achieved efficacy responses comparable to those in corresponding treatment groups of the ITT population at 24 wks (Table), with a suggestion that these earlier, relatively treatment-naive pts had higher response rates. In all populatio
perior to MTX (mean dose 15.5 mg/wk) across all outcomes measured.

<img3363|center>

Conclusions: After 24 wks of treatment, TCZ monotherapy was superior to MTX monotherapy in pts with RA regardless of prior MTX or DMARD exposure.

Commentary on abstract FRI0252

The effects of previous exposure to MTX or other DMARDs on the efficacy of TCZ were hitherto unknown. This AMBITION post-hoc analysis included MTX-naive and DMARD-naive patients, roughly two-thirds of whom were truly MTX-naive. All patients received TCZ 8 mg/kg for 24 weeks. Results showed that ACR responses to TCZ were not affected by prior exposure to MTX or a DMARD. At week 24, approximately 70% of the ITT, MTX-naive and DMARD-naive groups had achieved an ACR20 compared to slightly over 50% in the MTX groups. Approximately 45% of TCZ patients in all three groups achieved an ACR50 compared with approximately 33% in the MTX group, and approximately 30% of TCZ patients in all three groups achieved an ACR70 compared with approximately 15% of MTX recipients. Neither DAS28 remission rates at 24 weeks nor EULAR response rates were affected by prior MTX or DMARD exposure. Significantly greater proportions of patients in all three groups on TCZ achieved DAS28 remission (~33 to 40% vs. ~12 to 14%) and EULAR good response rates (~40 to 49% vs. ~16 to 18%). The safety profile of TCZ was also deemed manageable, regardless of previous MTX or DMARD exposure.

Questions and answers with Prof. Graeme Jones, Professor of Rheumatology and Epidemiology, University of Tasmania, Hobart, Australia

Q: What was the rationale behind introducing TCZ to MTX/DMARD-naive patients?

A: The rationale was, the earlier you treat RA, the better the outcomes. Since TCZ seems to be a very promising treatment, we wanted to see what happens to this group of patients and we saw substantially higher remission rates with TCZ than with MTX. In addition, patients with disease duration of less than two years did very well on TCZ with remission rates of 45%.

Q: What do you believe TCZ alone can offer RA patients?

A: If people had asked me a few years ago what I would do if I had RA, I would have said, I’d go with MTX and an anti-TNF. But TCZ monotherapy is actually equivalent to MTX and an anti-TNF and it’s the only agent that is equivalent. For example, over one-third of the whole group in this study was in DAS28 remission by week 24 vs. only 12% of those on MTX. So TCZ is clearly more effective than MTX and it’s also more effective than anti-TNF agents on their own, where remission rates of about 16% to 20% have been reported.

ABSTRACT OP-0157 - Tocilizumab Inhibits Structural Joint Damage, Improves Physical Function and Increases DAS28 Remission Rates in RA Patients Who Respond Inadequately to Methotrexate: The LITHE Study

J. Kremer, R. Fleischmann, J. Brzezicki, P. Ambs, E. Alecock, R. Burgos-Vargas, A. Halland

Background: Tocilizumab (TCZ) improves signs and symptoms of RA in patients with inadequate response to methotrexate (MTX-IR).

Objectives: To investigate the efficacy of adding TCZ to MTX in MTX-IR patients.

Methods: Phase 3, randomized (1:1:1), double-blind, placebo-controlled 2-year trial with planned week 24 and 52 analyses. Patients received stable doses of MTX with TCZ (4 mg/kg or 8 mg/kg) or placebo (control) every 4 weeks and could receive blinded rescue therapy from week 16. Primary end points included ACR20 response at week 24 and change from baseline in Genant-modified Total Sharp Score (GmTSS) and physical function (AUC of change from baseline in the Health Assessment Questionnaire Disability Index [HAQ-DI]) at week 52. Missing data for primary end points at week 52 were imputed using linear extrapolation or standardization. A key secondary end point was DAS28 remission at each time point.

Results: Primary end points were met in the ITT population (N=1190). At week 52, patients in the TCZ8 group had significantly greater inhibition of radiographic progression (mean GmTSS) vs control (74%), and there were significantly more patients in the TCZ groups without radiographic progression from baseline vs control (P=0.0001; Table). Improvement in physical function was significant for both TCZ groups vs control (P=0.0001; Table). ACR20 at week 24 was achieved by 56% (TCZ8), 51% (TCZ4), and 27% (control, P<0.0001) of patients. Significantly more patients in both TCZ groups vs control achieved ACR20/50/70 at week 52 (P=0.0001; Table). DAS28 remission rates (DAS28 <2.6, week 24/52) were significantly higher in the TZC8 (33%/47%) and TCZ4 (18%/30%) groups vs control (4%/8%; P=0.0002/P<0.0001). In subgroup analyses,
rved regardless of baseline parameters, such as disease duration, disease status, or baseline rheumatoid factor.

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Conclusions: TCZ with MTX inhibited the progression of structural joint damage and improved physical function and clinical disease activity significantly more than MTX alone. DAS28 remission increased from week 24 to 52, indicating increasing magnitude of clinical benefit over time. TCZ8 was numerically superior to TCZ4 in all end points.

Commentary on abstract OP-0157

Local destruction of articular bone and cartilage is a major cause of disability in patients with RA. Up to 70% of RA patients have evidence of radiological joint damage within two years of diagnosis. Inhibition of structural joint damage is therefore an important end point in RA clinical trials. Patients in the LITHE study received TCZ 4 mg/kg or 8 mg/kg plus MTX or MTX alone. At week 52, 47%, 30% and 8% of patients, respectively, had achieved a DAS28 remission, while 64%, 45% and 19% had achieved a low DAS. DAS28 remission rates also increased from week 24 to 52, suggesting an increasing magnitude of benefit over time with TCZ. ACR70 rates at 52 weeks were lower at 20%, 16% and 4% for each of the respective three groups but ACR70 responses are typically lower than DAS28 rates because core components differ in the two scoring indices. At 52 weeks, patients on both doses of TCZ had minimal or no evidence of radiographic progression, with TCZ 8 mg/kg leading to a 74% inhibition of radiographic progression at study end point. No unexpected safety signals emerged across the 52-week trial compared with earlier studies, suggesting the side effect profile of TCZ is predictable.

Questions and answers with Dr. Joel Kremer, Professor of Medicine, Albany Medical College, New York

Q: You saw very minimal radiographic progression after 52 weeks with both doses of TCZ. Would you anticipate continued inhibition of structural joint damage with longer-term follow-up?

A: I think it’s a bit risky to predict outcomes. We’ll just have to wait and see what happens as we follow these patients up.

Q: If patients achieve minimal to no radiographic progression on treatment, does this safeguard them against disability?

A: Yes, that is generally assumed to be the case.

Q: Many patients already have evidence of radiographic damage within two years of RA diagnosis. Would this argue in favour of early introduction of TCZ?

A: Early treatment is always better, no matter what biologic agent is used.

Q: What features of TCZ do you find most appealing?

A: It works quickly and in a robust fashion.

ABSTRACT SAT0111 - Long-term Safety and Tolerability of Tocilizumab in Patients with a Mean Treatment Duration of 1.5 Years

R. van Vollenhoven, A. Rubbert-Roth, A. Cantagrel, D. Ridley, J. Dudler, D. P. Grimaldi, E. Alecock, J. S. Smolen

Background: The efficacy and safety of tocilizumab (TCZ) as monotherapy or with DMARDs, including methotrexate (MTX), has been demonstrated in pts with rheumatoid arthritis (RA) in randomised, controlled, phase 3 clinical trials for up to 12 months and in long-term extension studies.

Objectives: To assess safety and tolerability of TCZ, an updated interim analysis of pooled data from longterm extension studies and an ongoing phase 3 trial was performed.

Methods: The study population is composed of all pts who received at least 1 dose of TCZ in studies OPTION, AMBITION, RADIATE, TOWARD; a phase 1 study; and the open-label extension studies GROWTH95 and GROWTH96 up to the clinical cutoff date of March 10, 2008. In addition, it also includes pts from the ongoing study LITHE up to 52 weeks.

Results: TCZ was administered to 3857 pts for a mean duration of 1.48 years, providing 5590 pt-years (PY) of exposure and 5700PY of observation. The overall rate per 100PY of adverse events (AEs) was 369.8, with the highest rate occurring in the first 6 mos (475.7) and decreasing thereafter. The rate of withdrawals due to AEs was 9.6% or 6.5/100PY and was driven by elevated liver enzymes, infections, and benign and malignant neoplasms. The highest rate of withdrawals was in the first 6 mo (11.2/100PY) and decreased with time. Overall rate per 100PY of serious AEs was 15.1; of myocardial infarction, 0.26; of stroke, 0.18; and of serious infections, 4.37. No increasing rate over time was seen for any of these events with continued TCZ exposure. Overall rates per 100PY of deaths and deaths from infection were 0.53 and 0.18, respectively. Rates per 1000PY of upper and lower GI tract perforations were 0.60 and 1.71. Grades 3/4 neutropenia were reported in 4% of pts, none of whom experienced serious infections. Elevations in ALT to a post-baseline value >1-3×ULN (on at least 1 occasion) and >3-5×ULN were seen in 48.5% and 6.9% of pts, respectively; elevations in AST >1-3×ULN (on at least 1 occasion) and >3-5×ULN occurred in 43.4% and 2.3% of pts, respectively. These elevations were normalized in most pts, and none of the elevations led to clinically apparent hepatitis or drug-induced liver injury.

Conclusions: This long-term safety analysis demonstrates that rates of malignancies and cardiovascular events did not increase with continued TCZ treatment and did not exceed the rates expected in this RA population. Rates of serious infections and other serious AEs were stable over time. Neutrophil decreases and elevated liver enzymes occurred but were not associated with clinical events. The manageable longterm safety profile in RA pts, as demonstrated in this study, supports a favorable risk/benefit ratio for TCZ.

Commentary on abstract SAT0111

An interim analysis of the long-term extension studies involving TCZ as well as one ongoing study included 3857 patients who had received TCZ for a mean of 1.5 years. The withdrawal rate attributable to adverse events (AEs) was 6.5 per 100 patient-years, dropping from 11.2 per 100 patient-years during the first six months of treatment to 3.7 per 100 patient-years from months 13 to 18. Serious infections were the most frequently reported serious AE, occurring at an overall rate of 4.3 per 100 patient-years. Continued exposure to TCZ was not associated with an increasing risk of serious infection and opportunistic infection rates were very low. Clinically significant neutropenia was seen in 4% of patients during at least one visit but was reversible when TCZ was interrupted; nor did neutropenia have any effect on serious infection rate. Infusion reactions resulting in treatment discontinuation occurred in only 15 patients, while rates of upper and lower GI tract perforations were 0.6 and 1.7 per 100 patient-years, respectively. Slightly less than 2% of patients discontinued treatment due to elevations in transaminase enzymes. Based on these data, investigators saw no new safety signals after prolonged exposure to TCZ and they concluded that it has a well-defined and manageable safety profile.

Questions and answers with Prof. Josef Smolen, Professor of Medicine, Medical University of Vienna, Austria

Q: In these extension studies, the incidence of single liver elevations was highest during the first 24 weeks and decreased with continuing treatment. Do you think physicians are taking patients off TCZ too soon for elevations in liver enzymes?

A: It is always worrisome if a patient develops a significant elevation in liver enzymes. On the other hand, we know that elevations in liver enzymes are much more common when patients receive the combination of MTX and TCZ than with monotherapy, where the proportion of problems with liver enzymes is no higher with TCZ monotherapy than with MTX alone. So it’s the combination that seems to be the problem, but since there were no clinical hepatic events in these studies, physicians could consider delaying the next infusion for several weeks if enzymes are elevated to see if they come down, as they often do.

Q: Would inhibition of IL-6 be of some concern when it comes to malignancies or tuberculosis?

A: There is always a theoretical concern about neoplasms when we do anything that interferes with the inflammatory system, but in our trials, there was no evidence of excessive neoplasms. Tuberculosis has the potential to occur as well but again, this does not appear to be an issue with TCZ.

Q: What do you like about TCZ when you use it to treat RA patients?

A: It’s easy to use, it’s well tolerated as an infusion and patients like it.

ABSTRACT OP-0158 - Defining Remission in Patients Receiving Tocilizumab Is Influenced by the Choice of the Composite Index Rather than by Specific Effects on the Acute Phase Response

D. Aletaha, F. Alasti, J. S. Smolen

Background: Remission is an important therapeutic aim in RA but its definitions vary. Tocilizumab (TCZ) is a novel biological agent targeting the interleukin-6-receptor (IL-6R). In addition to its effects on signs, symptoms, physical function, and radiographic progression, TCZ exerts more or less direct and profound effects on the hepatic acute phase response (APR), of which IL-6 is the major activator.

Objective: To assess the relevance of APR improvement in the definition of remission (REM) and other disease activity states in RA patients treated with TCZ by comparing composite indices with and without APR measures.

Methods: We obtained an 80% random sample of patient level data from 3 tocilizumab clinical trials on patients with active disease despite MTX or DMARD therapy (LITHE, OPTION, TOWARD) and pooled the 8mg/kg arms for which we had all data for this study available (n=899). We compared REM rates as defined by the Disease Activity Score (DAS28), which uses ESR as the APR; by the Simplified Disease Activity Index (SDAI), which uses the C-reactive protein (CRP) for APR measurement; or by the Clinical Disease Activity Index (CDAI), the only one of these three indices not comprising a measure of APR. The respective cutpoints for REM are: DAS28<2.6, SDAI =3.3, CDAI =2.8. Among the patients in CDAI-REM, we investigated how many would have not achieved REM by the other two indices and vice versa.

Results: Among all 899 patients studied, REM at 6 months was attained in 270 (30.0%), 71 (7.9%), and 59 (6.6%), respectively, using the DAS28, SDAI or CDAI criteria. Of patients in CDAI-REM, 95.0% and 98.3% were also in DAS28-REM or SDAI-REM, respectively; the remainder were all in the LDA states of the respective other indices. In contrast, of patients in DAS28-REM or SDAI-REM, 20.7% and 81.7%, respectively, were also in CDAI-REM. The large group of patients in DAS28-REM, but not CDAI-REM (79.3%), comprised mainly patients in CDAI-LDA (62.2%), but 16.7% were in CDAI-MDA, and 1 was in CDAI-HDA. We further analysed this group of patients in DAS28-REM and compared the individual disease activity core variables of those who also attained CDAI-REM with those who had CDAI-LDA or CDAI-MDA. All clinical variables were significantly higher (P<0.001 by Analysis of Variance) in the latter; for example, swollen joint counts increased from means of <1 in patients with DAS28-REM/CDAI-REM to ~6 in DAS28-REM/CDAI-MDA and HAQ scores from ~0.4 to ~1. In contrast, even though it was only 6mm/h in patients with DAS28-REM/ CDAI-REM, ESR decreased significantly (P<0.001) in DAS28-REM patients with increasing levels of disease activity by the CDAI.

Conclusions: APR seems to have little impact on the classification of remission if SDAI and CDAI are directly compared. However, at least when using the DAS28 and extending previous observations, ESR has a strong impact on the index, and therefore, even if it is very low, small ESR changes can compensate for considerable clinical activity and disability. As a consequence, if remission rates are evaluated, CDAI and SDAI are not (CDAI) or not importantly (SDAI) biased by therapeutic effects on APR. Using these composite scores, the effects of TCZ are reflected by its influence on all their components, with direct effects on APR not being a significant confounder.

Commentary on abstract OP-0158

Study findings indicate that the efficacy of TCZ is not overestimated on disease activity measurements that contain an APR component, as efficacy was not compromised on either the SDAI or CDAI remission scores, which give little to no weight to changes in APR. Since IL-6 directly activates APRs, including ESR and CRP, IL-6 inhibition may contribute to improvement in disease activity when measured by DAS28, an index that includes ESR. In a re-analysis of three pivotal TCZ trials, Aletaha et al. evaluated if CRP significantly contributed to changes in disease activity. They used SDAI score, which contains CRP as a lightly weighted APR component, and the CDAI score, which is a purely clinical measure of disease activity and does not contain an APR component. Out of some 900 patients included in the re-analysis, changes in both the SDAI and the CDAI scores were significantly higher when compared with placebo in all TCZ groups and in all three trials, rescue TCZ was used in some placebo patients (34%, >16 weeks). Indeed, 98% of patients who achieved remission by CDAI criteria were also in remission based on SDAI criteria; of all patients in SDAI remission, 82% were also in CDAI remission. Overall, 30% achieved DAS28 remission in the trials; 7.9% achieved SDAI remission and 6.6% were in CDAI remission. These findings indicate that CRP has a minimal impact on clinical disease activity measures in TCZ trials. They also suggest that a composite measure that stringently defines remission such as the CDAI should be used in clinical trials and in clinical practice more often.

Questions and answers with Dr. Daniel Aletaha, Associate Professor of Medicine, Medical University of Vienna, Austria

Q: Why did you want to re-analyze the data using the SDAI and the CDAI scores?

A: The question was: are we overestimating remission or response rates when we use outcome measures that include the APR? To address this question, we compared results using the SDAI and the CDAI because they differ in only one parameter, which is the CRP, which is included in the SDAI, and the CDAI, where it is not.

Q: Since SDAI contains a measure of CRP and the CDAI does not, were there meaningful differences in results between the two comparisons?

A: Not really. SDAI changes were numerically higher than CDAI changes in all three trials and in all TCZ groups but changes in both measures were highly statistically significant in favour of TCZ vs. placebo.

Q: What is the take-home message of this re-analysis?

A: I think the message for investigators is, if they don’t want to have this discussion about the APR contribution to disease activity outcomes in TCZ trials, they should use the CDAI. With the CDAI, you have an index that you can calculate on the spot, there is no laboratory variable that you have to wait for like the CRP and it’s a good clinical measure of disease activity.

ABSTRACT THU0165 - Improvement of ACR Core Set Components Among Tocilizumab-treated Patients in DAS28 Remission: A Pooled Analysis of DMARD-IR Clinical Studies

E. C. Keystone, M. H. Schiff, J. Rovensky, M. Taylor, A. K. John, A. Balbir-Gurman

Background: Tocilizumab (TCZ) has been shown to be effective in DMARD-IR pts in 3 randomized, controlled, phase 3 trials (OPTION, TOWARD, LITHE). The proportion of pts achieving ACR70 response and DAS28 remission on TCZ 8 mg/kg was compared with placebo (PBO) control at wk 24 (ACR70: 13%-22% vs 2%-3%; DAS28<2.6: 27%-33% vs 1%-4%), with the DAS28 remission rate of pts receiving TCZ 8 mg/kg being higher than the ACR70 response rate.

Objective: To determine the reasons for not achieving an ACR70 response in pts with DAS28 remission at wk 24.

Methods: The analysis was performed in the intent-to-treat DMARD-IR pts pooled from OPTION (TCZ 8 mg/kg + MTX), TOWARD (TCZ 8 mg/kg + DMARD), and LITHE (TCZ 8 mg/kg + MTX; 6-month data only). The percentage improvements in ACR core criteria from baseline to wk 24 were assessed in pts who achieved DAS28 remission but not ACR70. LOCF was used for tender and swollen joint counts (TJC, SJC) and no imputation for other DAS or ACR components.

Results: A total of 2317 pts were included in this analysis. The DAS28 remission rate was 31% in TCZ 8 mg/kg + DMARD and 3% in control (PBO + DMARD) groups. Fifty percent of pts receiving TCZ 8 mg/kg + DMARD achieved DAS28 remission but not ACR70 at wk 24. Nevertheless, 167 (91.3%) of ACR70 nonresponders achieved =70% improvement in TJC and/or SJC, whereas only 16 (8.7%) achieved <70% improvement in TJC and
common reason for not achieving an ACR70 response in pts with =70% improvement in TJC and SJC was <70% improvement in pt global and pain VAS and HAQ-DI.

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Conclusions: The majority of TCZ-treated pts who achieved DAS28 remission at wk 24 also achieved good improvement in objective measurements of TJC and SJC. The difference between ACR70 response and DAS28 remission rate at wk 24 was primarily due to <70% improvement in the more subjective ACR core set components.

Commentary on abstract THU0165

In clinical trials of RA, more patients tend to achieve a DAS28 remission but improvement in ACR70 in generally within the same range. In a pooled analysis of TCZ-treated patients, Keystone et al. looked for factors that might have influenced patients achieving a DAS28 remission on TCZ but not an ACR70 response. In the analysis, 31% of patients receiving TCZ 8 mg/kg achieved DAS28 remission on TCZ but not an ACR70 response, of these, 19% achieved an ACR70 response; compared to 3% and 2% of placebo patients respectively. Most TCZ patients in DAS28 remission had at least a 70% improvement in swollen joint count, though fewer than half also achieved a 70% improvement in tender joint count. In order to achieve an ACR70 response, 70% improvement is required in both joint counts. Fifty-four per cent of TCZ-treated patients did not achieve this magnitude of improvement in both joint counts. However, patients who did achieve a DAS28 remission but not an ACR70 response at week 24 still achieved a mean improvement of 64.7 in ACR, a substantial clinical benefit from TCZ.

Questions and answers with Dr. Edward Keystone, Senior Consultant in Rheumatology, Mount Sinai Hospital, and Professor of Medicine, University of Toronto, Ontario

Q: What are the key factors that influenced ACR70 responses in this pooled analysis?

A: The main reason why the ACR70 was not met in the analysis, even though the DAS remission was, was because of inclusion of patient outcomes in the ACR70. So patients did not [experience] a 70% improvement in outcome measures such as pain and function, TJC and SJC, which are required for the ACR score. This is why they did not achieve an ACR70 response even though they did achieve a DAS28 remission.

Q: Do you think patient-related outcomes should be used in a measure of disease activity such as the ACR70?

A: The lowest responses of almost any agent you want to name are patient-related outcomes. So the health assessment questionnaire score typically has the least response, pain and global function [score] tends to be a bit higher, and this of course brings down the ACR70s. But this is a reflection of what is important to the patient. Patients care about pain and function and disability today, while physicians care about swollen and tender joints because if there is a significant improvement in joint counts, they know the patient will not progress over time. So physicians care about both symptoms and long-term disability while the patient only cares about symptoms.

Q: Which is the better score to use when measuring disease activity?

A: The ACR is an improvement score—it tells you what per cent improvement a patient has made on treatment—whereas the DAS score tells you not only how much improvement the patient has had but also what their current state of disease activity is. So if a patient has a 60% improvement in disease activity but they still have very active disease, I’m going to treat that patient based on the actual DAS score. So DAS gives you both, the ACR doesn’t.