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ABSTRACTS in PERSPECTIVE - based on presentations from the 12th Annual European Congress of Rheumatology (EULAR)

London, UK / May 25-28, 2011

EDITORIAL OVERVIEW:

Alfred A. Cividino, MD, FRCPC

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

A gents highly targeted at key molecular steps in the inflammatory process have substantially altered the prognosis for individuals with rheumatoid arthritis (RA). The dramatic responses first achieved with tumour necrosis factor-alpha (TNF-a) inhibitors have now been replicated with new or experimental agents inhibiting other pro-inflammatory factors such as the interleukins (IL) IL-6 and IL-1, and intracellular pathways mediated by Janus (JAK) and spleen kinases (Syk). There are also therapies designed to prevent immune activation, such as rituximab, which depletes B cells by targeting the CD20 protein on B cells, or abatacept, which blocks co-stimulation of T cells. The expansion of strategies to suppress inflammation, whether by inhibiting extracellular or intracellular targets, is important because no agent is uniformly effective. Yet all of the approved agents are capable of producing and sustaining a level of remission in moderate-to-severe disease that was previously uncommon. While targeted agents are reserved for patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs), they may alter the trajectory of disease progression by preventing joint damage.

Reduction in Disease Activity with Biologics

Importantly, the expansion of targeted therapies has provided the framework for more ambitious treatment goals in RA. Due to the limitations of DMARDs, particularly in highly active RA, symptom reduction was often the best possible response. The introduction of agents such as the TNF-a inhibitors etanercept, infliximab or adalimumab, and the IL-6 receptor inhibitor tocilizumab, have permitted treatment guidelines to be adjusted, identifying complete remission as a therapeutic goal. In data presented at the 2011 EULAR meeting, one underlying recurrent theme was the value of pursuing remission by switching among targeted therapies when an initial strategy does not provide adequate relief. This includes switching between TNF inhibitors and the IL-6 receptor inhibitor tocilizumab, but it may soon include new options in development.

The benefit, often dramatic, of inhibiting TNF-a in the treatment of RA and other autoimmune diseases, such as inflammatory bowel disorders or psoriasis, provided an important proof of principle that these inflammatory mediators are targetable. Although not all patients achieve complete remission on a TNF inhibitor, the frequency with which patients with long-standing disease became symptom-free on these agents was unprecedented. The introduction of these agents into clinical practice almost a decade ago accelerated efforts to identify other targets in the cascade of the inflammatory response. Inhibition of other important mediators of inflammation such as IL-6 with tocilizumab confirmed that it can also achieve profound reductions in RA activity.

IL-6 Inhibitor Long-term Safety Evaluation and Real-world Use

Indeed, newly released tocilizumab treatment data with a mean duration of 2.43 years on therapy have demonstrated inhibition of radiographic progression without any change in the safety profile (abstract FRI0367). In an extension study, patient responses increased up to week 72 and were sustained for more than 4 years of follow-up whether measured by ACR20 or ACR50/70 (abstract SAT0286). The sustained benefits over long periods on maintenance reinforce the importance of the IL-6 receptor inhibition in RA. With data that establish the long-term efficacy of tocilizumab, much of the attention at EULAR regarding this agent was directed towards long-term safety. While the phase III studies that led to its approval demonstrated the same types of sustained remissions previously achieved with the TNF inhibitors, extended safety data are important for all targeted therapies because of their potential to generate side effects related to altered immune function. In 2 sets of long-term safety monitoring data presented at EULAR, both could be characterized as reassuring (abstracts SAT0306, SAT0270). As shown previously, the IL-6 inhibitor, like the TNF inhibitors, increases the risk of infection, but there does not appear to be any cumulative risk over time. Rather, the relative risk appears to be stable. There has been no signal to date of an increased risk of malignancy and no unexpected events have emerged in follow-up that now extends past 5 years and includes more than 10,000 patient-years.

In addition to safety data collected and pooled from multiple trials, other significant new data with tocilizumab involved clinical testing in a real-world setting (abstract LB0006). Designed to permit the variations on treatment likely to be undertaken in daily practice, one study included patients who were switched to the IL-6 inhibitor directly from a TNF inhibitor (abstract SAT0306). Previous trials had required a washout after TNF exposure. In another study, response was compared in patients receiving the agent alone vs. those receiving it plus methotrexate (MTX) (abstract OP0020). In the initial trials, tocilizumab was studied as an adjunct to MTX and current labelling is for combination therapy. However, both studies demonstrated high rates of efficacy in each of the regimens employed, suggesting broad uses in daily practice.

Broadening Research in RA

Currently, all of the targeted therapies, including TNF inhibitors and the IL-6 receptor inhibitor, are indicated for patients who have inadequate response on a DMARD such as MTX or leflunomide. This limitation in most of the major guidelines is based on concerns about serious adverse events, such as infection, in patients with mild to moderate disease who may have a satisfactory response on a DMARD. It is also driven by concerns about cost. However, RA is a progressive disease in most individuals and there is interest in the potential for early initiation of targeted therapies to prevent joint deterioration, which is generally irreversible. Currently, the benefit:risk ratio from targeted therapies in early disease is unknown, but a study conducted with the TNF inhibitor certolizumab did provide evidence that complete remissions can be achieved in patients with low disease activity (abstract THU0244). In this study, which had a duration of only 24 weeks, protection against disability was not evaluated, but it is likely that there will be increasing discussion about when to start targeted therapies in patients likely to have poor outcomes.

Efforts to determine a rational order of targeted therapies are also expected to expand as the number of options increases. In a study of rituximab (abstract FRI0340) designed to identify specific characteristics that identified responders, one predictor was primary failure to an anti-TNF agent. However, the issues for a rational order of therapies include both efficacy and safety. One persistent concern with all agents early after their introduction is whether they can be used as effectively and safely outside of the tertiary care centres where many of the clinical trials are conducted. In a study of abatacept (abstract FRI0359), which is approved for use only after failure of an anti- TNF agent, a real-world study of safety and efficacy in routine clinical practice was reassuring.

Discontinuation of targeted therapies after a prolonged period of remission is another issue likely to be discussed with increasing frequency. A small but substantial proportion of patients treated with these agents achieve a complete remission with little or no evidence of disease activity as long as they remain on therapy. On the premise that prolonged remissions may be self-sustaining and resistant to relapse, it is appealing to consider discontinuation of therapy over set periods of time or until relapse. This concept was explored by a team of Japanese investigators who discontinued the TNF inhibitor adalimumab in patients who had a complete remission for at least 24 weeks (abstract OP0154). After discontinuation, about half remained in remission one year later and about 25% two years later. This study was small and uncontrolled, but it raises interest in the potential for targeted therapies to turn off the inflammatory response in at least some individuals, who may then be able to remain symptom-free for extended periods without treatment. Larger studies are needed to explore this concept, which has major implications for patient well-being and for the cost of care.

Studies of new small-molecule inhibitors that target intracellular enzymatic pathways are promising. These oral agents are designed to inhibit enzymes that control pathways of inflammation. While one of these, the Syk inhibitor fostamatinib, has now completed a phase II trial (abstract OP0057), phase III data were presented at EULAR on tofacitinib, a JAK-3 inhibitor (abstract SAT0243). So far, the data, which have associated this agent with highly significant efficacy relative to placebo and acceptable safety, are very encouraging and predict that this agent will eventually become one of the options for RA management.

Summary

Targeted therapies have not only permitted a larger proportion of individuals with RA to achieve remission, they are also redefining the goals of treatment. If effective therapies can halt the disease process, not just reduce symptoms, treatment can be directed at altering the natural history of the disease. The degree to which control of RA can be improved with a growing array of targeted therapies is still not fully understood, but there is an increasing number of options even for those individuals who do not achieve an adequate response on TNF inhibitors. The long-term safety data with tocilizumab are bringing this therapy into the front lines of therapy, while newer agents in development suggest that other highly targeted treatments are on the horizon. The heterogeneity of response to current treatments encourages efforts to increase the number of options with the promise that patients insufficiently responsive to one may respond to another.

ABSTRACT OP0020 - Tocilizumab (TCZ) plus Methotrexate (MTX) Does Not Have Superior Clinical Efficacy to TCZ Alone in RA Patients with Inadequate Response to MTX: 24-week Results of the ACT-RAY Study M. Dougados, T. Huizinga, T. Sheeran, P. Tak, P. Conaghan, F. Navarro-Sarabia, A. Hou, C. Bernasconi, K. Kissel

Background: The efficacy and safety of TCZ combined with MTX and TCZ monotherapy have been established in RA. However, data comparing TCZ alone vs MTX in combination with TCZ are currently lacking.

Objectives: To evaluate efficacy and safety of adding TCZ to MTX vs switching from MTX to TCZ monotherapy (placebo [PBO]-controlled) in MTX-IR, biologic naïve, adult patients with moderate to severe active RA (DAS28>4.4).

Methods: In this double-blind 2-year phase 3b study, patients who were on stable doses of oral weekly MTX were randomized to either adding TCZ 8 mg/kg IV every 4 weeks + continued MTX or to switching to TCZ 8 mg/kg IV every 4 weeks + oral PBO. The primary efficacy outcome of this superiority study was DAS28 remission rate (DAS28<2.6) at week 24. Baseline and efficacy results are shown for the ITT population with missing data set to non-responder.

Results: 556 patients were randomized (TCZ+MTX=279; TCZ+PBO=277) and 92% (n=512) completed the initial 24-week period. Baseline demographic characteristics were similar for both groups (female, 80.3%; mean age, 53.3 years; mean RA duration, 8.2 years; mean DAS28, 6.35). Efficacy results are shown in the table. The DAS28 remission rate was 40.4% for TCZ+MTX and 34.8% for TCZ+PBO (P=0.19, difference not significant). There was no difference for ACR scores and core set components. Onset of action was rapid with 18.1% and 15.2% of patients achieving DAS28 remission at week 8 in the TCZ+MTX and TCZ+PBO groups, respectively. Rates of AEs, SAEs, and serious infections per 100 patient-years were 491, 21, and 6 for TCZ+MTX and 467, 18, and 6 for TCZ+PBO, respectively, with the most frequent AEs and SAEs being infections. AE-related discontinuations and dose modifications occurred in 3.9% and 27.4% of TCZ +MTX and 2.9% and 18.5% of TCZ+PBO patients. ALT elevations >60 U/L were observed in 16% and 6% of TCZ+MTX and TCZ+PBO patients, respectively.

Table.

Conclusion: MTX+TCZ did not lead to additional clinical benefit vs TCZ alone. DAS28 remission rates and other clinical efficacy parameters at week 24 were comparable for both groups. No overt differences in the safety profile were observed.

Commentary on abstract OP0020

In the initial clinical testing program, several registration trials tested the addition of tocilizumab to MTX in patients not achieving an adequate response on MTX alone. Although subsequent studies demonstrated that it is also effective as a monotherapy, there have been no studies directly comparing it alone to tocilizumab plus MTX. In this double-blind phase IIIb study, patients with an inadequate response to MTX were randomized to 8 mg/kg tocilizumab alone or the same dose plus MTX. The very modest numerical gain in the DAS28 remission rate with the combination (40.4% vs. 34.8%; P=0.19) did not reach statistical significance. Similarly, although adverse events by several measures, including discontinuations (3.9% vs. 2.9%), were modestly higher on the combination, the differences were not significant. The results of the study suggest that there is no major benefit to maintain MTX in combination with tocilizumab.

Questions and answers with Dr. Maxime Dougados, Professor of Rheumatology, Université Paris Descartes, France

Q: Was there an expectation that tocilizumab would do just as well without MTX?

A: There are now a lot of data demonstrating that tocilizumab is very active as a monotherapy in RA. We did not know whether it was more effective or not in combination with MTX, which is why the trial was conducted. The study indicates that the addition of MTX does not add much to what can be achieved with tocilizumab alone.

Q: Were you surprised that the combination was so well tolerated? There was no significant increase in adverse events when the agents were used together.

A: There have been several large studies indicating that the safety of this combination is acceptable. Both of these drugs pose a risk of side effects, but our data are consistent with past studies suggesting that the side effects overlap very little so that there is no substantial increase in risk when the drugs are used together.

Q: Is it a disappointment that the combination was not more effective than tocilizumab monotherapy?

A: The question posed in this study was whether it is better to add tocilizumab to the treatment of patients with RA who are failing MTX or to switch to tocilizumab. This is an important clinical question for which we had no clear evidence until now. There is no issue of disappointment. The results of the study suggest that there is no major benefit from maintaining MTX, so this provides us with a clear answer to the question. The efficacy of tocilizumab monotherapy was quite good with moderate-to-good responses in almost 90% of patients.

ABSTRACT SAT0306 - Tocilizumab Treatment in Patients with Rheumatoid Arthritis and Inadequate Response to DMARDs and/or TNF Inhibitors: ACT-SURE Final Results V. Bykerk, J. Álvaro-Gracia, J. Román Ivorra, M. T. Nurmohamed, K. Pavelka, C. Bernasconi, A. Stancati, J. Sibilia, A. Östör and ACT-SURE Study Group

Background: TCZ safety and efficacy have been demonstrated in 7 phase 3 controlled studies in RA patients (pts) with DMARD-IR or TNFi-IR but not in TNFi-IR pts who switched to TCZ without TNFi washout.

Objectives: ACT-SURE evaluated TCZ safety and efficacy in RA pts treated in academic/nonacademic centers and in private practice setting. Methods: ACT-SURE was a phase 3b, open-label, single-arm, 6-mo study of DMARD-IR/TNFi-IR RA pts treated with TCZ 8 mg/kg Q4W alone or with DMARDs. Safety end points included adverse events (AEs) and serious AEs (SAEs). Efficacy end points included ACR and DAS28 responses. Analyses were stratified by prestudy TNFi use: TNFi-naive (DMARD-IR) pts, previous TNFi users (>2 mo since TNFi use), or recent TNFi users (=2 mo since TNFi use). Subanalysis of TCZ monotherapy was also performed. Results: Of 1681 evaluable pts, 58% were DMARD-IR, 18% were previous TNFi users, and 24% were recent TNFi users. Mean age of pts was 54 y; 81% were women. Mean RA duration was 8.2 y in DMARD-IR pts and 11.2/11.7 y in previous/recent TNFi users. Baseline DAS28 was similar among groups (5.9-6.2). Overall, 12.8% pts withdrew, 4.8% for safety-related reasons; most common cause was infections (1.1% or 1.8/100 pt-y [PY]). Rates/100PY of AEs/SAEs/serious infections (SIs) were slightly lower in TNFi-naive pts than in pts with previous TNFi exposure (Table). ALT shifts from normal at baseline to >3×ULN occurred in =3% of pts (Table). Efficacy onset was rapid and increased over time: among the groups, DAS28 <2.6 was achieved by 24%>38% of pts at wk 8 and 49%>62% of pts at wk 24. Clinical response tended to be higher in DMARD-IR pts, with little difference between recent/previous TNFi users (Table). At wk 24, mean DAS28 was 2.34, 2.83, and 2.76 in DMARD-IR pts, previous TNFi users, and recent TNFi users. In the TCZ monotherapy subgroup, 66.9%, 43.5%, and 23.8% achieved ACR20/50/70 response at wk 2
8 <2.6.

Table.

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Conclusions: ACT-SURE was performed in a setting closer to clinical practice than is typical of phase 3 studies and confirmed TCZ safety profile as shown in previous phase 3 trials. TCZ is effective when used in DMARD-IR pts as the first-line biologic and in TNFi-IR pts. TCZ was effective as monotherapy or with DMARDs. Efficacy was rapid in onset, and response increased over time. TCZ safety was similar for pts who were previous or recent TNFi users, which supports treatment with TCZ immediately after stopping TNFi use.

Commentary on abstract SAT0306

Since the introduction of targeted therapies, the risks of suppressing important mediators of the immune response have been a major concern. With the TNF inhibitors, it is now clear that the risk of serious infections is relatively low, providing a benefit:risk ratio that is very acceptable in patients with significant RA symptoms. In a more real-world setting, the phase IIIb study has confirmed results of phase III studies. In this multinational study of 1681 evaluable patients, efficacy was confirmed but there was a great deal of interest in the safety end points, particularly safety measures in patients receiving tocilizumab after a previous inadequate response to a TNF inhibitor. It is notable that only 4.8% of patients withdrew from ACT-SURE for safety reasons. The most common cause was infection, but this accounted for only 1.1% of the population. The authors did note that adverse events, including infections, occurred less frequently in patients without previous TNF inhibitor exposure, but the differences were small. Overall, the efficacy results were higher than in the phase III studies and at 24 weeks 49.8% of patients in TCZ monotherapy subset achieved a DAS28 <2.6.

Questions and answers with Dr. Vivian P. Bykerk, Division of Rheumatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Q: What was different about this study relative to previous phase III trials with tocilizumab?

A: The safety and efficacy of tocilizumab has now been demonstrated in 7 phase III trials. Although some included patients with inadequate response to a TNF inhibitor, none of the previous studies allowed patients to be switched to tocilizumab from a TNF inhibitor without a washout. ACT-SURE was an open-label study, and there were very few restrictions for entry. This provided a setting closer to clinical practice than is typical of phase III studies. We included patients treated in private practice settings as well as patients treated at academic centres.

Q: You allowed patients to be switched to tocilizumab without a washout, but you stratified previous TNF inhibitor users by those who were switched immediately and those who had been off this therapy for more than 2 months. Why?

A: We wanted to evaluate any difference in safety or efficacy when patients were switched immediately from a TNF inhibitor to an IL-6 receptor inhibitor relative to those with prior biologic exposure but who were not moving immediately from one targeted agent to another. By stratifying patients with recent use and more remote previous exposure, this allowed us comparative data for both efficacy and safety. We did not see any significant difference between these groups.

Q: So there is no need for a washout when switching from TNF inhibitor to tocilizumab?

A: This study supports treatment with tocilizumab immediately after stopping TNF inhibitors. Whether it was used in TNF inhibitor-experienced patients or in those who were TNF inhibitor-naive, the onset of efficacy was rapid and we saw an increasing rate of response over time. The results are consistent with other phase III studies, indicating that this is an effective and well tolerated therapy in RA.

ABSTRACT SAT0286 - Long-term Efficacy of Tocilizumab (TCZ) in RA Patients (PTS) Who Have Inadequate Response to Anti-TNF Therapy (TNF-IR) P. Emery, H.-P. Tony, J. Kremer, A. Sanchez, L. Thompson, D. Musselman, E. Keystone

Background: Efficacy and safety of TCZ in RA pts who were inadequate responders to TNF antagonists (TNF-IR) has been demonstrated in RADIATE, a 24-wk, phase 3, randomized controlled trial.¹

Objectives: To analyze maintenance of response to TCZ in TNF-IR pts in an ongoing long-term extension study (GROWTH96).

Methods: This long-term analysis included pts who were TNF-IR and received =1 dose of TCZ+MTX in RADIATE or GROWTH96, with baseline as the first TCZ dose. Outcomes were assessed every 12 wks from first TCZ dose to February 17, 2010 (data cutoff). Pts with insufficient data at a visit were excluded from analysis for that visit. Numbers of pts with assessments decreased over time because some pts had not yet reached later assessments or withdrew. Results include pts who had assessments at each visit; no imputation was performed for missing data.

Results: The analysis included 464 TNF-IR pts. The overall withdrawal rate was stable over time, and the proportion of pts who withdrew for insufficient therapeutic response was low (<4% in year 2 of treatment). Absolute numbers of pts achieving ACR20 and ACR50/70 increased to wk 48 and to wk 72; rates were maintained thereafter (Table). At wk 120, proportions achieving =1 SJC/TJC were 37%/25%, and the proportion with HAQ-DI =0.5 was 23.6%. At wk 156, 17% (47/276) of assessed pts ha
ical response (ACR70 maintained for 24 consecutive wks).

Table.

<img5041|center>

Conclusions: In this analysis of pts with RA who were TNF-IR, efficacy during long-term treatment with TCZ was maintained for up to 4.2 years. Numbers of pts responding increased until approximately wk 72, and response rates were maintained thereafter.

Reference: 1. Emery et al. Ann Rheum Dis 2008;67:1516-23.

Commentary on abstract SAT0286

The major advantage of an increasing number of targeted therapies is that patients who fail or are intolerant to one option have other choices. In this study, the goal was to determine whether patients who had an inadequate response to a TNF inhibitor and were switched to the IL-6 receptor antagonist tocilizumab could be maintained indefinitely on the second agent. The results were highly encouraging. The proportion of patients who withdrew for insufficient therapeutic response was <4% in the second year of treatment and rates of response, whether measured by ACR20 or ACR50/70, were sustained for more than 4 years of follow-up. The study demonstrates that poor response to one type of targeted therapy does not predict poor response to another. It also suggests that patients who respond poorly to TNF inhibitors do not necessarily have an inherently resistant disease phenotype but can achieve sustained benefit from another type of targeted therapy. It is notable that the improvement in the quality of response continued up to week 72 of this follow-up. This is intriguing because there is a great deal of interest in the question of whether a sustained inhibition of molecular events can produce a higher barrier to relapse.

Questions and answers with Prof. Paul Emery, Head, Academic Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, UK

Q: TNF inhibitors and IL-6 receptor antagonists work on different mediators of inflammation, so I presume that it was reasonable to predict efficacy from tocilizumab even in patients with an inadequate response to a TNF inhibitor?

A: We already have double-blind trial evidence that tocilizumab is active in patients with an inadequate response to TNF inhibitors, so the question was not whether patients on one of the anti-TNF drugs can be treated effectively with tocilizumab but whether the benefits are sustained over time. The TNF inhibitors are capable of providing very long-term remissions with maintenance therapy, and this study demonstrates that IL-6 receptor inhibition will also provide sustained benefits over long periods on maintenance. It reinforces the importance of the IL-6 receptor as a target for RA.

Q: But these patients are defined as having refractory disease by the fact that they had an inadequate response to TNF inhibition, so isn’t this a more difficult population?

A: These patients were characterized as highly refractory. They had been placed on a TNF inhibitor because of an inadequate response to DMARDs and then were not sufficiently controlled on the TNF inhibitor, but we may find that refractory RA is specific to the therapy. One of the exciting developments in RA is the identification of new drugs with different mechanisms. This study demonstrates that patients refractory to one type of targeted therapy are not necessarily refractory to another.

Q: What is the take-home message from this study?

A: Tocilizumab is an appropriate long-term therapeutic option for patients with RA, including those with an inadequate response to TNF inhibitors.

ABSTRACT FRI0367 - LITHE: Tocilizumab (TCZ) Inhibits Radiographic Progression, Maintains Clinical Efficacy in Rheumatoid Arthritis (RA) Patients (Pts) at 3 Years J. Kremer, D. Furst, R. Burgos-Vargas, J. Dudler, C. M. Mela, L. Thompson, R. Fleischmann

Objectives: To investigate ongoing safety and efficacy from data at 3 yrs from LITHE,a double-blind, phase 3, randomized controlled trial of TCZ in pts with moderate to severe RA who were MTX inadequate responders.

Methods: 1190 pts were randomized to TCZ (4 [TCZ4] or 8 [TCZ8] mg/kg) or placebo (control) every 4 wks plus MTX (10-25 mg/wk). After wk 52, pts switched to open-label TCZ8, an option chosen by most pts (62%>68% across all groups). Radiographs were analyzed by Genant-modified Total Sharp Score (GmTSS) for any pt with baseline, wk 52, wk 104, and at least 1 post-wk 104 assessments. If a patient had a post-wk 104 but not a wk 152 value, linear extrapolation was used to impute up to wk 152. Signs/symptoms and safety data were pooled (all TCZ) in all pts who received =1 TCZ dose; data are presented from first dose of TCZ to August 28, 2009 (mean duration, 2.43 yrs). LOCF was used for missing tender and swollen joint counts; no imputation was used for missing HAQ, CRP, ESR, and VAS assessments. Results: The radiographic population consisted of 704 pts (~80% of pts with a post-wk 104 assessment: 244 TCZ8, 241 TCZ4, 219 control). Most pts had received open-label TCZ8 for at least 2 of 3 yrs; 9% of control and 19% of TCZ4 pts had remained on original blinded treatment at 1 yr. Mean change in GmTSS from baseline to yr 3 was 60% lower in pts randomized to TCZ than pts randomized to control (Table). Most radiographic progression in pts randomized to control occurred in the first yr (before switch to TCZ). By yr 3, no progression was seen in 67% and 69% of pts originally assigned TCZ4 and TCZ8 versus 51% in the original control arm (P< 0.001). In the All-TCZ group (n = 1149; exposure = 2790 pt-yrs [PY]), proportions achieving ACR responses and DAS28<2.6 were high (Table). Rate/100 PY of serious adverse events, serious infections, deaths, and deaths from infections were 11.0, 3.2,
/100 PY were 0.7 for all malignancies, 0.6 for solid cancers, and 0.0 for nonmelanoma skin cancer 0.0 (1 case).

<img5042|center>

Conclusions: During long-term treatment, TCZ + MTX continued to inhibit radiographic progression. Improvements in clinical benefits were maintained at high levels. The safety profile did not change compared with 2-yr findings.¹

References: Kremer et al. Ann Rheum Dis 2010;69(suppl 3):387.

Commentary on abstract FRI0367

One of the most important promises of targeted therapies is protection against radiologic progression of RA. Relative to DMARDs, the profound inhibition of key molecular steps to inflammation provides the rationale for predicting complete remission of disease activity, not just symptomatic control. In these analyses from an extension of the LITHE double-blind, phase III study, radiographic changes were assessed in a subgroup of 704 patients who had been followed for at least 104 weeks on the IL-6 receptor inhibitor tocilizumab. Of these, 485 had received the IL-6 receptor inhibitor and 219 were controls. When radiographs were assessed by the Genant-modified Total Sharp Score (GmTSS), there was no progression observed in 51% of those initially randomized to control and 69% of those initially randomized to 8 mg/kg tocilizumab (P<0.001), even though both groups were permitted to receive other therapies after the double-blind trial. Approximately 60% of controls switched to tocilizumab at this time. According to the authors, most of the radiographic progression in the control group occurred in the first year of treatment before the switch. The results corroborate other evidence that long-term treatment with targeted therapies such as the IL-6 receptor inhibitor tocilizumab can protect patients from radiographic progression, reducing risk of disability and improving long-term outcome.

Questions and answers with Dr. Joel Kremer, Center for Rheumatology, Albany, New York

Q: Radiographic progression is a potentially important end point but has not been used frequently in past studies. Why?

A: Preventing radiographic progression is now a reasonable expectation in patients who achieve clinical remission on the targeted therapies. As radiographic progression is an important predictor of long-term outcome, I think an increasing number of studies will include this as a measure of treatment efficacy.

Q: Would the data have been easier to interpret if you had not crossed over the control patients to the tocilizumab arm?

A: The more important question may be whether outcomes are just as good if you delay the start of therapy like tocilizumab in patients with moderate-to-severe RA who are inadequate responders to MTX, and this, in essence, is what we evaluated in this study. Even if patients were switched to tocilizumab at 1 year, fewer of those who started on tocilizumab had radiographic progression at the end of 2 or 3 years. This is important information when we are trying to change long-term outcomes.

Q: Was there a cost in safety from being on tocilizumab for a longer period?

A: On the basis of serious adverse events per 100 patient-years of follow-up, the rates were higher in those who started on tocilizumab than in those who started on controls, but the safety profile of this agent was consistent with past studies, and the most common serious adverse event was infections. There was no change in the safety profile over time, and this agent is generally well tolerated. In the context of avoiding irreversible radiographic changes, the safety profile of tocilizumab, like other targeted therapies, is generally considered acceptable in patients with persistent, symptomatic RA.

ABSTRACT SAT0270 - Long-term Safety of Tocilizumab in Rheumatoid Arthritis Clinical Trials M. Genovese, A. Sebba, A. Rubbert-Roth, J. Scali, M. Zilberstein, L. Thompson, R. F. Van Vollenhoven

Background: Targeting interleukin-6 receptor (IL-6R) signal transduction by tocilizumab (TCZ) has been shown to be an effective treatment for patients with RA.

Objectives: To assess the long-term safety of TCZ in patients with RA.

Methods: For assessment, data from patients who received =1 TCZ dose from initial exposure through February 17, 2010 were included. Data from clinical trials (OPTION, TOWARD, RADIATE, AMBITION, and LITHE) and long-term extension studies (GROWTH95 and GROWTH96) were pooled.

Results: A total of 4009 patients received TCZ with a median (mean) duration of 3.6 (3.1) years and a total observation time of 12,293 patient-years (PY). Rates of SAEs, serious infections, myocardial infarction (MI), and stroke have remained stable over time (Table) and are consistent with those reported in the RA population.1-5 The overall AE rate was 314.6/100 PY (95% CI: 311.5, 317.7); infections were the most frequent AE (103.7/100 PY, 95% CI: 101.9, 105.5). The rate of AEs leading to withdrawal was 5.2/100 PY; the most common AEs leading to withdrawal were laboratory abnormalities (1.1/100 PY, primarily transaminase elevations), infections/ infestations (1.0/100 PY), and neoplasms (benign, malignant, or unspecified, 0.7/100 PY). The overall SAE rate was 14.7/100 PY (95% CI: 14.0, 15.4); infections were the most frequent SAE (4.6/100 PY; 95% CI: 4.3, 5.0). The rate of GI perforations was 0.24/100 PY (95% CI: 0.17, 0.37) and has remained consistent with that previously reported. Most of these events (59%, 17/29) were colonic diverticular perforations. Rates of MI and stroke were, respectively, 0.3/100 PY (95% CI: 0.2, 0.4) and 0.2 (95% CI: 0.1, 0.3), were stable over time (Table), and did not exc
the RA population (MI, 0.4-0.8/100 PY; stroke, 0.5-0.9/100 PY).3-5 Eight patients experienced anaphylactic reactions and withdrew from the study.

Table 1.

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Conclusions: Rates of SAEs, serious infections, and cardiovascular events have remained stable with continued exposure to TCZ in long-term clinical trials. These results suggest that the longer-term safety profile of TCZ seen in open-label extension trials is not changing with longer exposure.

References: 1. Donahue et al. Ann Intern Med 2008;148:124-34. 2. Doran et al. Arthritis Rheum 2002;46:2287-93. 3. Gabriel SE. Am J Med 2008;121(suppl 1):S9-S14. 4. Wolfe et al. J Rheumatol 2003;30:36-40. 5. Solomon et al. Ann Rheum Dis 2006;65:1608-12.

Commentary on abstract SAT0270

The TNF inhibitors have been used in RA for almost 10 years, providing a large body of experience, particularly with the oldest agents in this class such as etanercept, infliximab and certolizumab. The pooled data from the tocilizumab trials program presented in this study are based on experience with more than 4000 patients and more than 12,000 patient-years of exposure. The median duration of exposure in this pooled data is 3.6 years and there is now experience on treatment for more than 5 years. These data are reassuring in that they do not reveal any new adverse events and suggest that the safety profile from long-term use is not different from that of the initial studies. Of serious adverse events, the most common was infection, occurring at a rate of 4.6/100 patient-years of follow-up. The rate of gastrointestinal perforations was 0.24/100 patient-years of follow-up, which is also consistent with earlier reports. Cardiovascular events, such as myocardial infarction and stroke, have occurred at expected rates in an age-matched population with RA. Overall, rates of serious adverse events and serious infections have remained stable over time and are consistent with those reported in patients with RA who were treated with biologic agents.

Questions and answers with Dr. Mark C. Genovese, Co-Chief, Division of Immunology and Rheumatology, Stanford University Medical Center, California

Q: Is tocilizumab as safe as the TNF inhibitors?

A: It may be too early to lump the TNF inhibitors together. The relative safety of these agents is still unclear as there have been no large multicentre studies comparing these agents for safety or efficacy. According to our data, tocilizumab is a well-tolerated drug, and we now have a clear picture of the types of risks and their frequency. We now have a reasonably large data pool from which to identify relatively uncommon side effects, and we are not seeing a change in the safety profile from that observed in the initial clinical trials.

Q: One of the biggest concerns with agents that modify the immune response is an increased risk of infection or cancer. What did these data reveal specifically?

A: While the overall rate of infection was <5/100 years of patient follow-up, the most important finding may be that there was no increase in the rate of infections with increased exposure. The most common serious infections were pneumonia and skin and soft tissue infections, but these were rare, both occurring at a rate of 0.9/100 years of patient follow-up. The rate of opportunistic infections, at 0.3/100 patient-years of follow-up, was even lower. Only one patient had more than one occurrence of the same infection. The rates of malignancy overall were similar to what would be expected in the background rate.

Q: Are the safety data sufficient to consider tocilizumab as a first-line agent?

A: The indication for tocilizumab in the US and Europe is for moderate-to-severe RA in patients for whom other drugs, such as DMARDs and TNF inhibitors, have been ineffective. This is where it has been studied primarily and for which we have the most information. The safety data continue to be reassuring in regard to its clinical application.

ABSTRACT LB0006 - Safety of Tocilizumab (TCZ) Monotherapy and TCZ plus DMARDs in a US RA Population with Inadequate Response (IR) to Biologics or DMARDs: The ACT-STAR Study M. Weinblatt, J. Kremer, J. Cush, W. Rigby, L. Teng, N. Singh, R. Malamet, M. Genovese

Background: The long-term safety profile for TCZ has been reported from extension studies of the pivotal phase 3 program. This study evaluated laboratory abnormalities and adverse outcomes as a result of a protocol-driven, risk-mitigation strategy for TCZ in a real-world setting to delineate its value and application in clinical practice.

Objectives: To evaluate safety, tolerability, and efficacy of TCZ monotherapy (MONO) and TCZ+DMARDs in adults with moderate-severe, active RA who were IR or had safety/tolerability related issues with stable dose(s) of their current DMARDs/biologics regimen.

Methods: In this 24-wk, prospective, open-label, 3-arm US study, pts on DMARDs only or combination with biologics prior to baseline (BL) were randomized to TCZ (4 mg/kg [TCZ 4] or 8 mg/kg [TCZ 8])+ =1 DMARD (COMBO); pts on biologic only prior to BL were assigned to TCZ 8 MONO. All biologics were discontinued before BL. At wk 8, pts randomized to TCZ 4+DMARD who did not achieve =20% improvement in tender and swollen joint counts had their TCZ dose increased to 8 mg/kg; thereafter pts on TCZ 4+DMARD could have dose increased at investigator’s discretion. For pts on TCZ 8+DMARD, the dose could be decreased any time for safety reasons. The primary outcome was number/% of pts with serious adverse events (SAEs).

Results: 886 pts were randomized, 883 received treatment (TCZ 4+DMARD=364; TCZ 8+DMARD=381; TCZ 8=138) and 731 (82.5%) completed the study. Over half of TCZ 4 pts were eventually switched to TCZ 8 (n=211; at wk 8=142). At BL, mean RA disease duration=11.4 yrs, 30.6% pts =2 previous anti-TNFs. Rates of SAEs/100 Pt-Yrs (95% CI) were comparable [29.1 (21.0, 39.2), 30.3 (22.2, 40.2), and 20.6 (10.3, 36.9)] for TCZ 4/8+DMARD (including switchers), TCZ 8+DMARD and TCZ 8 groups. The most common SAE was serious infections (SIEs, 3.6% [n=32]); tuberculosis was not reported. GI perforatio
CZ 4+DMARD (n=3). AEs/SAEs/lab values are summarized in the Table. Efficacy outcomes (DAS28 remission; DAS28 mean change from BL; ACR20/50/70 response) were similar for all groups in the ITT population.

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Conclusions: In this first report of TCZ safety and efficacy in a US real-world practice setting with DMARD-IR and biologic-IR pts, similar rates of SAEs, SIEs, and uncommon lab abnormalities were observed in both groups of COMBO pts and MONO pts.

Commentary on abstract LB0006

Autoimmune diseases such as RA are driven by upregulation of inflammatory pathways. The profound benefits provided by biologics are derived from their ability to modify this inflammatory response. However, the modification of the immune system does carry potential risks, including reduced defenses against infection. One concern is that risks may be different in a real-world setting than they are in the clinical trial setting, where follow-up may be more rigorous and investigators may have greater relative experience with the experimental agents. As a result, it is now common to test safety and efficacy of new agents within a setting more similar to clinical practice. In ACT-STAR, the safety of the IL-6 receptor inhibitor tocilizumab was tracked in a study that included non-academic treatment centres, no limitations of co-therapies and very few exclusions. When compared to the published trials, the rate of adverse events and serious adverse events were comparable to the clinical trials that led to regulatory approval. There were no unusual safety signals, whether tocilizumab was used alone or in combination with DMARDs. The results support the role of this agent in routine patient care.

Questions and answers with Dr. Michael E. Weinblatt, Division of Rheumatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Q: Who was enrolled into the ACT-STAR study?

A: Basically any adult was permitted entry into the study if they had moderate-to-severe RA and were either not achieving an adequate response on their current therapy, whether it was a DMARD or another biologic, or had safety or tolerability issues with their current therapy. In other words, exactly the types of patients that would be considered for a change of therapy in typical practice, although we did exclude patients with liver enzyme elevations, a low hemoglobin, thrombocytopenia or very high triglyceride levels [>13 mmol/L].

Q: Had many taken a biologic previously?

A: About one-third had been on a biologic; essentially all of them, of course, had taken a DMARD. The average duration of disease in the patients enrolled was more than 10 years.

Q: About 20% of the patients discontinued treatment over the 24 weeks. Was this what you had anticipated?

A: Yes, this was a good result and it was consistent with what we have seen in the phase III studies. The discontinuation rate for adverse events was only about 6% to 8%, and the discontinuation for inadequate response was <5%. Most of the other discontinuations were patients who did not return after an initial dose or withdrew consent. There was no signal that this agent does not perform any less well in the real world than it did in the clinical trials.

ABSTRACT THU0244 - Efficacy and Safety of Certolizumab Pegol After Incomplete Response to DMARDs in RA Patients with Low Moderate Disease Activity: Results from CERTAIN, a Phase IIIB Study J. S. Smolen, P. Emery, G. F. Ferraccioli, W. Samborski, F. Berenbaum, O. Davies, J. Ambrugeat, B. Bennett, H. Burkhardt

Background: There is a need to understand whether treatment with anti-TNFs can provide therapeutic benefits to RA patients (pts) with low to moderate disease activity (DA).

Objectives: To evaluate certolizumab pegol (CZP) in combination with non-biologic DMARDs in pts with low to moderate DA.

Methods: CERTAIN (CERTolizumab pegol in the treatment of RA: remission INduction and maintenance in pts with low DA) was designed to enrol pts with low to moderate DA (CDAI >6 and =16) (NCT00674362). Pts were randomised (1:1) to CZP (400mg at Wks 0, 2 and 4, then 200mg every other wk) or placebo (PBO) + existing DMARDs. Primary efficacy analysis was % of pts in CDAI remission at both Wks 20 and 24. Other analyses included DAS28 and SDAI remission at both Wks 20 and 24, ACR20/50/70 responses and change from baseline (BL) in HAQ-DI at Wk 24, and safety. CDAI/SDAI/DAS28 remission and ACR responses were assessed using NRI, and HAQ-DI using LOCF. Pts with CDAI remission (=2.8) at Wks 20 and 24 stopped CZP and were monitored to Wk 52. Here, we report Wk-24 data.

Results: A total of 194 pts were randomised (CZP: n=96, PBO: n=98; mean age 54 y, mean TJC 3.8, mean SJC 3.3, mean CRP 7.9mg/L). Mean RA duration was 4.5 y in CZP pts and 4.7 y in PBO pts. Mean BL scores were similar between CZP and PBO for CDAI (13.5 vs 13.3), HAQ-DI (1.1 vs 1.0) and DAS28 (4.50 vs 4.47). At BL, >90% of pts had moderate DA (CDAI, moderate DA range: >10–22). More than twice as many CZP pts had CDAI remission at both Wks 20 and 24 than PBO pts (18.8% vs 7.1%, P<0.05). More CZP pts had DAS28 (19.8% vs 3.1%, P<0.01) or SDAI remission (14.6% vs 4.1%, P<0.05) at both Wks 20 and 24. Mean CDAI improved in CZP pts to 9.4 and deteriorated to 16.5 in PBO pts at Wk 24 (mean change from BL: –4.20 vs 2.71, P<0.001; Fig. 1A). At Wk 24, more CZP pts had CDAI remission/low DA (63.1% vs 30.4%, P<0.001) and fewer CZP pts had moderate/high DA (37.0% vs 69.6%, Fig. 1B). Despite low BL mean joint counts, ACR20/50/70 responses at Wk 24 were higher with CZP (ACR20: 36.5% vs 16.3%, P<0.01; ACR50: 20.8% vs 8.2%,
.4% vs 3.1%, P=NS). CZP pts had greater HAQ-DI improvements at Wk 24 (mean change from BL: –0.25 vs –0.06, P<0.01). CZP was well tolerated with AE and serious AE rates comparable between CZP and PBO (66.7% vs 66.3%; 4.2% vs 4.1%).

Figure 1.

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Conclusions: In RA pts with long-standing low moderate DA, addition of CZP to non-biologic DMARDs increased rates of remission and low DA and inhibited progression to high DA.

Commentary on abstract THU0244

Several guidelines, including those issued last year by EULAR, have identified the therapeutic goal in RA as complete remission. This goal is based on the proliferation of therapies that can offer disease control even in patients with moderate-to-severe disease activity and on the premise that complete remission will reduce the risk of progressive joint destruction with persistent disease activity. In patients with moderate-to-severe disease activity, the improvement in quality of life with targeted therapies, such as TNF inhibitors, makes the expense and small but significant risks of these agents easy to justify. The benefit:risk ratio in patients with low-to-moderate disease activity is less well established. In this study, RA patients with low to moderate disease activity on DMARDs were randomized to receive the TNF inhibitor certolizumab or placebo. Not surprisingly, the proportion of patients in remission at 24 weeks was significantly higher in the group that received the TNF inhibitor (18.8% vs. 7.1%; P<0.05). There were also fewer patients with high disease activity (16.2% vs. 42.4%) in the certolizumab group. The TNF inhibitor was characterized as generally well tolerated. While this study did confirm that patients with long-standing low-to-moderate RA on DMARDs can achieve remission with the addition of a TNF inhibitor, longer follow-up showing a reduction in joint destruction would be useful for confirming that the benefit:risk ratio warrants this approach.

Questions and answers with Prof. Josef S. Smolen, Division of Rheumatology, Medical University of Vienna, Austria

Q: Most current guidelines suggest TNF inhibitors should be reserved for patients who have failed at least 2 DMARDs. Does this study go beyond the guidelines?

A: While we appreciate the concept of complete remission, which may not only provide protection against progressive joint deterioration but also provide a greater barrier to relapse, there is more interest in tighter control of RA. We do not really have much data about whether anti-TNF agents can provide additional control in patients with low disease activity on a DMARD, and I think there is a growing need to answer this question as we place greater emphasis on clinical remission.

Q: However, is the real question whether treatment in such patients does provide a better long-term outcome, such as better mobility or better quality of life?

A: Yes, this is the ultimate question, but first it is necessary to establish that anti-TNF drugs are effective and safe in patients who continue to have low-to-moderate disease activity on a DMARD. We would expect the same types of response that have been obtained in patients with moderate-to-severe disease, but this has never been evaluated before in a randomized study. After 24 weeks, the rate of ACR20/50/70 responses was more than twice as high in the group that received certolizumab (36.5% vs. 16.3%; P<0.01).

Q: So is this a strategy you would advocate?

A: This study was not designed to evaluate all the variables that might be considered when attempting to increase the complete remission rate, particularly the cost of doing this. However, we did show that it can increase the number of patients who will get into a complete remission with a relatively low cost in terms of adverse events. In fact, there was essentially no difference in the rate of serious adverse events [4.2% vs. 4.1%]. There is a larger, unanswered question about when this approach might be used.

ABSTRACT OP0154 - Discontinuation of Adalimumab After Attaining Remission in Patients with Rheumatoid Arthritis Y. Tanaka, S. Hirata, M. Nawata, S. Kubo, K. Saito

Background: TNF inhibitors have enabled high clinical remission rate when used for treatment of RA, which has made us approach to biologic-free remission. Discontinuation of TNF inhibitors after acquisition of remission is an important issue from the viewpoints of safety and economy. We have reported that infliximab could be discontinued after attaining low disease activity by the RRR study.

Objective: The present study was undertaken to seek the possibility of discontinuing adalimumab therapy after acquiring clinical remission of RA and to evaluate progression of articular destruction during adalimumab discontinuation.

Methods: The study included patients with any disease duration, but excluded patients who had received steroids at dosages greater than 5 mg/day. After obtaining DAS28<2.6 for more than 24 weeks, adalimumab was discontinued. The primary endpoint was DAS28<2.6 at 6 months after the discontinuation.

Results: Among 133 RA patients treated with adalimumab and MTX, 32 patients discontinued adalimumab because DAS28<2.6 was kept for more than 24 weeks. The average of age was 62, mean disease duration was 25.5 months and mean duration treated with adalimumab was 52 weeks. The disease duration was significantly shorter in patients who could discontinue adalimumab than those who kept the therapy. At 6 months after the discontinuation, 13 of 14 patients (93%) achieved clinical remission for 6 months. HAQ remission was kept in 12 of 14 patients (84%) and structural remission was also maintained in all 7 patients who discontinued for more than 1 year.

Conclusions: Taken together, although it is a limited study, after reduction of disease activity to clinical remission in patients with RA by adalimumab, the majority of patients could discontinue adalimumab for more than 6 months without clinical flare and radiologic progression of articular destruction.

Commentary on abstract OP0154

One of the most intriguing questions with the introduction of targeted agents that can have a profound effect on pro-inflammatory signals is whether sustained suppression of these signals will produce lasting remissions without therapy. In theory, the molecular steps that initiate an inflammatory response leading to autoimmune diseases, such as inflammatory bowel disorders or psoriasis, could be turned off by a therapy targeted at a key event. In this relatively small study, the investigators monitored disease activity after the TNF inhibitor adalimumab was discontinued in patients with clinical remission, defined as a DAS28 score of <2.6 for more than 24 weeks. At the end of 6 months off therapy, 13 of 14 evaluable patients remained in clinical remission. In 7 patients who were in remission at 6 months and then were followed for another 6 months, all remained in remission with radiological evaluations showing no progressive joint destruction. Although it is important to recognize that those with long-term remissions represented a small fraction of an initial series of 133 RA patients from which responders were drawn, it does encourage the possibility that targeted therapies, such as TNF inhibitors, may provide a level of disease control that may serve as a barrier to relapse in at least some patients. It is notable that those patients who did achieve a sustained remission during adalimumab treatment had a significantly shorter duration of RA than those who did not, suggesting that inflammatory signalling may be more difficult to turn off as disease persists.

Questions and answers with Dr. Yoshiya Tanaka, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan

Q: Is this the first time that long-term remissions have been reported after discontinuation of a biologic in RA?

A: No, there are now several reports, and we presented a study previously showing very similar rates of remission off therapy in patients who discontinued infliximab. These remissions off therapy have been mostly seen in patients who had a long-term remission on therapy, but then these are the types of patients most often studied off therapy. It does not appear that most patients can receive a biologic and then expect a longterm remission off therapy, but we show that a minority of them can.

Q: You have some patients still in complete remission off therapy for a year. Do you think cure is possible?

A: It is not appropriate to talk about cure of this disease after such a short follow-up. For most patients, RA is a life-long condition once it develops. Cure is probably not very likely with current therapies, but it is possible that a better understanding of how to turn off the inflammatory process might eventually lead to some drug or combination of drugs that would produce remissions with a low risk of relapse.

Q: What are the implications of your study?

A: The current targeted therapies are expensive and cumbersome because they require frequent infusions. If we could identify some subgroup of patients likely to have a sustained remission off therapy, then this would have major implications for cost and for quality of life. Much work is needed. Not least important, it will be necessary to understand the consequences for patients who do go off therapy for several years and then relapse. Are relapses more severe? Can control be regained? There are potential safety advantages for discontinuing therapy in those with the potential for sustained remissions, so there are a lot of factors to weigh.

ABSTRACT OP0057 - Improved Health-related Quality of Life in Patients with Active Rheumatoid Arthritis Receiving Fostamatinib (R788) M. E. Weinblatt, A. Kavanaugh, M. C. Genovese, D. Jones, T. K. Musser, E. B. Grossbard, D. B. Magilavy

Background: Patient-reported outcomes (PRO) are important for evaluating health-related quality of life (HRQoL) in rheumatoid arthritis (RA) patients. The efficacy of fostamatinib (R788), an oral spleen tyrosine kinase (Syk) inhibitor, has previously been demonstrated in a phase II, multicenter, randomized, doubleblind, placebo-controlled study in patients with RA who failed to respond to methotrexate [NCT00665925].¹ In this study, patient-reported pain, global disease activity, and physical functioning (as measured by the Health Assessment Questionnaire-Disability Index [HAQ-DI]) were improved at 6 months in patients receiving fostamatinib 100 mg twice daily (bid) compared with placebo.¹

Objective: To evaluate the effect of fostamatinib on further HRQoL measures in RA patients who failed to respond to long-term treatment with methotrexate.

Methods: Patients with active RA despite long-term methotrexate therapy (n=457) were enrolled in a 6-month, double-blind, placebo-controlled trial, and randomized to receive either fostamatinib (150 mg once daily [qd] [n=152] or 100 mg bid [n=152]) or placebo (n=153). Patients completed the short form (SF)-36 at baseline and month 6, the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale at baseline and months 3 and 6, the HAQ-DI, a pain visual analog scale (VAS), and a global assessment of disease activity VAS at baseline and weeks 1, 2, 4, 6, and 8, and monthly, thereafter. A general linear model was used to test the change from baseline to each post-dosing time point for all stated PROs.

Results: Details of the study population at baseline have been described previously.¹ Compared with placebo, fostamatinib 100 mg bid was associated with significant improvements from baseline to month 6 in physical health status and in fatigue as measured by the SF-36 Physical Component Summary (PCS) and FACIT-Fatigue, respectively (Table). Significant improvement in each of the physical domains of the SF-36 was seen.^{1<
t improvements were observed in the Mental Component Summary (MCS) of the SF-36. Improvements in physical functioning as measured by the HAQ-DI, and in patient-reported pain and global disease activity were observed as early as the end of week 1 and were sustained for the duration of the trial.}

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Conclusions: In this phase II study involving RA patients, 100 mg bid fostamatinib was associated with significant improvements in HRQoL outcomes including physical functioning, pain, fatigue, and overall physical health status.

References: 1. Weinblatt et al. N Engl J Med 2010;363:1303-12.

Commentary on abstract OP0057

TNF inhibitors and IL-6 receptor antagonists have revolutionized treatment of moderate-to-severe RA inadequately controlled with DMARDs. Another strategy, small-molecule inhibitors of intracellular enzymatic mediators of inflammation, have reached advanced stages of clinical testing. In this followup of a phase II study that associated the Syk inhibitor fostamatinib with improvement in RA control in patients with inadequate response to DMARDs, health-related quality of life (HRQOL) was assessed. An important measure of benefit independent of joint symptoms and function, HRQOL provides another perspective on the activity of treatment. In this analysis, the authors associated the Syk inhibitor with significant improvements in physical functioning, pain and fatigue. The agent also produced an improvement in overall health status. Like the efficacy responses reported previously, the improvement in HRQOL encourages the phase III studies needed to establish the safety and efficacy of this therapy in an RA population. Although an expansion of effective therapies in RA is welcome, there are very little data as of yet to predict whether the efficacy and the safety of small-molecule inhibitors such as fostamatinib will be similar, less or more favourable relative to the existing targeted therapies which all act on extracellular signalling systems.

Questions and answers with Dr. Michael E. Weinblatt, Division of Rheumatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Q: What is a small-molecule inhibitor and what is Syk specifically?

A: Most drugs are small molecules, but the term small-molecule inhibitors generally refers to drugs that target specific intracellular enzymatic pathways to alter cell function such as signals for proliferation. A number of these agents are in widespread use in cancer, such as erlotinib, a tyrosine kinase inhibitor that blocks epidermal growth factor signalling to halt cancer growth. In RA, there are several drugs in development that target enzymes important to inflammation. Fostamatinib acts on Syk kinase which, among other actions, is implicated in B-cell activation. Based on the phase II activity with this agent and the phase III activity reported with tofacitinib, a JAK inhibitor, this is a promising area of clinical study in RA.

Q: How do you expect these drugs to be used in RA if approved?

A: The phase II trial was conducted in RA patients who had an inadequate response to MTX, which is where TNF inhibitors and IL-6 receptor inhibitors are now employed. We do not yet know whether these agents are as active as the targeted therapies that work extracellularly or as safe, so it is unclear whether they might eventually fit with other options. However, more effective drugs in RA are needed because there is no single agent that is effective in all individuals.

Q: If patients have fewer joint symptoms, does an improvement in QOL follow?

A: It is important to assess these separately because QOL assessments provide a more global picture of the effect of therapy. It is possible for a drug to improve joint symptoms without having an overall favourable impact on well-being. QOL studies are particularly important in chronic diseases.

ABSTRACT SAT0243 - ORAL SOLO (A3921045): A Phase 3 Study of Oral JAK Inhibitor Tofacitinib (CP-690,550) Monotherapy in Patients with Active Rheumatoid Arthritis: Subgroup Analysis of Efficacy R. Fleischmann, J. Kremer, C. A. Connell, B. Benda, J. D. Bradley, D. Gruben, S. H. Zwillich, K. S. Kanik

Background: Tofacitinib (CP-690,550; referred to here as CP) is a novel, oral Janus kinase (JAK) inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis (RA).

Objectives: To compare the effects of CP 5 and 10 mg BID with placebo (PBO) on efficacy and safety with subgroup analyses by baseline demographic characteristics, in a randomised, double-blind, PBO-controlled, parallel group Phase 3 study. Primary analyses have been reported previously.

Methods: Patients (pts) with active RA (=6 tender/swollen joints; ESR >28 mm or CRP >7 mg/L) and prior DMARD failure were randomised (4:4:1:1) to either: CP 5 mg BID Mo 0-6; CP 10 mg BID Mo 0-6; PBO Mo 0-3, CP 5 mg BID Mo 3-6; and PBO Mo 0-3, CP 10 mg BID Mo 3-6. The Mo 3 primary ACR20 endpoint and post-hoc subgroup analyses of ACR20 response rates in major demographic subgroups are presented here. No adjustment of p-values is made to correct for multiple testing.

Results: 610 pts received treatment. The Mo 3 ACR20 response rate was 59.8% (CP 5 mg) and 65.7%
PBO), P<0.0001. As early as Week 2, ACR20 response rates vs PBO were significant for 5 and 10 mg BID (P<0.0001). ACR20 response rates at Mo 3 were also greater for CP 5 and 10 mg BID compared with PBO, regardless of serological (RF or anti-CCP) status, age, weight and sex. Results are summarised by subgroup in Table 1.

Table 1.

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In Mo 0-3, 330 (54.1%) pts had 701 treatment-emergent adverse events (TEAEs) (54.9% PBO, 51.0% 5 mg, 56.7% 10 mg) and 13 pts (2.1%) discontinued due to TEAEs, with similar frequency across groups and was consistent with previously reported safety data from clinical studies with CP. Safety analyses showed similarities and differences between subgroups, but further analysis in a larger population is required to assess the relevance of these observations.

Conclusions: In this first Phase 3 study in pts with RA, clinically significant efficacy and acceptable safety vs PBO was demonstrated with CP 5 and 10 mg BID monotherapy at Mo 3 and in the majority of major demographic subgroups investigated.

Commentary on abstract SAT0243

All of the approved targeted therapies in rheumatology are biologics that act extracellularly and require injection. Tofacitinib is one of a new group of small-molecule agents that acts on intracellular enzymatic pathways and can be taken orally. Although the enzymatic pathways are complex and appear in many cases to be interlinked to some degree, the principle of the small-molecule inhibitors is similar to the biologics in that they interrupt very specific pro-inflammatory molecular events. This agent inhibits one of the 4 JAK enzymes, JAK-3, and has shown promise in experimental studies as well as acceptable safety in initial early-phase human trials. In this placebo-controlled phase III trial, the ACR20 response rates on either of the 2 doses at month 3 were highly statistically superior and on the order of rates of response observed with the TNF inhibitors. The rates of adverse events were comparable to biologics, but the types of adverse events differed. In particular, this agent appears to increase LDL-C levels substantially. Much longer-term safety data are needed to assess the risk of relatively rare events, including an increased susceptibility to infection, which has been observed with other targeted therapies that affect immune function.

Questions and answers with Dr. Roy Fleischmann, Co-director, Division of Rheumatology, Texas Southwestern Medical Center, Dallas

Q: In a disease for which there is now an array of effective therapies, why was tofacitinib not compared to another active agent rather than placebo?

A: This trial was designed in consultation with the Food and Drug Administration (FDA), so the design was partially dictated by the demands of regulatory review. However, there can be a substantial placebo response to medications in RA, for which an assessment of change in symptoms is essentially subjective, so a placebo control is reasonable. Even more importantly, a placebo control, relative to an active comparator with its own side effects, makes it easier to quantify adverse events.

Q: Based on the results, do you think the agent will move forward?

A: The results were promising. They established that the drug is active, and we did not observe any unexpected or severe side effects that would slow further development. With new agents that have a novel mechanism of action, it is important to establish long-term safety as well as initial tolerability, so extension studies are planned.

ABSTRACT FRI0340 - Anti-TNF Failure and Response to Rituximab in Seropositive and Seronegative RA A. Khan, A. Leak

Background: Patients with rheumatoid arthritis (RA) with an inadequate response to anti-TNF may switch to an alternative anti-TNF or start treatment from a different class of drugs such as rituximab (RTX). NICE guidance in the UK states that RTX is indicated for severe active RA (usually DAS28 >5.1) when patient has had inadequate response to DMARDs and also failed anti-TNF therapy (1).NICE defines an adequate response to RTX as improvement in DAS28 by 1.2 or more. Data is emerging to show that patients with seropositive RA respond better to RTX than those with seronegative disease (Isaacs J et al EULAR 2009, Tak P et al EULAR 2009).

Objectives: We have analysed the response to one course of RTX in all RA patients treated within Kent & Medway Rheumatology Network comparing seropositive and seronegative patients and their response to RTX in primary and secondary TNF failure.

Methods: In 140 patients known to have at least 6 months follow-up after their first course of RTX (dosage 1000mg on day 1 and 15) for active RA we have shown patients with seropositive RA had significant higher pre-treatment DAS28 score mean 6.1 compared to 5.8 for seronegatives (p=0.02) but achieved significant greater fall in DAS after 6 months (p<0.001) We have subdivided patients into primary and secondary TNF failure as well as analyse the number of previous anti-TNFs. Unpaired t-test was used to compare primary and secondary groups, ANOVA to compare the DAS scores according to number of prior TNF drugs used. Results: Seropositive RA: Of 85 patients (RF+CCP+30, RF+CCP-41, CCP+RF-14) 63 with primary TNF failure, 16 with secondary TNF failure (1TNF 28, 2TNF 45, 3TNF 6) noTNF 6. No difference in baseline DAS28 between two groups primary failure 6.0 (SD 0.9), secondary failure 6.3 (SD1.2) (p=0.32). Post RTX: Primary TNF failure had significantly lower DAS (mean 3.8) compared to secondary TNF failure (mean 4.5) (p=0.03). Reduction in DAS was greater in primary TNF failure (mean 2.2) compared to 1.8 in secondary TNF failure (p=0.18). Post RTX those with no prior TNF had the best mean DAS score 2.9 (SD 0.9) and significant reduction of 3.4. There was a relationship between lower no of TNFs and better response to RTX (1TNF DAS 3.3 (SD 0.8) 2TNF 4.0 (SD 1.3) 3TNF 3.7 (SD 0.6) (p=0.07) and reduction DAS of 2.7, 2.1, 2.0 (p=0.02). Seronegative RA: Of 55 patients (all RF negative, CCP negative) 32 with primary TNF failure, 19 with secondary TNF failure (1TNF 15, 2TNF 32, 3TNF 4) noTNF 4. No difference in baseline DAS28 score between primary and secon
5048" />.8 (SD 0.8) secondary 5.8 (SD 0.8) (p=0.99). Post RTX: No significant falls in DAS28 score and no difference between the primary and secondary TNF failure groups 5.1 (SD 1.0), 5.2 (SD 0.9) (p=0.67) mean reduction 0.7(SD1.0) 0.6(SD1.1) (p=0.70) No significant differences post RTX in DAS score or mean DAS reduction (p=0.38) according to the number of prior TNF drugs.

Table 1.

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Table 2.

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Conclusions: Seropositive RA respond more effectively to RTX than seronegative RA even when matched for disease activity, disease duration and prior treatment. Seropositive RA who have not tried anti-TNF or have primary failure respond best to RTX but even those with secondary failure had a mean fall in DAS of 1.8. Use of fewer TNF drugs was associated with better RTX response. By contrast patients with seronegative RA had poor response to RTX with no significant difference according to primary or secondary failure nor number of TNF drugs tried.

Commentary on abstract FRI0340

The level of response to targeted therapies is often exceptional with patients with relatively severe disease refractory to DMARDs achieving complete or near complete remissions. However, this level of response is unpredictable, and as yet there are no consistently reliable patient characteristics useful to guide first- or second-line choices. The data from this study suggesting that rituximab may be particularly effective in patients with primary failure to an anti-TNF agent and in those who are seropositive for RA provide some preliminary evidence that specific characteristics may help guide treatment choice. Although this study of 85 patients was quite small, the increasing number of options for targeted therapy is likely to encourage more studies designed to evaluate which treatments should be considered for first-line therapy and which should be reserved for refractory patients. As the mechanisms of many of the newer targeted therapies differ markedly from the initial anti-TNF agents, there is a reasonable likelihood that the order of treatments may matter, particularly if the goal is to preserve options not only for those with primary failure to a first-line agent but also for those who lose response after prolonged exposure. The results of this trial are intriguing but larger studies, particularly those involving randomization, are needed to develop clinically relevant strategies.

ABSTRACT FRI0359 - Efficacy and Safety of Abatacept Treatment for Rheumatoid Arthritis (RA) in a Real-life Setting in European and Canadian Populations: A 6-month Interim Analysis of the ACTION Study H. Nüßlein, H. M. Lorenz, R. Alten, W. G. Bensen, L. Bessette, G. Burmester, H.-H. Peter, M. Chartier, C. Poncet, C. Rauch, M. Le Bars

Background: Randomized controlled trials (RCTs) of abatacept (ABA) in RA pts have demonstrated sustained, long-term efficacy, high pt retention and favourable safety.¹ Information from the clinical setting is required to determine if these benefits translate into the real world.

Objectives: Evaluate retention, efficacy and safety of ABA in RA pts treated in routine clinical practice (according to label) in Europe and Canada.

Methods: ACTION (AbataCepT In rOutiNe clinical practice) is a non-interventional, prospective, longitudinal study in ABA-treated RA pts. We present a 6-mth interim analysis of ABA+DMARD-treated pts who received prior anti-TNF treatment. Follow-up was every 3 mths. Retention rate (Kaplan–Meier estimation) and disease activity (DAS28ESR and/or CRP, CDAI, for pts with available data) are reported over 6 mths. Serious adverse events (SAEs) were assessed in all enrolled pts, and are reported up to study cut-off date.

Results: Of 546 enrolled pts (Mar 2008 - Aug 2010), 526 received IV ABA (Germany, 374; Canada, 152). Of 455 pts who had prior anti-TNF treatment, 327 subsequently received ABA+DMARDs and are evaluated here, 128 received monotherapy. Not all 327 pts had reached Mth 6 at
baseline, mean (SD) age was 54.4 (12.4), disease duration was 11.1 (8.6) yrs and 82% were female. 68.4 and 66.2% were RF and anti-CCP positive and 73.1% had erosions. 45.6, 42.8 and 11.6% had failed 1, 2 and 3 anti- TNFs, respectively. At entry, 56.3, 11.3, 32.4 and 77.4% of pts were receiving MTX, MTX+DMARD, DMARD and corticosteroids. At Mth 6, estimated retention rate was 83.4% (95% CI: 77.6–87.8). Efficacy at baseline and Mth 6 is shown for pts with eligible assessments.

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15 SAEs were reported in 14/546 (2.6%) pts (8 led to discontinuation, 1 death [aspiration pneumonia secondary to benzodiazepine withdrawal syndrome]). 7 serious infections (1.3%; viral encephalitis, 2 abscesses, wound infection, pneumonia, urinary tract infection, cholangitis), 2 malignancies (0.4%; breast cancer, pelvic mass), 1 acute infusional event (0.2%; systemic hypersensitivity reaction) and 3 cardiovascular events (0.5%; stroke, transient ischaemic event, DVT) were reported. No events of TB or opportunistic infection were reported.

Conclusions: This is the first large-scale, global observational study of abatacept use in a real-life setting, which confirms its clinical effectiveness and safety in anti-TNF refractory RA pts with long-term, erosive disease. These data are consistent with previous RCT1 and real-life findings² and need to be confirmed in further analyses of long-term ACTION data.

References: 1. Genovese et al. N Engl J Med 2005;353:1114-23. 2. Schiff et al. Int J Clin Rheumatol 2010;5:581-91.

Commentary on abstract FRI0359

Abatacept, a fusion protein composed of an immunoglobulin fused to the extracellular domain of CTLA-4 that blocks co-stimulation of lymphocytes, is currently licensed for use in RA patients refractory to anti-TNF agents. In this study, which included Canadian enrolment, the goal was to assess efficacy and safety in a real-world setting outside of a randomized, clinical trial. These preliminary results at 6 months are consistent with the performance of this agent in controlled trials. At month 6, more than 80% of patients remained on therapy, and although serious adverse events (SAEs) did occur they were uncommon (2.6%). Like SAEs associated with other targeted therapies, infection was the most common with abatacept, accounting for almost half of these events. However, there were no cases of tuberculosis or opportunistic infections. There was one death in this series, but it was secondary to benzodiazepine withdrawal syndrome and therefore not clearly linked to the targeted therapy. With each of the targeted agents, all of which pose some risk for SAEs, there is concern that risks will be greater when these agents are administered in routine practice and outside of the setting of tertiary care centres capable of rapid response to unexpected events. However, this concern has been consistently refuted with post-marketing studies conducted with each of the approved agents. Although side effects with these agents may be serious, they appear to be readily managed in the real-world clinical setting.