Perspectives on Diagnosis and Management of Inflammatory Diseases, From ACR
Perspectives on Diagnosis and Management of Inflammatory Diseases, From ACR
Medscape: Early RA diagnosis is important for optimal patient outcome. Various diagnostic tools are used, and at this conference, data were presented supporting the use of ultrasound for early diagnosis of RA. What are your views on the implication of this for rheumatologists?
Dr. Emery: Although there is a lot of current interest surrounding the use of ultrasound for monitoring disease activity, we started investigating the application of ultrasound technology in RA as far back as 10 years ago, and presented an abstract on use of ultrasound in early RA at this meeting.
Indeed ultrasound is generally considered to be more sensitive than clinical examination in the small joints of the hand, although little is known about its diagnostic predictive ability. The study we presented investigated the relationship between baseline ultrasound findings (Grey scale and power Doppler) at symptom onset with clinical diagnosis at 6 months in a cohort of patients with very early inflammatory hand symptoms. The secondary aim was to explore whether using a higher cut-off (grade 2 or more) in a typical semi-quantitative scoring system for ultrasound-detected synovitis results in a greater specificity for clinical outcome.
Medscape: What did your study findings show?
Dr. Emery: Well, the results show that power Doppler is useful in very early disease, in fact as early as the first 12 weeks of disease. I think this is extremely important data because it effectively shows which patients are likely going to develop joint erosion. Previously we have used ultrasound to diagnose erosions; however, what we are now doing, particularly in the study presented, is using ultrasound to predict the likelihood of joint erosions. This allows for the earliest possible introduction of a disease-modifying antirheumatic agent.
Medscape: Is the application of power Doppler effective only at the early RA disease stage, or is it useful even at the later stages of the disease?
Dr. Emery: This technology is actually predicting which patients at the very early stages of the disease, before the RA is apparent, will go on to develop erosions which characterize the disease. At the late stages of the disease, power Doppler is perhaps less effective because you do not need to predict erosions on ultrasound; you see them.
Medscape: Although the goal of RA treatment is disease remission, most studies report treatment effectiveness as a reduction in radiographic progression. Can you comment on the significance of your recent study, which uses remission rate as the primary endpoint?
Dr. Emery: In my opinion, patients want disease remission -- they want to be completely well. As clinicians, previously we have not been able to achieve remission in patients in frequent enough numbers; but with the newer biologic agent, remission is now an achievable goal. So in this respect, I think disease remission is the only important endpoint.
The Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis (COMET) study, which compared clinical efficacy and safety of etanercept plus methotrexate (MTX) with MTX alone in patients with active early RA, was the first major RA clinical trial to use remission as a primary endpoint. The study demonstrated that in this population of early RA patients, 50% of the patients treated with etanercept plus MTX achieved remission relatively quickly and without an increase in treatment side effects -- an enormously important point to emphasize. In comparison, standard nonbiologic therapy produced remission in about 20% of patients or less. The results also provide additional support for the effectiveness of combination therapy with a biologic agent early in the RA disease process.
Medscape: Since the introduction of anti-tumor necrosis factor (TNF) agents, newer biologics have emerged. What are some of the latest data supporting the safety and efficacy of these newer agents?
Dr. Emery: The efficacy and safety data for the newer agents, such as abatacept and rituximab, are pretty good. Rituximab was the more worrisome of the 2 biologic agents because it causes B-cell depletion, and there were concerns that repeated B-cell depletion would be problematic. However, much data have now been gathered to show that patients with repeated B-cell depletion do not have a significant increased risk for infection. This is a very important point to note. Available data show that abatacept appears to be very safe over the long term.
Although it is difficult to compare the safety and efficacy of the newer biologic agents with that of the anti-TNF agents (because most of the data are in TNF failures), overall we can say that they are comparable.
Medscape: In terms of the risk for infection and malignancy, do we see the same level of risk with the newer biologic agents as we do with the anti-TNF agents?
Dr. Emery: With abatacept, 4 cases of lung cancer were seen in the original placebo-controlled study, and there were concerns that this might be an adverse effect of treatment. However, this finding is currently being studied very carefully, and there appears to be no increased risk nor cumulative risk with abatacept. It appears that the 4 cases of lung cancer previously seen had more to do with the fact that RA itself is associated with lung cancer. Indeed in the dataset for rituximab, no hematologic malignancies have been reported, which is very reassuring and probably due to the fact that the anti-CD20 agent is used for treating lymphoma.
Medscape: For any therapeutic agent (and specifically biologics for RA), how well do the responses seen in clinical trials translate in clinical practice, and should there be caution in interpreting clinical trial results in order to manage expectations in the clinical setting?
Dr. Emery: This is an interesting point. The Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN) showed that at 6 months, significantly more patients in the abatacept group had clinically meaningful improvementin physical function compared with the placebo group. However, it appears that in clinical practice, according to the study presented by Singh and his colleagues, patients treated with abatacept did not experience the same success with regard to clinically meaningful improvementin physical function, as was reported in the phase 3 study. Their study did show that the actual clinical improvement seen with patients on abatacept, in an outpatient clinical setting, was much lower compared with the improvements seen in the ATTAIN trial.
However, our experience in the clinical setting is that we have seen better results than in the clinical trials. This perhaps partly reflects the fact that in our clinic we have a more defined RA patient population. We spend a lot more time defining our patients and trying to target treatment to the correct patient, so we get better treatment efficacy with no increase in the side effects compared with the clinical trials. This is pretty good and very reassuring. So careful patient selection appears to be very important to outcome. For example, abatacept treats most patients but rituximab is much better for seropositive patients.
Medscape: What about switching treatments -- for example, from an anti-TNF to a rituximab or abatacept; how safe and effective is this?
Dr. Emery: Well, in Europe the only approval for using abatacept or rituximab is in TNF failures, so most of the data are in those patients; however, we use rituximab when TNF is contraindicated, although it is not approved for that.
Medscape: Raynaud's phenomenon can be disabling for many patients. What is the significance of the recent study surrounding MQX-503.
Dr. Emery: MQX-503 is a novel topical microemulsion of nitroglycerin that is designed to induce local vasodilatation with minimal systemic effects. Our group evaluated this agent as a potential treatment for primary or secondary Raynaud's phenomenon. MQX-503 reduces the severity of this disease and is very well tolerated, and we are hoping that future studies will help to delineate the clinical impact of this positive treatment effect. The theoretical underpinning in this treatment approach is that if you treat the Raynaud's part of the disease, progression is inhibited. That's completely unproven at the moment, but it would be a positive aspect -- that you could actually have an impact on the disease as well as the immediate symptomatology.
Medscape: What is the current standard treatment approach for Raynaud's phenomenon?
Dr. Emery: It's something like amlodipine, a vasodilator. ACE (angiotensin-converting enzyme) inhibitors are also used, although the evidence for them is not as good. We also use fluoxetine sometimes, which has been shown to be beneficial. This new compound,MQX-503, is definitely advantageous over the standard treatment approachbecause, from the available evidence, it does not produce systemic effects. However, some patients cannot tolerate the current oral agents because they cause side effects such as flushing and headaches. So this new compound definitely meets a previously unmet need.
Medscape: What do you see as the key educational needs to improve the clinical use of newer, more effective therapies, such as biologic agents in the clinical setting?
Dr. Emery: There are some rheumatologists who still are very reluctant to use biologics. It does involve a lot more hassle because there are a lot of forms to fill out, it is more expensive, and they have to be convinced of the cost benefit of these agents. With the volume of data that is now accumulating supporting the benefits of biologic agents in RA, I think it is difficult for any rheumatologist to be unaware of the efficacy of these agents; however, some evidence -- such the COMET data, which show that you can get the efficacy without increased toxicity -- are enormously important and need to be communicated. So in my opinion, I think in terms of implementation of the evidence into clinical practice: Clinicians need to realize that if they are not using the evidence, they are not doing their best for their patients. It may be equally important to explain how the different drugs work; one would hope that most clinicians are familiar with the mode of action of the different therapeutic agents, although some may need reinforcement. Stressing that these agents have unique differences in their modes of action and with different side effects is very important when considering a particular treatment or considering switching to a different agent.
Medscape: In terms of managing a patient with RA, do you see any difference in approach between what is done in Europe and what is done in the United States, and do you think a standardized approach is feasible?
Dr. Emery: There is a move towards standardization worldwide, and particularly in Europe; so there is much more uniformity, but that's a big task because of the reimbursement arrangements. In Europe, at least in the United Kingdom, we do not actually pay for the drugs ourselves; they are paid for by the government, so we essentially have to stick to their rules. With regard to a standardized approach, the big factor in the United Kingdom would be changing the National Institute of Clinical Excellence (NICE) which is currently involved in reviewing approaches to the management of RA with anti-TNF. Nonetheless, I think it is important to make sure that patients and clinicians are aware of the potential benefit of therapy and the great benefits that can occur if it is used optimally. If they do that, the pressure will come from patients, who ultimately are the population who will change things.
Medscape: Early RA diagnosis is important for optimal patient outcome. Various diagnostic tools are used, and at this conference, data were presented supporting the use of ultrasound for early diagnosis of RA. What are your views on the implication of this for rheumatologists?
Dr. Emery: Although there is a lot of current interest surrounding the use of ultrasound for monitoring disease activity, we started investigating the application of ultrasound technology in RA as far back as 10 years ago, and presented an abstract on use of ultrasound in early RA at this meeting.
Indeed ultrasound is generally considered to be more sensitive than clinical examination in the small joints of the hand, although little is known about its diagnostic predictive ability. The study we presented investigated the relationship between baseline ultrasound findings (Grey scale and power Doppler) at symptom onset with clinical diagnosis at 6 months in a cohort of patients with very early inflammatory hand symptoms. The secondary aim was to explore whether using a higher cut-off (grade 2 or more) in a typical semi-quantitative scoring system for ultrasound-detected synovitis results in a greater specificity for clinical outcome.
Medscape: What did your study findings show?
Dr. Emery: Well, the results show that power Doppler is useful in very early disease, in fact as early as the first 12 weeks of disease. I think this is extremely important data because it effectively shows which patients are likely going to develop joint erosion. Previously we have used ultrasound to diagnose erosions; however, what we are now doing, particularly in the study presented, is using ultrasound to predict the likelihood of joint erosions. This allows for the earliest possible introduction of a disease-modifying antirheumatic agent.
Medscape: Is the application of power Doppler effective only at the early RA disease stage, or is it useful even at the later stages of the disease?
Dr. Emery: This technology is actually predicting which patients at the very early stages of the disease, before the RA is apparent, will go on to develop erosions which characterize the disease. At the late stages of the disease, power Doppler is perhaps less effective because you do not need to predict erosions on ultrasound; you see them.
Medscape: Although the goal of RA treatment is disease remission, most studies report treatment effectiveness as a reduction in radiographic progression. Can you comment on the significance of your recent study, which uses remission rate as the primary endpoint?
Dr. Emery: In my opinion, patients want disease remission -- they want to be completely well. As clinicians, previously we have not been able to achieve remission in patients in frequent enough numbers; but with the newer biologic agent, remission is now an achievable goal. So in this respect, I think disease remission is the only important endpoint.
The Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis (COMET) study, which compared clinical efficacy and safety of etanercept plus methotrexate (MTX) with MTX alone in patients with active early RA, was the first major RA clinical trial to use remission as a primary endpoint. The study demonstrated that in this population of early RA patients, 50% of the patients treated with etanercept plus MTX achieved remission relatively quickly and without an increase in treatment side effects -- an enormously important point to emphasize. In comparison, standard nonbiologic therapy produced remission in about 20% of patients or less. The results also provide additional support for the effectiveness of combination therapy with a biologic agent early in the RA disease process.
Medscape: Since the introduction of anti-tumor necrosis factor (TNF) agents, newer biologics have emerged. What are some of the latest data supporting the safety and efficacy of these newer agents?
Dr. Emery: The efficacy and safety data for the newer agents, such as abatacept and rituximab, are pretty good. Rituximab was the more worrisome of the 2 biologic agents because it causes B-cell depletion, and there were concerns that repeated B-cell depletion would be problematic. However, much data have now been gathered to show that patients with repeated B-cell depletion do not have a significant increased risk for infection. This is a very important point to note. Available data show that abatacept appears to be very safe over the long term.
Although it is difficult to compare the safety and efficacy of the newer biologic agents with that of the anti-TNF agents (because most of the data are in TNF failures), overall we can say that they are comparable.
Medscape: In terms of the risk for infection and malignancy, do we see the same level of risk with the newer biologic agents as we do with the anti-TNF agents?
Dr. Emery: With abatacept, 4 cases of lung cancer were seen in the original placebo-controlled study, and there were concerns that this might be an adverse effect of treatment. However, this finding is currently being studied very carefully, and there appears to be no increased risk nor cumulative risk with abatacept. It appears that the 4 cases of lung cancer previously seen had more to do with the fact that RA itself is associated with lung cancer. Indeed in the dataset for rituximab, no hematologic malignancies have been reported, which is very reassuring and probably due to the fact that the anti-CD20 agent is used for treating lymphoma.
Medscape: For any therapeutic agent (and specifically biologics for RA), how well do the responses seen in clinical trials translate in clinical practice, and should there be caution in interpreting clinical trial results in order to manage expectations in the clinical setting?
Dr. Emery: This is an interesting point. The Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN) showed that at 6 months, significantly more patients in the abatacept group had clinically meaningful improvementin physical function compared with the placebo group. However, it appears that in clinical practice, according to the study presented by Singh and his colleagues, patients treated with abatacept did not experience the same success with regard to clinically meaningful improvementin physical function, as was reported in the phase 3 study. Their study did show that the actual clinical improvement seen with patients on abatacept, in an outpatient clinical setting, was much lower compared with the improvements seen in the ATTAIN trial.
However, our experience in the clinical setting is that we have seen better results than in the clinical trials. This perhaps partly reflects the fact that in our clinic we have a more defined RA patient population. We spend a lot more time defining our patients and trying to target treatment to the correct patient, so we get better treatment efficacy with no increase in the side effects compared with the clinical trials. This is pretty good and very reassuring. So careful patient selection appears to be very important to outcome. For example, abatacept treats most patients but rituximab is much better for seropositive patients.
Medscape: What about switching treatments -- for example, from an anti-TNF to a rituximab or abatacept; how safe and effective is this?
Dr. Emery: Well, in Europe the only approval for using abatacept or rituximab is in TNF failures, so most of the data are in those patients; however, we use rituximab when TNF is contraindicated, although it is not approved for that.
Medscape: Raynaud's phenomenon can be disabling for many patients. What is the significance of the recent study surrounding MQX-503.
Dr. Emery: MQX-503 is a novel topical microemulsion of nitroglycerin that is designed to induce local vasodilatation with minimal systemic effects. Our group evaluated this agent as a potential treatment for primary or secondary Raynaud's phenomenon. MQX-503 reduces the severity of this disease and is very well tolerated, and we are hoping that future studies will help to delineate the clinical impact of this positive treatment effect. The theoretical underpinning in this treatment approach is that if you treat the Raynaud's part of the disease, progression is inhibited. That's completely unproven at the moment, but it would be a positive aspect -- that you could actually have an impact on the disease as well as the immediate symptomatology.
Medscape: What is the current standard treatment approach for Raynaud's phenomenon?
Dr. Emery: It's something like amlodipine, a vasodilator. ACE (angiotensin-converting enzyme) inhibitors are also used, although the evidence for them is not as good. We also use fluoxetine sometimes, which has been shown to be beneficial. This new compound,MQX-503, is definitely advantageous over the standard treatment approachbecause, from the available evidence, it does not produce systemic effects. However, some patients cannot tolerate the current oral agents because they cause side effects such as flushing and headaches. So this new compound definitely meets a previously unmet need.
Medscape: What do you see as the key educational needs to improve the clinical use of newer, more effective therapies, such as biologic agents in the clinical setting?
Dr. Emery: There are some rheumatologists who still are very reluctant to use biologics. It does involve a lot more hassle because there are a lot of forms to fill out, it is more expensive, and they have to be convinced of the cost benefit of these agents. With the volume of data that is now accumulating supporting the benefits of biologic agents in RA, I think it is difficult for any rheumatologist to be unaware of the efficacy of these agents; however, some evidence -- such the COMET data, which show that you can get the efficacy without increased toxicity -- are enormously important and need to be communicated. So in my opinion, I think in terms of implementation of the evidence into clinical practice: Clinicians need to realize that if they are not using the evidence, they are not doing their best for their patients. It may be equally important to explain how the different drugs work; one would hope that most clinicians are familiar with the mode of action of the different therapeutic agents, although some may need reinforcement. Stressing that these agents have unique differences in their modes of action and with different side effects is very important when considering a particular treatment or considering switching to a different agent.
Medscape: In terms of managing a patient with RA, do you see any difference in approach between what is done in Europe and what is done in the United States, and do you think a standardized approach is feasible?
Dr. Emery: There is a move towards standardization worldwide, and particularly in Europe; so there is much more uniformity, but that's a big task because of the reimbursement arrangements. In Europe, at least in the United Kingdom, we do not actually pay for the drugs ourselves; they are paid for by the government, so we essentially have to stick to their rules. With regard to a standardized approach, the big factor in the United Kingdom would be changing the National Institute of Clinical Excellence (NICE) which is currently involved in reviewing approaches to the management of RA with anti-TNF. Nonetheless, I think it is important to make sure that patients and clinicians are aware of the potential benefit of therapy and the great benefits that can occur if it is used optimally. If they do that, the pressure will come from patients, who ultimately are the population who will change things.
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