Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. Marc Cohen. This program is available as read only and with accompanying audio.
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Slide 1: Welcome to the Coalition of Rheumatology Educators program entitled “Safety and Efficacy of Biologics in Rheumatoid Arthritis.” This activity is jointly sponsored by the American Academy of CME, Inc and Princeton CME. The activity is supported by educational grants from Amgen, Inc, Wyeth Pharmaceuticals, Bristol Myers Squibb Company, Genentech, Inc, Biogen IDEC, Inc, and Abbott Laboratories. I am Marc Cohen, now from the National Jewish Medical and Research Center in Denver, Colorado, and I will be your presenter for today’s activity.
Slide 2: This module includes the safety and efficacy of biologics in rheumatoid arthritis, and our learning objectives today are to (1) employ current data on the clinical benefits and limitations of biologic therapies to discuss the management of rheumatoid arthritis, and (2) to identify the role of new therapies in the treatment of RA and related conditions.
Slide 3: I would like to start with a brief presentation about efficacy of a couple of biologics in combination with methotrexate, and compare that to methotrexate monotherapy.
Slide 4: There are currently 3 anti-TNF products available on the market: etanercept, infliximab, and adalimumab. As there are several other products in phase 3 of clinical trials, that number may increase quite quickly in the next year or 2. The anti-TNF drugs have been demonstrated in several rather sophisticated studies to be more efficacious than either methotrexate alone or the monotherapy with the biologic alone. An example of that—and actually this data is available for all 3 compounds—is the ASPIRE trial. We are going to look at results at week 54 of that trial, and clearly, as you look at the way we have traditionally measured clinical responses—the ACR20, 50, and 70 criteria—it is quite clear from looking at the slide that the combination of infliximab plus methotrexate is better than methotrexate alone at all of these clinical end points, ACR20, 50, and 70. In addition, if you would like a measurement of function—which is probably best measured in some form, in what is called the Health Assessment Questionnaire or the Mini-Health Assessment Questionnaire—again, it is obvious that infliximab plus methotrexate in 2 different doses of infliximab is superior to methotrexate alone in changing functional performance in patients with rheumatoid arthritis.
As we go down now in the right-hand corner, going clockwise, we can look at change in the DAS28 score, which is another clinical measurement tool used in disease assessment. You would like to have a very large change in DAS28 to signify the most improvement. As you can see, the combination of infliximab plus methotrexate is significantly better than methotrexate alone. Lastly, in the lower left-hand corner, we are looking at 3 measurements of radiographic or x-ray progression. Here you would like to have the least amount of progression in the total Van der Heijde score, and in the first figure, the combination of infliximab plus methotrexate is much better than methotrexate alone in preventing radiographic progression. That is also true for the individual components of erosion and joint space narrowing.
Although this kind of data was available for etanercept and adalimumab, it was the ASPIRE trial that looked at very early disease, which established the efficacy of the combination of a biologic—here infliximab, although it would be true for any anti-TNF plus methotrexate—is better than methotrexate alone. Extending that, that is also true for the biologic alone.
Slide 5: In the next slide, we are looking at a study with a different compound here, the PREMIER study, which looked at adalimumab plus methotrexate in early rheumatoid arthritis versus methotrexate alone or adalimumab alone. In this trial, we are going to look at the combination of adalimumab plus methotrexate versus methotrexate alone. I like this subanalysis even though, in general, I am not really a fan of post hoc subset analysis. This is a very interesting slide to demonstrate that, at every level of clinical activity, the combination of the anti-TNF—here adalimumab plus methotrexate—is better than methotrexate alone at preventing radiographic progression.
There are a small number of patients in this trial on methotrexate, for instance, who achieved an ACR70 score and there were more patients who achieved an ACR70 who received the combination of adalimumab plus methotrexate. Clinically, those 2 groups are virtually indistinguishable. There are more patients in the combination, fewer in the methotrexate, but clinically they look the same. Now, even though clinically they might look the same, if you look at radiographic scoring, those patients who received a combination have far less radiographic progression. That is true at the ACR20 level, the ACR15 level, the ACR50 to 70 level, the ACR70 to 100 level, and it is only at the ACR100 level where it is difficult to make that distinction.
On this slide, you are really looking at the power of the combination, not just to achieve a clinical response, but you get more for your money in the clinical response because you also get this radiographic progression. For each level of clinical response, you get more radiographic progression with the combination of the anti-TNF plus methotrexate. As I mentioned, there are a variety of studies that really look at the power of the combination of the biologic plus methotrexate, compared to either the biologic alone or methotrexate alone. I have shown you 2 very interesting examples of that.
Slide 6: As most of the clinicians out there know, there are certain subsets of patients who do not seem to respond to biologics. If you look at the ACR70 responses, or perhaps even the concept of remission, currently everybody receiving the combination of an anti-TNF plus methotrexate does not go into remission. In the past, I think there was not much choice out there about what to do in that situation. When we had our first 2 anti-TNF products, and then the third, if somebody did not respond there was a fair amount of enthusiasm for switching from one anti-TNF to another. Now we have several other biologics with different mechanisms of action, and I think we need to reevaluate this concept of switching amongst TNFs. There have been no head-to-head trials—nor do I really expect there to be—any head-to-head trials looking at whether or not we should switch or move to a compound with a different mechanism of action.
There have been several small studies and then some comments from the larger registries about what happens when we switch.
Slide 7: The next slide is from the British Society of Rheumatology Registry, and it looks at what happens to patients when we switch. I think this is very interesting, and I think it brings up another concept: how valuable some of these registries can be to answer some of these general questions. There are criticisms of registries, reasons for switching are not always clear, but this really is a fairly sophisticated registry that can answer fairly sophisticated questions. Looking at patients who started an anti-TNF therapy from 2001 to 2005, 496 did that because of loss of efficacy and 446 because of an adverse event. You have patients who are on one anti-TNF who switch to a second, either from loss of efficacy to the first or for an adverse event. They were switched, and then you look at what happens. I think it is very interesting in this particular registry that there was a 3-fold increase in loss of efficacy to the second TNF. In other words, once patients failed one, they were actually 3 times more likely to fail a second. It was similar, regardless of why you switched—loss of efficacy or an adverse event—because there was a 2- to 3-fold increase in adverse events. Once you did not respond to the first, you were more likely not to respond to the second. In the adverse events group, if you were going to switch because of an adverse event, you were far more likely to get an adverse event to the second. Again, this enthusiasm for switching needs to be tempered, because now we have some data available.
Slide 8: There are a number of questions to consider when you, as individual practitioners, think about switching between anti-TNF therapies. We have some questions here for you to consider. They are, what percentage of patients fail their first anti-TNF therapy? Is it as high as approximately 60%? And secondly, is improvement more marked when switching anti-TNF therapy due to primary treatment failure? In other words, patients are not getting a response. Then, is there an order for switching? Should we be switching from a soluble receptor to a monoclonal, or vice versa, and does that matter? Or really none of those, the way the data would suggest we should work. I think it is very interesting to consider those questions and then to be more specific.
Slide 9: Here is another question to consider. In a patient with RA who fails treatment with a second anti-TNF, is a third anti-TNF therapy or a newer biologic with an alternative mechanism of action the appropriate therapeutic option? Which do you do in your practice?
Slide 10: On this slide, I have made some comments on the number of small uncontrolled switching trials amongst the anti-TNFs. One oft-quoted study is the Hansen trial among others. Some of the trials listed here for you are: Gomez-Puerta, Combe study, and the Finckh trial. These studies are generally with less than 100 patients and tend to be observational, short-term, open-label, uncontrolled, and not randomized. As I mentioned, head-to-head studies are not available. Be careful about what they are measuring such as improvement in ACR and DAS responses. The responses have not been particularly robust. I think there have been comments, and we quoted one in the fourth bullet, “some patients with RA may respond to one anti-TNF agent, but not another, in what appears to be an idiosyncratic manner,” suggesting perhaps that there is no order yet. The next bullet is interesting. Some people feel in these small studies, an improvement might be more marked if switching is due to secondary failure or toxicity rather than primary treatment failure. I will give you the statistic that about 30% of patients from studies seem to fail the first anti-TNF. About half of those will fail the second, and about a third who switch to the third actually discontinue, again, because of loss of efficacy, as I showed you. I think there is enough data to suggest that each of the anti-TNFs in their own studies have been demonstrated to be efficacious, but which of them to use in which order remains very uncertain. At least that would be my take on these switch studies.
Slide 11: An example of the switch study that we can look at in more detail was the Bingham trial, which was published in the Annals of Rheumatic Disease in abstract form in 2005. This was a 16-week study looking at etanercept after infliximab. Again, you could look at either of these drugs in either order; this happened to look at etanercept after infliximab. They did make the distinction between the type 1 nonresponder who never responded or that type 2 who had an initial response to infliximab, but then lost it.
Slide 12: In the next slide details the EMBARK study results. The response to etanercept following infliximab treatment at week 16 does demonstrate that switching to etanercept may provide clinical benefit in a certain subset of patients. The ACR20 responses of 40%+ are interesting. The higher-order responses, 50 and 70, are not all that impressive. In this study, there is really no distinction between the type 1 nonresponder who never responded or the type 2 responder. This is an example of a small study, 84 patients, with switching in one direction that had some interesting conclusions that sort of fit with some of our hypotheses, but not necessarily all. This is sort of the state of the literature today.
Slide 13: In the next study by Dan Furst, also published in abstract form in the Annals, we are looking to infliximab after etanercept just to reverse the switch. Again, there are small switch studies for each of the anti-TNFs in each order. Here, though, for infliximab after etanercept, 27 patients really did not make a distinction between why they switched primary or secondary. But clearly, a subset of patients, 8 of 13, really did do fairly well after being switched. This is a little more interesting than some of the other studies because it is randomized and also open label. This is an example of yet another small switch study that demonstrates some benefit in some patients when you switch.
Slide 14: The next trial is the largest trial about switching. There are concerns here, though, about why patients were switched. This is the ReAct trial that really has thousands of patients in real-world practices in Europe. They talk about unsatisfactory response and some intolerance to one anti-TNF before they were switched to adalimumab.
Slide 15: The results from ReAct show that adalimumab did allow for some responses no matter where they had started, whether they had been etanercept first or infliximab first, whether they had not been on a biologic or on a biologic. A significant proportion of patients did achieve an ACR20 and in this study; a reasonable number achieved an ACR50 and an ACR70 response. It is clear from here that in this switch study—here adalimumab—may be effective in patients previously treated with other anti-TNF therapies. Again, it is rather open label, and there are some questions about why patients were switched, but it gives some basis for the concept of switch.
Slide 16: The STURE registry is really the next large registry to think about. This is the Swedish registry, last presented by Ron van Vollenhoven at the ACR in 2007 in Boston. He had looked at this previously, but now is up to 258 patients from his very sophisticated registry who were switched. Interestingly, patients who were switched from infliximab to etanercept seemed to do fairly well as well as patients who were switched from etanercept to infliximab. In this trial, it appears that switching, from the fusion receptor or etanercept to infliximab or from the monoclonal antibody infliximab to etanercept, may provide some additional therapeutic benefit. However, who exactly those patients are and how we can identify them remains uncertain.
Slide 17: The last 2 studies to consider really have to do with patients who were switched to other agents. We are looking at Keystone’s presentation at EULAR 2006 and the REFLEX trial, just the clinical results in patients who have previously failed an anti-TNF. Remember, this is a very much different group of patients. These are patients some of whom failed all 3 anti-TNFs before they were switched. This is a randomized, placebo-controlled trial. This is the piece of REFLEX that deserves some emphasis because this is clearly changing to an agent that has a different mechanism of action. If you do that, you are looking at fairly potent ACR20, 50, and 70 responses in this slide. In fact, this particular study does have radiographic end points as well. Even in patients who were switched to a drug with a different mechanism of action, they achieved a clinical response, but also some radiographic suppression even though they had failed the anti-TNF. We have known that about rituximab in this particular study. In a study I will show you shortly, we have known that clinically about abatacept, that this piece has the radiographic arm as well.
Slide 18: In the next slide, the MIRAR study just talks about the variables influencing treatment choices after you have failed an anti-TNF. This was an epidemiologic breakdown of a 452 RA patient cohort and really the question is, why are physicians thinking about switching to an alternative agent? Why would they consider another anti-TNF? Let us look at the conclusion; most of the patient-related clinical variables which would establish more active disease seemed to be most relevant in the decision to use the different mechanism of action, which in this study was rituximab instead of an anti-TNF. What I am trying to say is that patients who have been on a lot more DMARDs, patients who have had a lot more toxicity, will have a lot more extraarticular manifestations. Those who use more steroids, who use more analgesics, who have had longer and more active disease, when those patients do not respond dramatically to anti-TNF, those patients are a little more likely to be switched to drugs with a different mechanism of action.
Slide 19: Lastly, think about abatacept from the ATTAIN trial. This is the trial for abatacept in patients who had failed an anti-TNF with numbers very similar to the clinical responses we saw with the rituximab. This study did not have a radiographic arm reported with it, so we cannot talk about radiographic responses. Clinically, the patients responded. This section really could go on and on because this is where rheumatologists live currently. We are clearly dealing with very high expectations of these drugs now. Both we and our patients want dramatic clinical responses. The anti-TNF drugs have revolutionized treatments for patients with RA. What to do when they do not work remains a little bit uncertain. We have options and await even further data from some of the registries about whether or not to switch, when to switch, and to what. I think this continues to be a ripe area for discussion amongst rheumatologists today.
Slide 20: I would like to sort of change our focus and think about safety among biologics. If we are going to be using these drugs aggressively, clearly, we need to think about safety issues and we need to remain vigilant about them. The safety issues that I would like to consider include infection, malignancy, mortality, demyelination, and the new drama about progressive multifocal leukoencephalopathy, or PML.
Slide 21: Now for some questions to consider. Well, a patient with active RA has an opportunistic infection on methotrexate and low-dose prednisone. The infection is treated and resolved. Then the question is, is treatment with an anti-TNF contraindicated? Is it reasonable with standard precautions? Is it risky, but, if you follow them very closely, you might? Or is it very risky and should be avoided?
Slide 22: Then if you are willing to go on and treat in the same patient, which of the following treatment choices might be reasonable? That would be abatacept, or anakinra, or rituximab, or the first 2, or all of them.
Slide 23: Now in the last 2 years, there have been some very interesting studies looking at the risk of significant infection and malignancy in patients with anti-TNF therapy. I would like to start with the Bongartz study that was published in JAMA in 2006. This was a meta-analysis which has been oft criticized, and I have certainly done my share, because there have been some inconsistencies in which trials were concluded and the way malignancy was looked at. At any rate, I think it was a sincere sort of systematic review of these questions. The standard definition of serious infectious events was requiring antibiotics or hospitalization, and then all these associations are not necessarily cause and effect, as you know.
Slide 24: Bongartz reported a serious infection rate with an odds ratio of about 2, so increased over normal, and a malignancy odds ratio of 3.3. The 3.3 was compared to the control group, and there were questions about the control groups. Clearly, you can just take from this some feeling that there might be an increased risk of serious infectious events and malignancy and that risk is relatively small, but probably real.
Slide 25: : I think that sets up some of the other studies to evaluate this question, one of which was done by Askling in 2006, where he looked at the anti-TNF therapy and the risk of hospitalization for infection. Beyond serious infectious events, he is only looking at the patients who are hospitalized. A lot of patients in his Swedish registry were included, and I think it is very interesting to see that infections were increased significantly in this trial, specifically articular infections. Why should that be? I do not know, and respiratory infections I would have expected, but there is an all-over increased risk of about 1.39 even when adjusted for age, sex, and propensity. There is an increased risk in this database. That does not surprise us. The question is, is the risk manageable?
Slide 26: Listing, then, from the German database called RABBIT, looked at risk of infection and really concluded that there was not a very high risk. Look at the odds ratio. Again, the adjusted odds ratio did show a very slight infectious risk when compared to the control group of RA patients who had not received an anti-TNF. I would remind you, in these studies, you need to be very careful about what the comparative group is really doing. Here, there was a small increased risk again.
Slide 27: Yet, Jacobsson, from a different Swedish database on the next slide, really could not find an increased risk of serious infectious events. I think there probably is a slight risk. I think we need to think about it. We need to be vigilant about it. It does not—I can tell you from sort of careful review of this—necessarily appear to be increasing as we use these drugs more and more.
Slide 28: The next study by Curtis is a very interesting one from a database in the States that looks at serious bacterial infections in patients with anti-TNF. The conclusion here is that the risk is in the first 6 months of using the drug. I think that is very interesting. There is an increased risk of infection, but it is early when we initiate therapy and when our vigilance would be the highest.
Slide 29: In fact, in the data slide from the Curtis study, you note that there was actually a little difference between infliximab and etanercept in this trial. Though whether it is important is not really known, but clearly, I think the risk here is real, but early.
Slide 30: Then, I think if you look at postoperative risk, this time from the British database and Dixon, this is a very interesting trial with some interesting choices. The question was, when you can electively stop the anti-TNF, when should you do it? They chose 28 days, which I think is interesting. Then, when you are able to stop it, which is not always the case—you could do it for elective surgery, but not emergency surgery—is the risk of infection really reduced?
Slide 31: If you look at the data slide of this trial, there is no question that if you do not have the opportunity to stop it, there is a slight increased risk. If you can, then there was a 60% reduction in serious post-op infections. I think this data does support discontinuing anti-TNF therapies prior to surgery when the surgery is elective, to reduce that small, but real, risk.
Slide 32: The next slide is about abatacept and infections. If we look at hospitalized infections from their clinical development program, the risk of infection was very slightly increased, and actually has been stable over time. The risk with this particular drug, abatacept, even though it has a different mechanism of action from the anti-TNFs, the risk is quite similar to that seen with anti-TNF drugs.
Slide 33: If you look at the next slide about rituximab, again, I think you get the feeling that there is a small risk. In this study, looking at subsequent treatment courses of rituximab, it does not appear. Look at the serious infectious events per 100 patient-years. The reason you do that is because there are not equal patients receiving each course. If you normalize that by serious infection for 100 patient-years, the risk does not seem to be increased. It is higher probably and was higher than placebo, although placebo here was, remember, patients who had failed an anti-TNF on methotrexate, etc. That was the control group, higher than the control and not increasing the subsequent courses.
Slide 34: In order to extend the rituximab data a little bit, we have information from the presentations at ACR 2007 in Boston. Ron van Vollenhoven, again, presented the subsequent rituximab treatment serious infection data that we reviewed and Ron Genovese looked at immunoglobulin levels with repeated courses. There has been the observation that a significant number of patients reduce their immunoglobulin levels, particularly IgG and IgM, at some point after being given rituximab. There is no clear relationship between those patients who have had a low level and when they get their infection. What I am saying is there is no clear relationship between dropping in an individual patient between a drop at some point in time, dropping an immunoglobulin IgG or IgM and getting an infection.
Slide 35: Although the next slide, the last slide from the Genovese presentation, makes the suggestion that, in patients treated with repeated courses of rituximab who have a low level of IgG, perhaps that group of patients—if you were to measure that and if you were to know that—may have a slightly increased level of infection after the drop. In individual patients, there is really no clear relationship. As a group, perhaps that group is at a higher risk after they have dropped their IgG. I guess that brings up the question of whether we should be measuring immunoglobulin levels, which we are really not doing routinely now. The other thing is that there was no clear relationship between peripheral B-cell levels and getting an infection, which we had suspected previously.
Slide 36: Clearly, opportunistic infections like TB have been an issue for a while. Most practicing rheumatologists are screening almost all patients now for TB with an appropriate skin test and perhaps a chest radiograph. When you look at the original data from the FDA advisory meeting, back in 2003, regarding the incidence of tuberculosis, it appeared that the incidence might be slightly higher in the monoclonal antibody groups. That may or may not have held up. What we think is not that we need to screen carefully, but we need to treat those people who have positive studies to suggest prior exposure, that the interval between treatment and starting an anti-TNF probably does not have to be very long.
Slide 37: If you look at the next slide, there is just more and more data. This, again, from ACR in Boston, looks at what it means if you have a positive skin test and then you are treated with etanercept. These patients were at least partially treated for latent TB prior to the initiation of the anti-TNF, and they did fine. If you screen and you find risk, and you treat it with appropriate drugs, you can give them the anti-TNF and you can probably give it to them fairly quickly.
Slide 38: Switching gears, I would like to just make a couple of comments about the risk of cancer. Remember, the Bongartz analysis suggested that the risk of cancer was increased. I think we have probably been suspicious of that. What kind of cancer? Here, I think, we need to be very careful in whether or not we can attribute the risk of cancer to the drug or the disease. The first study in this presentation today was looking at the British database where we found the risk of lymphoma was increased in RA patients, not necessarily RA patients treated with anything specific. There was a slight risk of any malignancy, and the highest risk was lymphoma. Look at the lung cancer risk. RA patients, independent of treatments, seem to be at a higher risk for certain malignancies and that may be related to inflammatory load.
Slide 39: Fred Wolfe then looked at his very large database and tried to get at the question of whether lymphoma was related to the disease or the treatment. He concluded that there was no association of lymphoma with anti-TNF, that the lymphoma risk was related to the underlying disease and the inflammatory load not the treatment, and it would be fascinating to see in the future whether or not the risk of lymphoma can be reduced with anti-TNF drugs.
Slide 40: We have got a couple of slides by Askling in his very sophisticated presentation from EULAR this year, where he asked very specific questions from large databases in Sweden. This was very nicely done at the time, and I think his slides are very nice, as well, and I thank him for allowing us to use them. The first question, are overall cancer rates or certain types of cancer increased in RA patients alone? That was the first question, and they were, just like we had seen before. There was an increased cancer risk. That risk was not particularly related to the anti-TNF drugs in his database.
Slide 41: This slide looks at the RA cohort itself and it compares other large cohorts. He is commenting on Bongartz and Fred Wolfe’s work and here, it looks like there is no real association with anti-TNF except in the Bongartz database. It is hard to know what that difference it is attributed to except to analysis differences.
Slide 42: The next slide looks at whether overall cancer risks are increased in patients, specifically those patients treated with anti-TNF. Here you can clearly see that it is respiratory tract cancers with that risk of 1.29 that is most significant, as well as nonmelanoma skin cancers. Lung cancer and nonmelanoma skin cancers had the highest relative risk. He also makes the comment that breast cancer seemed to be reduced. I think that is fascinating. The risk of a second malignancy was a little higher than the first, and I think mining these kinds of databases over extended periods of time in the future will be very helpful at continuing to reassure us that the risk of malignancy in particular is small, and that we can be vigilant, but perhaps not as anxious as we might have been originally. I think these are very interesting studies.
Slide 43: The Greenberg trial looked at the CORRONA database and concluded that there really was not an increased cancer risk with short-term exposures to anti-TNF, and I think that is the key. These trials will have to be extended, because it is the long-term exposure that we are really ultimately interested in, we just do not have it yet.
Slide 44: If you look at the newer drugs, there is a question of malignancy, for instance, with abatacept. The Simon review, presented at the 2007 ACR meeting in Boston—although she originally did it at EULAR in Barcelona, but looking at registries where patients had been exposed to abatacept, there was really no significant increased risk of malignancy from abatacept. I think that was probably reassuring to a lot of us. For the first time, there was a list of malignancies after exposure to rituximab, but again, not higher than we would have predicted. Attributing cancers to the disease itself and/or the drugs continues to be an issue. I expect that over time, we will find that the risk is very small and we will probably learn to screen and answer questions about whether or not we can be comfortable discussing risk intelligently with our patients as we initiate these drugs and leave our patients on.
Slide 45: The cardiovascular risk has come up several times. Again, the cardiovascular risk in RA itself is known, and the question is whether anti-TNF drugs really lower by treating the inflammatory load, whether they can lower the risk of cardiovascular disease. In the Dixon trial, looking at MI and cardiovascular accidents, he probably did not have enough patients to look at the question seriously. Superficially, it appears that the anti-TNF drugs might reduce the risk, but the differences were not statistically significant yet. There was a hint in that direction and, in fact, there has been a hint from other databases as well, but we will have to wait for more sophisticated long-term trials.
Slide 46: Demyelination had been an issue as these drugs emerged on the market, particularly looking at the anti-TNF drugs. This stuff has not been reported with the other biologics with different mechanisms of action. With regards to demyelination, the number of cases has remained extremely small. I do not think we give these drugs to patients who clearly have or are at high risk for demyelination. This has been a relatively stable issue over time, and this slide just summarizes the small number of cases ever reported with these anti-TNF drugs.
Slide 47: And lastly, the question of PML has come up and there has been an FDA alert about this. There have been a couple of patients exposed to rituximab who developed PML. These patients did not have rheumatoid arthritis. In fact, there are no patients from the RA trials and yet no patients from the clinical practice of rituximab in RA where there has been any PML. In fact, the studies have been in lupus and in vasculitis and in patients with exposure to other immunosuppressants for the most part. PML is caused by a latent JC virus. It is present in a lot of adults. The true incidence of this in patients with autoimmune disease is not well known. Clearly, there is some feeling that patients are at risk for this and whether or not the drugs, the immunosuppressants, let alone the biologics, are allowing the development of neurologic disease remains uncertain. My conclusion would be that anybody on any of these drugs who develops neurologic signs and symptoms needs to be evaluated very carefully. Although, I would remind you that the approved uses for these drugs in RA has not been an issue.
Slide 48: Now to conclude, let’s go back to the efficacy with biologics. I would remind you that the biologics have been established in combination with methotrexate to be more effective than methotrexate alone. That is true for the anti-TNFs and for abatacept and rituximab, although they were studied in different groups of patients. This whole concept of switching, I think, is controversial. There is data that switching may be an effective alternative in some patients. It is perhaps emerging that patients who switch when they fail another biologic really might be able to do better, particularly if they were switched for toxicity rather than primary failure. Although, really, I think that is still controversial.
Slide 49: With regards to biologics and safety, I think the risks are known. I think they are small. I think they have been consistent. I think the infectious risks are real. We need to be vigilant, but I think these are controllable. Cardiovascular risks, it will be very interesting to see whether we can reduce that with aggressive therapy. The second bullet point on the safety conclusion slide is important. It says that the current literature suggests that our RA patients are at a greater a priori risk. That is dependent on disease duration, severity, presence of inflammation, and concomitant meds. Again, the next bullet, potential risks, are not, obviously, increasing. We have to always weigh the benefits, which are also substantial, versus the risks, which are now being sort of elucidated and are now calculable. I think the standard of care is that we monitor carefully, but treat aggressively.
