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Professor Moots talks about the limitations of anti-TNF therapy.
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I think the other thing that's important to bear in mind is what your expectation of a response would be. I've mentioned about how good these biologic drugs can be, but it's important to bear in mind that they don't work for everybody, and also what they do is to suppress inflammation. And we must remember that rheumatoid arthritis can cause problems in a variety of ways. First of all, the pain and the stiffness that patients get can be due to the inflammation, and if we suppress the inflammation this will help get rid of those symptoms, reduce the pain and the stiffness. But on the other hand, patients with rheumatoid arthritis can get pain because the joints have been damaged. What we can't do at the moment is reverse damage. So if you have bad rheumatoid, you've got very damaged joints and there isn't much inflammation going on, you will not really expect to receive much benefit from a biologic drug. And I think these drugs are best given earlier on to try and prevent damage. But on the other hand, it's often hard to tell whether your pain is due to inflammation or damage. In some situations it's a matter of waiting and seeing how much better you can get with a drug. But I think it's always important to bear in mind that one of these new biologic drugs, like any drug to treat rheumatoid arthritis, may really have no effect at all. |
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Professor Robert Moots explains about biologic treatments for rheumatoid arthritis.
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I'm Robert Moots. I'm Professor of Rheumatology at the University of Liverpool and a consultant rheumatologist. I'm going to talk with you now about biologic treatments for rheumatoid arthritis. And there's a group of drugs that have been developed really as designer drugs, particularly to inhibit certain parts of the process that cause inflammation, and that's what causes rheumatoid arthritis. First of all, we have to remember that before the biologic drugs, all of the drugs that we used to treat rheumatoid arthritis, we really didn't fully understand why they worked. We know that they could help disease, but we didn't really know fully why. And also because in many ways they're crude drugs, they also had lots of potential side effects.
Over recent years however we've learnt much more about what causes rheumatoid arthritis, and as we've learnt these things we've been able to design new drugs that specifically inhibit important parts of the pathways that cause the inflammation. The first drugs that were developed in this way were the TNF alpha blockers. TNF stands for tumour necrosis factor, and this is an important chemical that causes inflammation and is particularly high in rheumatoid arthritis. What we learnt is that if we inhibit this chemical, patients get better. And there are three drugs that are available at the moment that do this. First of all infliximab, then etanercept and adalimumab. So they're very complicated names, but the bottom line is that they neutralise this inflammation chemical and this can help get people better.
So let's consider these individually. First of all infliximab. This is a protein like the others, but an antibody. And the antibody is made up of a tiny fragment of part of a mouse antibody coupled to a human antibody. And this drug is given by intravenous infusion. So patients have to go in and have a drip gradually going though into the vein over a period of a few hours. And once patients are stable on this treatment, the drug is given every eight weeks. The other drug, adalimumab, is also an antibody, but it's a fully human antibody and therefore people are a bit less prone to develop an intolerance to it, which I'll explain in a minute. The third drug, etanercept, also a protein, is coupled, is a human antibody coupled to the natural receptor for TNF alpha. So adalimumab and etanercept are actually given by the patient as an injection under the skin, a subcutaneous injection. Etanercept is given once a week, and adalimumab is given once a fortnight.
These drugs are also known by their trade names. Infliximab is also known as Remicade. Adalimumab as Humira, which is much easier to pronounce. And etanercept is also known as Enbrel. We know that all three of these TNF blockers work very well. In fact these have become the gold standard for treating rheumatoid arthritis because they give the best results. However, it's important to know that not everybody with rheumatoid arthritis needs a TNF alpha blocker. Patients with milder disease can do perfectly well on simple drugs. And at the moment in the United Kingdom we have to reserve the TNF blockers for people who have got bad disease and who have also not responded to the simple drugs, including methotrexate. But if you're in that situation, you're not responding to the simple drugs and you do have bad disease, then you will be eligible to have this treatment. TNF blockers are given by rheumatologists, and it's important that their delivery is supervised by a rheumatologist from a hospital.
As I've mentioned, these drugs give the best chance of responding if your disease is bad. But also, like any drug, there is always a risk of a side effect. The side effects that we know about which are likely in some patients on a TNF blocker really involve infections. So like almost any treatment for rheumatoid arthritis, the TNF blockers can weaken your resistance to infection and make it a little bit more likely that you will get an infection. However, this doesn't need to be bad. The important thing to remember is, if you do have an infection, it might mean you need antibiotics a bit sooner than normal. And also if you have an infection, it's sensible to temporarily stop the drug and then start it up again when that's finished. In addition to infections, the patients that have adalimumab/Humira or etanercept/Enbrel are prone to get a little rash around the injection site. But this is nothing to worry about because it will usually go after a few injections. Otherwise we tend to be concerned that taking these drugs might increase somebody's risk of developing a cancer. That's a theoretical chance, because we know that the chemical these drugs suppress, TNF alpha, can sometimes be involved in killing cancer cells. On the other hand, we've now looked at these drugs in hundreds of thousands of patients over the last ten years, and it's very reassuring that although some patients on these drugs develop cancers, it's no more frequent than anybody else who has a risk of developing a cancer but isn't on a TNF blocker. So although there's a theoretical risk, in real life this does not seem to be a problem, certainly for a period of ten years. And it's important to know that there's always going to be patients who've been on these drugs for at least ten years longer, if you're just about to start it. And if there were any worries, we're looking very carefully to look for side effects and we'll be able to pick this up. But certainly at the moment the key issue tends to be a slightly increased risk of an infection. Which again isn't a problem for most patients, but something to be aware of.
TNF blockers have made a big improvement to the way we can treat rheumatoid arthritis. Particularly if somebody's on treatment with a TNF blocker, it tends to stop the gradual destruction of bones and joints that can otherwise occur. And I think this is really important. But as I mentioned earlier, TNF blockers are not necessary for everybody. A lot of patients will not have the bad disease that need these drugs. On the other hand, some patients that have a TNF blocker ultimately don't respond to it. We tend to find that about two-thirds of patients that have a TNF blocker will improve and get better. But that also means that a third of patients don't respond. And the important thing is to consider what we can do if somebody has got bad rheumatoid arthritis but they don't respond to a TNF blocker. We now have a number of choices. And that's very important because we can still help people like that. The first choice is if you have a TNF blocker and if it isn't working, we'll swap to one of the other blockers. We have three drugs, and if you try one and it doesn't work, we'll try another one and there's a good chance that it will then work for you. |
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Professor Robert Moots discusses a new drug called rituximab (Mabthera).
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But if another TNF blocker doesn't work, we now have a new drug called rituximab, or Mabthera, which can be very helpful in this situation. I'm going to say a little bit about rituximab now.
Rituximab is a protein. In fact it's an antibody that's delivered by an intravenous drip. This drug was first discovered or developed to treat patients with forms of leukaemia or lymphoma, because the drug works by depleting or killing a certain type of white blood cell. What we've learnt subsequently is that these white cells that rituximab depletes are also important in causing rheumatoid arthritis. So if we deplete these cells, the idea is that the arthritis gets better. And clinical trials have shown quite clearly that this is indeed the case. In fact, what's even more important is that we know that rituximab or Mabthera can be very effective even in patients that have tried and not responded to a TNF blocker. So there's a very important place for this drug. And on the whole we tend to use it for people that have got bad disease, that have tried a TNF blocker and haven't responded.
Now rituximab/Mabthera is given by two intravenous infusions. And that means coming into hospital, usually for a day case, but sometimes to stay overnight, to have a slow infusion of the drug. You can then go home, and then two weeks later come back for your second infusion, which can actually be given much faster than the first one. When patients have had a cycle, and that means two infusions of rituximab, there can be a beneficial effect that can last as long as a year. And some patients can actually go into remission or at least get a lot better and without any other treatment stay well for up to a year. But the usual time for people to respond is approximately about six months. And then if your disease starts to come back again, as is usually the case, the cycle of rituximab can be repeated. And this can go on through a number of cycles. Have the infusions, improve, flare up, and then have the two infusions again. And clearly there's a big advantage in getting better without drugs after a single cycle and then having that cycle repeated.
Now there are some potential issues with rituximab. We know that it works well. It doesn't work well in everybody, like any drug, but it can work well in a lot of people. The types of problems people can get with rituximab are short-term and longer-term problems. In the short term a few patients can develop reactions to the drug, so there can be a nasty allergic reaction during the infusion. And that's why it's important to have this drug in a hospital, where doctors and nurses can help stop that reaction if it happens. Otherwise, patients on rituximab in the long term may be a little bit more susceptible to infections, just like we find in patients with almost any other drug used to treat rheumatoid arthritis. But the benefits I think are actually very high, because in patients that fail on a TNF blocker it's difficult to find other drugs that are likely to be effective, and rituximab can be highly effective in these patients. Also the risk of a side effect is actually very low. And I think this is something that we give now to lots of patients with rheumatoid arthritis, and we're finding that we're getting very good responses. So this is an extra weapon we've got in our armament of drugs to fight the disease. |
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Professor Robert Moots advices and informs about biologic drugs and pregnancy.
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It's very important that we think about how these biologic drugs can have an impact on our lives. I think the important thing to remember is that rheumatoid arthritis is much more common in women, and in many women pregnancy is clearly an issue to consider. Obviously if one wishes to get pregnant and to go through pregnancy, the absolutely safest way is to not be on any drugs at all. On the other hand, we know that bad rheumatoid arthritis can make it very hard to become pregnant. And there's a variety of reasons for this. So it's important to consider how we might manage pregnancy in patients with bad rheumatoid arthritis, and the biologic drugs can be very helpful for this.
First of all, if a woman wants to become pregnant it's important to get the disease as well controlled as possible. And this might involve using a TNF blocker. Once the disease has become well controlled, then it's probably safe to try and get pregnant. But clearly during the pregnancy we want to try and avoid taking drugs where possible. So we tend not to recommend having a TNF blocker during pregnancy. But on the other hand, there are many women that have got pregnant on a TNF blocker and who've ended up staying on the drug through pregnancy without any problems either to them or to the baby. So whilst we think it probably will end up to be okay staying on these drugs through pregnancy, it's clearly premature to say that it really is safe. So we would recommend that you'd stop the drug either as soon as you realised you'd got pregnant or ideally just before you conceived. If you end up getting pregnant whilst taking it, then clearly it's important you discuss this with your rheumatologist.
For rituximab it's probably a similar situation. But as we don't have quite the same experience we would tend to recommend that women don't get pregnant when they've had a cycle of this until it's washed out of the system. I think the other thing that's very important to remember is that all of the biologic drugs work even better when they're given together with methotrexate. Now methotrexate is a drug that we clearly want to avoid in pregnancy. So that's another reason why if you're wishing to get pregnant it's important to think about in advance, and I think ideally to plan this with advice from your rheumatologist, who'll be in a good position to help you. |
