Choosing a Management Strategy in RA

Stephen Paget, MD: My name is Dr Stephen Paget. I'm the physician-in-chief emeritus at the Hospital for Special Surgery in New York City. This is Conversations With Experts.

Vivian Bykerk, MD: I'm Dr Vivian Bykerk, head of the Inflammatory Arthritis Center of Excellence here at the Hospital for Special Surgery.

Dr Paget: I wanted to give a little bit of background on the treatment of rheumatoid arthritis (RA) before we talk about the role of anti-tumor necrosis factor (TNF) agents plus methotrexate vs triple therapy, an important topic for today.

In the early 1950s, nonsteroidal anti-inflammatories were available, and a Nobel Prize was won for the use of steroids in the treatment of RA as well as rheumatic fever. They knew very quickly that steroids were a double-edged sword and kind of a "deal with the devil," because they were effective but had a lot of side effects. Then we used gold, penicillamine, and eventually methotrexate, which has really had a profound effect upon RA outcomes. Subsequently, anti-TNF medications were developed and are now in our armamentarium. They have given an extra boost in the treatment of this inflammatory systemic disease.

Defining Disease Modification

Dr Paget: Today, I'm going to talk with Vivian specifically about the near battle between the use of the anti-TNF and methotrexate combination versus triple therapy, which includes sulfasalazine, hydroxychloroquine, and methotrexate. First, I'd like to ask Vivian to talk about what disease modification in RA means to her.

Dr Bykerk: It's a great question, Steve. To most people, I think modification means that the disease course is altered for the better; that there will not be damage, progression of erosions, or more joint space narrowing; and that function will be maintained. However, modification may mean that you can actually improve the chance of even getting into sustained drug-free remission if you treat early enough, within 3 months.

Dr Paget: Where do comorbidities fit into the concept of disease modification?

Dr Bykerk: I think of comorbidities in two ways. First, comorbidities influence your choice of therapies in the sense that people tend to worry about them and may undertreat the patient in the wrong way because of this perceived risk. They'll use more steroids, which ironically increases comorbidities. If you think about cardiovascular comorbidity, which is a big one we worry about, if you treat the disease very effectively with our current armamentarium, you reduce the risk. You reduce the chance of having inflammatory disease of your vessels and other factors that end up causing cardiovascular comorbidities.

Secondly, we tend to see most infectious risks occurring in the first 3 months of treatment, which many studies show. Then that risk goes away, which suggests that actually treating the disease reduces the risk for infections versus the medications themselves. I think that people are starting to rethink comorbidities in the concept of using therapy.

Dr Paget: Do you think that premature cardiovascular disease is an extra-articular manifestation of RA?

Dr Bykerk: The studies are starting to suggest that. The highest risk of having a myocardial infarction in somebody who has RA is when they were just diagnosed.

Factors for Determining the Best Therapeutic Approach

Dr Paget: I'd like to move on to this concept of which is the best therapy. If a patient came to you who had RA for 1, 2, or 3 years; they have been on methotrexate in full doses, either orally or subcutaneously weekly; and they're not achieving a remission by any criteria—what do you then choose? Could you give us a little bit of an idea of how you make that choice on behalf of the patient?

Dr Bykerk: Four things come to mind. First of all, we still treat to target. I believe that the target should still be remission, if it's possible. There are plenty of data that show that patients who are in remission have better long-term function and less cardiovascular disease. Overall remission is the first place to go, and I explain that to the patient.

Secondly, what is the patient's risk tolerance? In other words, they have to agree to what they're going to take because if they don't, they're not going to take it. So adherence and patient preference come into play. Part of that is also what they can afford.

Thirdly, I would ideally add a biologic. If they hadn't been taking methotrexate well and perhaps had been underdosed but tolerated it fine, I would probably recommend methotrexate 25 mg/mL subcutaneously as an interim measure before adding a biologic because sometimes that really does work. Those situations are rare because most people are taking enough methotrexate. The question is whether we should go to triple therapy before we go to a biologic, and I personally think the answer is "no" to that if the methotrexate has been appropriately maxed out. There are no data that have looked at methotrexate 20-25 mg/mL subcutaneously versus triple therapy, which is something we're looking at now. When it comes to the added benefit of using sulfasalazine and hydroxychloroquine versus adding an anti-TNF, I think there's no contest.

The last issue is: You're asking people to take another six pills a day versus a single shot every 1 or 2 weeks, or even once a month. Again, it comes down to adherence; the patient has to take it, and no drug works if you don't use it.

Dr Paget: What about cost? This is an issue that comes up all the time. Insurance companies are almost defining which drugs they want. There are sufficient randomized controlled trials that have appeared in major journals supporting the use of triple therapy. I would imagine that costs much less than anti-TNF and methotrexate.

Dr Bykerk: I don't think that people have shown in long-standing disease that adding sulfasalazine and hydroxychloroquine is cost-effective. To be cost-effective, you have to improve quality of life and the quality-adjusted life years. Well, you don't improve quality of life hugely by adding six more pills that add another maybe 10% benefit. If you add another 30% benefit, and people are now able to work, to do their hobbies, then they're going to report way higher quality of life, and the quality-adjusted life years are going to be better.

It's a completely different situation in early RA. If you take someone with early RA, and you optimally treat them with disease-modifying antirheumatic drugs (DMARDs), you have a 30% chance of getting them in remission very quickly. You have a 60% chance of getting them in remission by 1 year. If you were to start a biologic at the beginning, you have an 80% chance of getting them into remission at 1 year. I think the insurance companies are willing to take that gamble and say, okay, let's try the DMARDs first because we've got pretty good odds of getting people into remission with just them.

If we treat our patients to target, and they aren't getting a good response by the first 3 months, then we have to seriously consider altering the approach, whether it's going from triple therapy to a biologic or something else. For example, let's equate methotrexate 25 mg/mL subcutaneously with triple therapy because I suspect they're pretty similar. If by 3 months you haven't seen somebody drop in their Charlson-Deyo Index by 5-10 points, or in their Disease Activity Score 28 by at least 1.2 points, you have to wonder if they're actually going to be a responder and at that point start thinking about a change in course.

Dr Paget: You brought up some interesting points about who values what. If you bring the societal and personal point of view into this, there's an economic benefit to being able to go back to work—not for the insurance company but for society. There's also the consideration about the need for surgery or someone's functional problems. Those need to be factored into it as well, don't they?

Dr Bykerk: I think so, and I actually disagree. If someone is not going to work, that is relevant to the insurance company, it's just a different department. It's siloed, so whoever is making the treatment decisions is not the person who's concerned that this patient will be on long-term disability.

It depends on their education level. If they have a higher education, they may have a more sedentary job and are less likely to lose work. If they have a lower education, they may have a more physical job and be more likely to lose work.

Future Treatment Approaches

Dr Paget: You're very much involved in RA research and have pushed the field wonderfully. Where are we going from here? What are newer medications doing to the outcome of the disease?

Dr Bykerk: As you know, we have blockers and costimulation, medications that reduce IL-6 and B cells, Janus kinase inhibitors, and perhaps in the future medications that will affect epigenetic changes.

I think what's going to happen is that we are going to try to figure out immunologically what is the best strategy to achieve drug-free remission if you treat early. Early diagnosis followed by early initial—some say aggressive, I would say optimal—treatment to get people into a great state of remission by as early as 6 months if not a year, and then trying for at least mostly drug-free remission. I think that is the way of the future.

My suspicion is that all of our medications could help achieve that, but it's quite possible that using an approach higher up in the immunologic food chain where the disease is being driven will be more effective in getting people into drug-free remission down the line. The AVERT study,^[1] which was something we would never do in practice, nonetheless showed some interesting results.

Patients received methotrexate, abatacept, and some were on steroids. They were treated for a year. Everyone with low disease activity had all drugs stopped within a month, and the only people who were able to successfully remain drug-free were those on the abatacept-plus-methotrexate combination, and there are some reasons for that. Secondly, if you were treated within 3 months, your chance of being drug-free 18 months later was 30%, which is higher than we've ever seen.

Dr Paget: This drug-free concept obviously is important, not only for the patient's life and cost but also the ability to stop a drug that has potential side effects.

Dr Bykerk: Exactly.

Dr Paget: What about in the setting of anti-TNFs? Is it a similar concept, with an early approach possibly giving you the ability to get off of all medicines?

Dr Bykerk: We haven't done that same study with the anti-TNFs. We have seen, though, in early disease if you add an anti-TNF plus methotrexate, if you're in remission at a year, you can drop the dose. In many patients, you can even leave the methotrexate and take the anti-TNF away. You can't stop everything. Only 40% of people can stop a TNF inhibitor completely, but about 60%-80% can drop the dose. That's already a cost savings and probably a risk savings as well, although people are still concerned that they have to maintain a biologic like an anti-TNF.

Dr Paget: What role do you think the biosimilars will play in this $40-$50 billion industry?

Dr Bykerk: The biosimilars will trump the regular medications. However, our regular medications will become biosimilars, so they'll just drop the price and stop marketing it. It's sort of like Abbott Laboratories making Synthroid® as an L-thyroxine. They're going to come in there with it, and as long as they're truly biosimilar, it doesn't matter from a cost perspective or from the patients' perspective.

I worry about a couple things. I don't think we should be interchanging biosimilars. I think there's a chance of immunogenicity and confusing what's going on because if the patients flare between them, we won't know. I don't have a problem with biosimilars, but pick one and keep on it from the beginning. Don't change. Whatever you start, you continue.

Dr Paget: Do you think the insurance companies will mandate it because it costs less?

Dr Bykerk: They'll mandate what costs less, so it doesn't matter if it's biosimilar. We already see that there are deals being made with pharma and the payers. Some payers have made a deal with one company; other payers have made a deal with a different company. I don't even talk to a patient yet about which one I'm going to start because I don't know yet what insurance company they have and which drug they're going to tell me to use. Is it going to be adalimumab, etanercept, certolizumab? They're all different. Every insurance company will let me start a different one, and quite frankly, I don’t care. They all work.

Dr Paget: If you push to target.

Dr Bykerk: Yes. That's the key.

Dr Paget: Thank you so much. This has been a wonderful discussion. And thank you for coming to this Conversations With Experts.