by Nancy Walsh Senior Staff Writer, MedPage Today: Dimitrios A. Pappas, MD, of Columbia University and the Corrona registry, talked to MedPage Today about a recent study evaluating whether or not the use of glucocorticoids influenced the time to initiating biologic therapy among patients with rheumatoid arthritis. This was published online in a special supplement to Arthritis & Rheumatology.
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Following is a transcript of his remarks:
The rationale for investigating what is the relationship between the dose of steroids and the time to initiate a biologic was the following. Steroids may make people feel better with rheumatoid arthritis. The pain goes away, inflammation decreases, and these may reassure the physician that the patient is doing well. So as a result, if a patient is on steroids, the disease activity is better controlled and this may delay the time to initiate the biologic.
So we want to see what is the relationship. Are high steroid doses delaying the initiation of a biologic, or are the higher steroid doses making the patient and the physician get on a biologic earlier?
So PQRS [Physician Quality Reporting System] mandates that if a patient is on more than 10 mg of prednisone, then a documentation of a plan should exist in the patient's chart, right? So this may be a problem for the physician to remember that the patient is on a moderate or high dose of steroids, and do something about that. But as I said, on the other hand, patients on steroids are doing better and this may delay the initiation of another medication such as a biologic agent.
The PQRS mandates that if a patient is on more, on 10mg of prednisone or more, then a plan about the management of steroids should be documented in the patient's chart. So physicians, rheumatologists, now have to be compliant about that. Every patient with 10 mg of prednisone or more should have a plan about decreasing the prednisone or doing something about the disease activity that necessitates such a moderate dose of steroids.
For this study, we used the Corrona registry. As you may know, the Corrona registry stands for Consortium of Rheumatology Researchers of North America. We have been following patients since 2001. Over this more than 10 years of follow-up in the registry, more than 40,000 patients have been enrolled and are being followed. More than 600 rheumatologists participate across the United States in more than 100 rheumatology practices. So as you can realize, with more than 40,000 patients enrolled in the registry, we can identify the patient phenotypes we're interested in.
For this particular study, we wanted to focus on patients who are ... who have early rheumatoid arthritis, who are biologic naive, and who have tried at least one conventional synthetic DMARD. Then we took this patient cohort and we followed up for 24 months. We tried to identify patients, on higher, or moderate, or a lower dose of steroids, and we wanted to see whether the time to initiation of a biologic differs.
So the population for this study, following the exclusion and inclusion criteria, was around 2,000 patients. The majority of them, as it happens in patients with rheumatoid arthritis, more than 60% were females. Average ages, if I remember well, was around 40-50 years old, and the duration of rheumatoid arthritis was less than one year because this was one of the inclusion criteria we used. 60% approximately of the patients were seropositive, for 63% it was rheumatoid factor (RF), and all of them had to have used at least one conventional, synthetic DMARD before they were included in the study.
We had patients with moderate and high disease activity, and some of them were also on low disease activity. We shouldn't forget that these patients were already ... some of these patients were already on steroids, so the fact that they were low disease activity or remission could be due to the fact that they were using prednisone.
The Clinical Disease Activity Index (CDAI) is a metric ... is a tool to evaluate how active rheumatoid arthritis is for every single patient. So in order to calculate that, we count the number of joints that are swollen. You know, rheumatoid arthritis causes swollen joints and painful joints, plus the number of joints that are tender. Plus, we're using a visual analog scale to calculate how active the disease is in the physician's impression, in the physician's mind, and the same for the patient, how active the disease is in the patient's opinion. So we add all of those together, and there are cutoffs, right? For the CDAI, the Clinical Disease Activity Index, more than 10 means moderate disease activity. Less than 10 means low disease activity. Less than 2.6 means remission, for example.
It's getting more and more frequent and the habit for rheumatologists in the United States, and elsewhere as well, to use these tools every time we evaluate the patient. You may be familiar with the treat-to-target guidelines that entail that every patient should be evaluated very frequently until disease activity has reached the low level of disease activity or remission, right? So as long as the patient doesn't reach that, we should do something.
In the center of this here is that the fact that we have to use a tool to evaluate disease activity, and one of the tools that can be used is the Clinical Disease Activity Index. What is good about the Clinical Disease Activity Index or CDAI? It's that you don't need any inflammatory marker to calculate it, right? It's just the physician and the patient. So you don't have to wait for the laboratory to send you back the results of the sed rate or for CRP. Okay? So you can calculate that at the time of the visit and you can make decisions about further therapy.
There is literature showing that CDAI, RAPID-3, DAS28, any metric that a rheumatologist can use is equivalent in helping the rheumatologist and the physician, and the patient, to reach their common goal, which is put the disease under control.
Within all 2,000 patients, approximately 800 of them had to be on steroids. Some of them were on a low dose of steroids, less than 4 mg. Some of them who are on a higher dose of steroids, more than 10 mg, up to 20, 30, 40 or more, and we followed these patients for 24 months. So the majority of patients who needed a higher dose of steroids start the biologic agent earlier. The majority of the patients who need the lower dose of steroids start the biologic agent later.
In other words, patients who need a higher dose of steroids start a biologic agent earlier. What this means? That the rheumatologists are doing what they're supposed to do, so they don't forget the patients on steroids for long periods of time. Steroids are great medications. They can help us put the disease under control. They can help us bridge the therapy ... you know, we can use steroids for a couple of months until methotrexate or biologic agents start to work. The biologic agents and methotrexate and the other conventional DMARDs do not start to work ... do not start working immediately, so we need something in the meanwhile.
In summary, patients, the physicians did what they were expected to do, overall. So, yes. They stayed on steroids without starting a biologic. For example, in the patients who are ... in the patient cohort who were taking the higher dose of steroids, 60% of them started the biologic agent in the 24 months we followed the patients. So another 40% did not start the biologic. Similar results we've had for patients on lower dose of steroids. So, yes. There is a fraction of patients that could have been managed in a better way. That's true.
The other 60% or more started biologic relatively early. So we could have investigated whether patients who didn't start the biologic had any contraindication to start a biologic. This was not part of the study, but that's a good question. Perhaps these patients, when they started biologic, had a contraindication. Perhaps, they had a serious infection. Perhaps they had a recent malignancy that could have contraindicate. Perhaps, they were planning ... they were females planning a pregnancy. Perhaps they were pregnant females, and rheumatoid arthritis is doing better during pregnancy. All this could be possible explanations, but we need to investigate that as part of this study. Yes.
Strengths and Limitations
The strength of the study was that we were able to identify the phenotype of patients we were interested in. So we wanted to find a lot of patients who were naive to biologics, who had early rheumatoid arthritis – less than 1 year since diagnosis -- who had used one or more conventional study DMARDs, and who were able to identify more than 2,000 patients among the pool of 40,000 patients that have been enrolled in Corrona. And we wanted these patients to have been diagnosed with rheumatoid arthritis after 2008. Corrona has been around since 2001. Among 40,000 patients, more than 40,000 patients, we were able to identify 2,000 patients with the specific phenotype we were interested in.
We wanted these patients to have at least 2 years of follow-up in Corrona. So that was the strength. The large pool of patients enabled us to identify the patients who we were interested in without relaxing the criteria we wanted at the beginning of the study.
What does this mean? So in a sense, this means that if you have such a large pool of patients, it's easier to identify patient cohorts you're interested in, patient cohorts that are more relevant to what's happened in real life. Okay?
The limitation of the study was that we didn't look, for example, what was the reason some patients did not start the biologic? We didn't look for contraindications. What was the reason some patients delayed the initiation of the biologic? That's the next step in this study. That's one of the next steps in this study.
The other implication of this study is that patients still need steroids. Disease-modifying medications we're using, the conventional synthetic DMARDs and the biologics take a while before they start working. You can never know if the patient is going to respond to one of those medications. So we do need steroids to manage the patients at the beginning of the disease. There are also studies that show that people who take steroids after diagnosis and until the disease modifying, then they start working, they do better in the long term. They have fewer erosions in their joints.
But steroids, on the other hand, are associated with adverse events. They increase the blood sugar levels. They may cause osteoporosis. They suppress the immune systems, perhaps a little more, compared to the disease-modifying agents. So we should have in mind that if we can have a patient on as low dose of steroids as possible, or even zero mg of steroids, then we shouldn't forget to deal with that. There should be a plan about increasing the steroids or even taking the patient off steroids. I think the recent guidelines say that up to 10 mg prednisone for up to 3 months, it's an acceptable solution for patients who need such dose of steroids. I would agree with that, but I think it will be ideal if the fewer possible number of patients stayed on the lower possible dose of steroids for the shorter period of time.
More About Corrona
So Corrona stands for Consortium of Rheumatology Researchers of North America [and] has been around since 2001. It enrolls patients ... it started with the enrollment of patients with rheumatoid arthritis across the United States, more than 40 sites, approximately 150 rheumatology practices – academic and private – more than 600 participating rheumatologists.
So what happens in Corrona is that we use questionnaires for the physician and questionnaires for the patient, and every time that the patient comes in for a regular clinical encounter, the physician and the patient fill out these questionnaires. The thing [is] that these questions are five, or six, or seven pages long. So I would say that we have a very good description of the disease at very specific time points for these patients.
The other is [that] the median time of follow-up for these patients is approximately 5 years. In other words, approximately all of our patients have been followed for 5 years. That's the other example. That's the median number of follow-ups. This has enabled us to publish a lot of articles in the high-tier medical journals and be present in every international meeting. The EULAR in Europe and the ACR here in the United States.
We ... I think we have generated breakthrough knowledge about the disease, about its phenotype, about the adverse events associated with medications, about the comorbidities associated with rheumatoid arthritis, about what's the best way to manage these patients. Academic rheumatologists, world authorities in rheumatoid arthritis participated in the board of Corrona and participate in our publications as well. We have a large team of epidemiologists, biostaticians, and support groups. I think the secret of success of Corrona is the relationship we have with every rheumatology practice in the United States.
Over the years, we have expanded to other diseases: spondyloarthropathies, psoriasis. We had the registry about gout. We're preparing the registry, so now they're doing autoimmune diseases as well.
The study was sponsored by Corrona, LLC., which has been supported by AbbVie, Amgen, Bristol-Myers Squibb, Crescendo, Eli Lilly, Genentch, GlaxoSmithKline, Horizon Pharma USA, Janssen, Momenta, Novartis, Pfizer, Roche, and UCB.
The authors reported financial relatioships with Corrona, Novartis, Axio Research, AbbVie, Amgen, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Medimmune, Pfizer, and Sanofi.
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Arthritis & Rheumatology
Source Reference: Pappas D, et al "Time to initiation of biologic agents is associated with glucocorticoid use: results from the Corrona registry" Arthritis Rheum 2016; poster 2597.