Diagnostic Criteria, CV Risk, and New Treatments: The Latest in RA

Introduction

Jonathan Kay, MD: Hello. I am Dr. Jonathan Kay, Professor of Medicine at the University of Massachusetts Medical School and Director of Clinical Research in the Division of Rheumatology at University of Massachusetts Memorial Medical Center, both in Worcester, Massachusetts. Welcome to this Medscape Peer-to- Peer session from the European League Against Rheumatism's (EULAR) 2011 Annual Scientific Congress in London in which we will discussing highlights about rheumatoid arthritis (RA) from this year's meeting. I am here today with Dr. Joseph Markenson, Professor of Clinical Medicine at Weill Cornell Medical College in New York City and attending physician at the Hospital for Special Surgery, also in New York. Welcome, Joe.

Joseph A. Markenson, MD: Thanks, Jon.

Dr. Kay: We are going to cover some topics about monitoring patients with inflammatory arthritis for cardiovascular (CV) risk factors, [we will] look at the new American College of Rheumatology (ACR)/EULAR diagnostic and classification criteria for RA, [we will] talk about signaling pathways in RA, and [we will] discuss some new data about the Janus kinase 3 (JAK 3) inhibitor tofacitinib. Dr. Markenson, in terms of new data in RA at this Congress, what has struck you as being most interesting or important?

CV Risk: The Rheumatologist's Responsibility?

Dr. Markenson: Some things are new, and some things we have expanded on with new information, and the topics are very interesting. The first abstract I want to talk about is titled "Are we monitoring patients with inflammatory arthritis for cardiovascular risk factors?"^[1] CV risk factors are very important in our treatment, and the question comes up, "Are we doing it and should we be doing it?" This abstract was authored by Dr. Nandagudi and Dr. Viner and others. The objective was to determine the appropriate monitoring of CV risk factors for patients with inflammatory arthritis.

It was a retrospective audit of 125 consecutive patients with inflammatory arthritis in the rheumatology department within a 2-week period. Investigators simply asked the question: Did the patient have a yearly cholesterol test and biannual blood pressure monitoring? They found that cholesterol was checked yearly in about 50% of the patients. Very high cholesterol was found in 21 of those patients, 5 of whom were actually treated with statins. For blood pressure, 80% had their blood pressure checked in the clinic.

I know that my nurse takes the patient's blood pressure right away, but oddly enough, only 50% of patients had a biannual check and 27% had blood pressures above 130/80, but in only 14 patients was action taken. Obviously, in our group the big debate is, do we go back to being internists? What is your relationship with your primary care [provider (PCP)]? We really have to take hold and be the providers who at least recognize that this is a problem. We are interested in reducing all kinds of CV risk factors, and we know that risk is reduced as we decrease inflammation, but somebody needs to bring it to light and do it. This abstract, which is very interesting, looked at the last 2 weeks, and found data on which nobody acted.

Dr. Kay: This is an important issue because patients with RA are at significant risk for CV disease. Visits with the rheumatologist take place more frequently than visits with the patient's [PCP], but we have lots of other things to deal with at the appointment. Do we really have time to pay attention to this? Perhaps electronic medical records can help prompt us to monitor cholesterol and potentially take action and provide reminders.

Dr. Markenson: The time it takes is less than the time required to do a joint callus [treatment]. Look at it that way. You simply tell a patient, "Your cholesterol is high." Check it off on the laboratory test and say, "Will you go to your [PCP] and have it taken care of?" It depends on your relationship with that PCP. I tend to call the PCP myself because he or she is hard to reach, but I could have my secretary make the call and say we have a problem and we could fax the values. Somehow, somebody has to deal with this and tell the patient that there is a problem, and hopefully the patient will also take action.

ACR/EULAR Diagnostic Criteria: Strengths and Weaknesses

Dr. Kay: Patient education is the key. The 2010 ACR/EULAR diagnostic and classification criteria for RA made quite an impact at the ACR meeting and now at the EULAR meeting. A number of groups have looked at their populations to see whether these criteria (which were derived largely from western European cohorts) are valid in their patients with RA. The Japanese were especially interested in looking at this and there was an abstract from this year's meeting that you were going to talk about from Japan that dealt with this.^[2]

Dr. Markenson: Before I talk about the article, let's think about the criteria. Everybody hates new criteria for how to practice medicine, so why were these even brought up? The problem with the 1987 criteria is that they didn't allow patients to be classified as having RA until they were fairly well along in their disease process. We have been trying to find ways to identify RA early so we can treat it earlier and that is what these criteria do. They look at things such as serology and weight them so that you can enter the criteria with only 1 swollen joint.

If you have some of the associated laboratory values, you actually get diagnosed and it has been validated because [RA does develop in] these patients. So in this abstract,^[2] they were looking to validate the sensitivity and specificity of these criteria in their own population. They identified characteristics of patients with RA who were not classified and patients who were classified, and they applied the criteria. They took 313 undiagnosed patients who presented with joint symptoms without any previous history except being treated with nonsteroidal anti-inflammatory drugs. The clinical diagnosis of RA was made by the rheumatologist. The gold standard in Japan at that time was that a diagnosis of RA was defined as an indication for instituting disease-modifying drugs.

They found that these criteria have a high sensitivity and have been verified [as being] useful for distinguishing early RA. The sensitivity decreased markedly when rheumatoid factor and anti-cyclic citrullinated protein (anti-CCP) were negative, suggesting that to use the 2010 criteria, the cutoff score would have to be 6, which we get easily by having those 2 positive tests, and perhaps dropping it to 5 so as not to miss RA. They talked about applying the criteria to their own population, thinking that there may be a little wiggle room for changes that would be more appropriate for them. We are going to see more validations. We are going to have to look to see whether this works in psoriatic populations (they excluded psoriatic arthritis) and the lupus population, but the most exciting thing about these criteria is that they allow you to enter a patient very early, make the diagnosis, and begin to treat.

Dr. Kay: When we were designing the criteria -- I was involved in this process -- we came up with weighted criteria and we chose a score of 6 as a cutoff because there was a relatively large jump between the patients above 6 and below 6. Certainly these criteria represent a continuum of disease and there are patients with scores lower than 6 who will require disease-modifying antirheumatic drug initiation to prevent the development of erosions. Different scores may be relevant for different populations, and 5 might be a more appropriate cutoff for the Japanese population.

Dr. Markenson: Yes, but we should just remind the audience that I made a mistake in saying that the criteria allow you to diagnose RA. These criteria allow you to classify the patient as having RA for purposes of registries in clinical studies, which will help when you are going to insurance companies and trying to justify medications. Obviously, diagnosis still remains with the doctor.

Dr. Kay: Diagnosis remains with the doctor, but you were correct initially in that these are diagnostic criteria. They were designed to be used to make a diagnosis because they reflect the clinician's diagnostic impression.

Exciting New Therapies

Dr. Kay: We are now faced with a whole new class of oral medications for RA -- the JAK 3 inhibitor, tofacitinib, and the spleen tyrosine kinase inhibitor (Syk) fostamatinib. At this meeting, Gary Firestein from University of California San Diego gave an educational presentation about the signaling pathways in RA that underpin the use of these therapeutic agents.

Dr. Markenson: These agents are exciting. We have all been waiting for the pill that would work as well as our intravenous, intramuscular, and subcutaneous medications. The abstracts on a couple of new compounds, which really have looked at a large group of patients, are very exciting. A significant number of patients do not do well after 4 or 5 years and need new medication. These new compounds (called small molecules because they are orally ingested) have been investigated, such as the Syk inhibitor. Preclinical studies demonstrated that the Syk inhibitor suppressed inflammatory arthritis and protected joints from damage to the extracellular matrix.

There was also an interesting report at this meeting on the JAK inhibitor, tofacitinib. They looked at whether it does well clinically and its ability to prevent x-ray damage. That is very important. Tofacitinib is a novel oral inhibitor (Janus kinase or JAK) that blocks the signal from the cell to the nucleus, which interrupts production of various cytokines such as tissue necrosis factor (TNF). It showed comparable clinical efficacy in large studies and safety equal to parental anti-TNF agents in RA, but I think the goal was [to find out whether] it prevents structural damage. This is important. We look for this in every new medication because we know that structural damage correlates with disability from this disease or the need for surgery.

We have asked for the data and are waiting to see whether this particular oral medication is as good as our parental medications in stopping structural damage. This is an early study and many others are in progress, but I am going to tell you what was reported at our meeting today. This was a retrospective cohort study^[3] of radiographic hand changes. [The study included] a small number of [patients with] RA (21) who had been enrolled in a 6-month phase 2B study of monotherapy with tofacitinib. [Treatment was] continued in these patients over the next year and x-rays [were made].

They looked first at the efficacy compared with the conventional disease-modifying antirheumatic drugs. Second, they looked at x-ray damage of the radiographic progression and they compared it before and after administration of the oral JAK inhibitor. Part one change in erosion score was significantly less and even reversed with tofacitinib., [In addition,] the rate of erosion per year score changed, significantly decreasing after the administration of tofacitinib. This is an exciting pilot study and other studies are in progress which we will probably hear about at later meetings, but the pilot study definitely showed that in this small group of patients, tofacitinib stopped structural damage just as well as the TNF inhibitor.

Dr. Kay: This is encouraging because if we are going to use these oral agents, we certainly want them to be effective in preventing the structural damage in this disease that can cause devastating effects if allowed to progress unchecked. It is going to be very interesting to hear about the radiographic data at future meetings. It is certainly encouraging that drug development for RA continues to progress at a very fruitful rate.

It was wonderful having you here and hearing about the broad range of topics about RA presented here in London at the EULAR 2011 meeting, and I hope to have you back in Chicago at the ACR meeting to hear more about what's going on. Thank you very much.

Dr. Markenson: You are welcome.

Dr. Kay: Thank you for participating in this Medscape Peer-to-Peer activity, and I look forward to seeing you again on Medscape.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.