Rheumatologists to Watch: Kenneth Saag, M.D.

A professor of medicine at the University of Alabama at Birmingham, Kenneth Saag, M.D., MSc, researches the way inflammatory diseases and their treatment relate to bone diseases. In particular, he has explored the affects of glucocorticoids on osteoporosis. He has published more than 250 original scientific reports. At UAB he directs the Center for Education and Research on Therapeutics of Musculoskeletal Disorders, the Center for Outcomes and Effectiveness Research and Education and the Center of Research Translation in Gout and Hyperuricemia.

Dr. Saag is the co-author of 2015 American College of Rheumatology Guidelines for the Treatment of Rheumatoid Arthritis, which, for the first time, addresses how steroids might be used in rheumatoid arthritis. Dr. Saag recently spoke with Rheumatology Network about glucocorticoid use for rheumatoid arthritis, which he says has experienced a resurgence of interest.

Q: Why are older DMARDs getting attention in the era of biologics?[[{"type":"media","view_mode":"media_crop","fid":"46137","attributes":{"alt":"Kenneth Saag, M.D.","class":"media-image media-image-right","id":"media_crop_8227568995207","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5338","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"Kenneth Saag, M.D.","typeof":"foaf:Image"}}]]

Biologics and new small molecules have revolutionized our approach to inflammatory disorders because these new therapeutics are much more targeted to the underlying biology. A big challenge is the cost and to a lesser, but still significant degree, their long term effectiveness and safety. If anything, the costs of these new drugs continue to go up instead of down. Maybe that will change in the era of the so-called biosimilars, but so far that has not been the case. In many parts of the world, and even in the U.S. healthcare system, which is increasingly strained by the financial burden of healthcare delivery, our ability to get the newest most expensive therapies to everyone is more and more limited. So despite all these new therapies, prednisone, in particular, continues to be a mainstay for many of the diseases that rheumatologists treat. It has been around for about 60 years. In all this time, there has been relatively scant literature around its effectiveness and safety. But some new data suggests that it may alter the course of diseases like rheumatoid arthritis. So we’re trying to figure out how to more effectively use this drug. 

Q: How could prednisone alter the course of rheumatoid arthritis?

 It suppresses inflammatory pathways. If patients feel better, they are able to increase their weight-bearing physical activity. As a result, there may be less damage to the bones that occurs in the form of bone erosion, the hallmark of rheumatoid arthritis, as well as potentially  generalized osteoporosis. On the other hand, steroids such as prednisone directly inhibit the formation of bone. As many as half of patients taking these drugs break bones over time and it’s not unusual to see a 5% or even 15% loss of bone density within a year or so of starting some of these steroid medications, if they’re used at sufficient doses. That’s one of the reasons my colleagues and I have been so interested in this topic. 

Q: What approach is your research taking?

 We are conducting and considering research in the context of pragmatic clinical trials that don’t have the contrived conditions of very strict inclusion or exclusion criteria, or very detailed follow up criteria. Typical studies don’t represent the full population of the people who have the condition. The patients may not be as sick, or they may not be as diverse. The study populations may not include as many women or minority population members. So the goal of pragmatic studies is to have the results reflect more what is going on in the real world. My colleagues here at UAB have been involved in starting to program these real-world scenarios. The other big area of emerging research we focus on is what’s been termed “comparative effectiveness,” typically comparing newer to older therapies. 

Q: What have you learned so far?

 The main takeaway is to use the lowest dose of steroids for the shortest duration of time. Not all physicians agree with that philosophy, because there has been a little bit of evidence that we could use these drugs in more aggressive ways early on or for slightly longer periods of time. And other diseases may merit more aggressive doses. But in the context of rheumatoid arthritis, that’s what the guidelines from the ACR suggest and what many U.S. rheumatologists do.

We’re starting to figure out the optimal dosing and duration in populations that may be at higher or lower risk. And we are finding out which patients need to use preventative strategies, such as other medications, that can be taken concurrently with prednisone to protect the bone. We need to know which bone medicines help most for those on steroids.  That’s been a big focus of mine.

Q: What have you learned so far about medications for this purpose?

We’ve been looking at different drugs commonly used for other forms of osteoporosis overall. The most commonly used medications, bisphosphonates, seem to work pretty well. The question is how long they should be used. It might turn out people should not get them indefinitely. This is particularly true in women not on steroids who have a good response initially to the drugs. They might take them for a five-year period then take a drug holiday to minimize the risk of very rare but well-documented side effects.

If you combine studies together it does look like patients on steroids can reduce their risk of fractures by taking bisphosphonate medicines. In terms of the bone density of the spine, most of the bone drugs seem to work about as well on patients taking steroids as on patients who aren’t on steroids. But we expect that people taking steroids are at slightly greater risk overall of bone loss, even when taking drugs to prevent it.

We have also done some studies looking at a medicine called teriparatide which works a bit differently than bisphosphonates do. It actually may stimulate new bone formation which could give it a special role in steroid-induced bone disease.

And we have a study underway looking at a newer agent called denosumab. That study is just wrapping up and that may provide some very important information. It’s similar to the bisphosphonates in how it works, blocking the breakdown of bone; but in a more targeted way and with a different specific mechanism of action.

Q: Are physicians who prescribe glucocorticoids generally aware of the risk of bone loss?

Rheumatologists generally are aware, but primary care practitioners still may not be. Despite all this evidence, it’s been hard to get a lot of patients on the right preventive therapies. That’s a big interest of ours: What things work and what things don’t work? We’ve looked at strategies such as giving people guidelines or providing them feedback on how they’re doing as compared to other colleagues in the field. And we’ve looked at educating their patients about possible therapies in an effort to promote a more meaningful discussion when the patient is in the doctor’s office. We did an experiment with the two Kaiser Permanente systems, just allowing people to schedule their own bone density tests. That was actually very effective in increasing the number of people who got tested. Just empower patients. On the other hand, providing feedback to patients or to physicians, and using adult-based learning theory, and other things that have worked in other disease disciplines, didn’t seem to have the same level of benefit in people on glucocorticoids.

Q: Why don’t practitioners pick up the information from professional guidelines, journal articles, meetings and so on?

A: It’s great question. We don’t know the answer. When patients see rheumatologists specializing in joint and bone problems, there does tend to be more attention to such a problem. Endocrinologists are also more likely to evaluate and intervene. Patients take glucocorticoids for asthma and emphysema, bowel inflammation, other rheumatic diseases, inflammatory skin disease and nerve diseases. All these patients are often seen by generalists and in some cases by specialists who have a very different focus, often not around bone. We know that doctors these days are incredibly busy. Osteoporosis does not tend to be one of their primary concerns in increasingly short and problem-oriented office visits for these sick adults. The risk often goes unevaluated. And, as with most preventive healthcare, you are often consider yourself fine until you develop a bad outcome such as a broken bone. So making patients more aware of this risk is also really key.

References:

2015 American College of Rheumatology Guidelines for the Treatment of Rheumatoid Arthritis

Kenneth S. Saag, MD, publications.