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The State-of-the-Art of Rheumatology
by Lara C. Pullen, PhD
Researchers and clinicians gathered in Chicago for the 2012 ACR State-of-the-Art Clinical Symposium, which was held April 28–29, to attend an overview of current topics of rheumatology. Attendees spent the day discussing gout, lupus (particularly during pregnancy), and rheumatoid arthritis. Nonrheumatologists provided outside perspectives on rheumatic disease: A dermatologist spoke about psoriasis, a hand surgeon spoke about rheumatic involvement in the hand, and a primary care physician spoke about musculoskeletal manifestations of HIV infection. [Editor’s Note: This session was recorded and is available via ACR SessionSelect] As session chair John J. Cush, MD, director of clinical rheumatology at Baylor Research Institute in Dallas, Texas, explained, “It is good when rheumatologists can hear from experts in another field.”
Dr. Cush noted that all of these topics are very clinically relevant and the presenters focused their talks on advances in disease management.
Hyperuricemia and Gout
The keynote address was given by Michael H. Pillinger, MD, a rheumatologist at the Manhattan VA Medical Center in New York. Dr. Pillinger elegantly described what Dr. Cush called, “the genesis of the inflammatory aspects of gout.”
Gout is a significant and growing problem. There are currently four million patients with gout in the United States. An epidemiological study of patients in Rochester, Minn., indicated a doubling in the incidence of gout from the 1970s to the 1990s. Dr. Pillinger explained that these patients are not only in pain, but they are also missing work. The median number of days lost due to gout or gout flares is about a week out of every year. Dr. Pillinger went on to describe gout as not just an acute problem, but rather one that may have significant health implications. Specifically, patients who have gout have worse survival rates over a five-year follow-up than do patients without gout.
The earliest documentation of gout occurred in 2640 BC by the Egyptians. Over the centuries, gout was further described, and, in 1961, McCarthy and Hollander introduced the polarizing microscope for the visualization of urate crystals. This was then followed by a dead zone in gout research and the treatment of gout did not appreciably advance for the next 40 years. Dr. Pillinger’s talk, however, described the renaissance in interest in gout that began in the year 2000 and has lead to new research and new therapies.
Up until three years ago, the renal excretion model was used to explain how an increase in high blood–uric acid levels is not effectively addressed by the kidney, leading to a buildup of uric acid in the body. This model was based on rat studies, but Dr. Pillinger explained that we now know that it is not true for humans.
The model has evolved as recent studies have identified the many transporters that move urate across membranes in the proximal tubule in the kidney. If these transporters don’t work properly, then the individual under-excretes uric acid. These transporters are being actively investigated as drug targets.
Major shifts in the gout model have occurred as a result of an increased understanding of the role of inflammation in the pathophysiology of gout. We now know that urate crystals activate complement and macrophages. The activated macrophages appear to be the most important contributor to the gouty attack because they secrete interleukin 1.
The inflammatory model of gout is based largely upon the danger hypothesis work of Polly Matzinger, PhD, a senior investigator at the National Institutes of Health in Bethesda, Md. According to this hypothesis, antigen-presenting cells are activated by endogenous cellular alarm signals from distressed or injured cells. In the case of gout, the uric acid crystals activate dendritic cells and act as adjuvants, resulting in a significant inflammatory response.
Epidemiology of Gout
Nutrition science has also contributed to the evolution of thinking about gout. Purines and ethanol have long been known to elevate serum urate levels. One of the recent novel discoveries, however, is the effect of fructose consumption on urate levels.
As early as 1893 (and possibly even earlier), physicians noticed that patients who consumed large amounts of fruit had a higher incidence of gout. In The Principles and Practice of Medicine section on gout, Sir William Osler noted that, “The sugar should be reduced to a minimum. The sweeter fruits should not be taken.” We now know that the hepatic metabolism of fructose results in the synthesis of uric acid.
Epidemiologists have also noted that the incidence of gout began to rise at the same time as fructose consumption increased. Two-thirds of the fructose in the U.S. diet is derived from added sugars. Sweetened soft drinks represent the single biggest source of calories in the U.S. (10.6%). Moreover, the ingestion of fructose in the form of soft drinks correlates with serum uric acid levels. This correlation is present even after adjusting for other patterns of dietary consumption.
In contrast, individuals with a larger consumption of dairy products have a decreased risk for gout. This is true in patients who are relatively thin as well as those patients who are slightly heavier. Milk consumption decreases urate levels. Interestingly, soy milk causes urate levels to rise.
Studies are currently underway to determine whether a particular substance can be identified in milk that can serve as a treatment for gout. Preliminary data suggest that there may be a factor in skim milk powder that decreases the frequency of gout flares.
Comorbidites of Gout
There is also an evolving appreciation of the comorbidities associated with gout and hyperuricemia. These multiple comorbidities are not seen in patients with other rheumatic diseases, Dr. Pillinger said. Patients with gout mostly have metabolic syndrome or, as Dr. Pillinger stated succinctly, “These are often sick people.”
The recently published Framingham Offspring Study enrolled 5,124 individuals and found that patients who had gout had a 50% to 150% increase in the risk of heart failure. The risk was not obvious in the first 10 to 15 years after diagnosis, but became evident 30 years out. This observation leads to the question: Is it hyperuricemia or gout that conveys risk of coronary artery disease? Unfortunately, this question has not yet been answered.
In Asia, a retrospective analysis of a patient database examined hyperuricema versus gout as risk factors for coronary and all-cause mortality. The investigators grouped patients into normal uricemia, hyperuricemia, and gout, and found an increasing risk of cardiovascular mortality as uric acid levels increased. This increase in cardiovascular risk decreased in the hyperuricemia group when adjustments were made for other risk factors for cardiovascular disease. The risk remained, however, in the gout group after adjustment for other cardiovascular risk factors.
Atherosclerosis can be viewed as an inflammatory disease, which leads to the question: Would the antiinflammatory drug colchicine be useful in preventing cardiovascular disease? This question was addressed in a study performed using the New York Veterans Administration gout cohort. The investigators examined cardiac endpoints in patients treated with colchicine versus those not given colchicine. The authors found that patients treated with colchicine had fewer than half the number of myocardial infarctions that the control group had.
Another study, performed in Taiwan, examined the effect of urate-lowering therapy (ULT) in cardiovascular mortality. Using a database review, the investigators found that ULT lowered the risk of mortality from cardiovascular disease and stroke in patients with gout.
Investigators are also studying whether gout contributes to kidney disease and whether lowering uric acid levels is associated with a reduction in kidney disease. Research suggests that lowering serum urate may preserve renal function in gout patients.
Dr. Pillinger concluded by stating that we desperately need to ascertain whether gout patients should be treated purely to prevent gout attacks or if there are additional benefits associated with the therapy. The recent increase in interest in gout has both underscored the need for new therapies and has advanced the development of new therapies.
Lupus and Pregnancy
Multiple cohort studies have shown that women with lupus have an increase in pregnancy loss when compared with the general population. The rate of pregnancy loss appears to be about 20% in women with lupus—a rate that is about twice that of the general population. Women with lupus also have about twice the rate of preterm births (30%) when compared with the general public.
Megan E.B. Clowse, MD, MPH, director of the Duke Automimmunity in Pregnancy Registry at Duke University Medical Center in Durham, N.C., began her presentation by explaining that pregnancy in lupus is not nearly as disastrous as most clinicians believe. Many lupus pregnancies are easy and result in a healthy baby and mother. Some lupus pregnancies, however, result in pregnancy loss, preeclampsia, preterm birth, and/or a very ill mother. Dr. Clowse’s talk focused on how to decrease the severity of the complications of lupus in pregnant women. Dr. Clowse suggested the use of daily aspirin (81 mg/day) to prevent preeclampsia.
A study of 275 pregnancies found that active systemic lupus erythematosus (SLE) in the three months prior to conception corresponded with a fourfold increase in pregnancy loss. Moreover, SLE activity during pregnancy doubled the risk of loss and preterm birth. Women with lupus nephritis also had an increase in pregnancy loss and preterm birth if the nephritis was active. One study placed the rate of pregnancy loss is as high as 50% in women with current nephritis and the rate of preterm birth close to 75%.
Dr. Clowse explained that the best way to achieve good pregnancy outcomes in patients with lupus is to counsel contraception when SLE is active. “Planning pregnancy is really important,” she said. Once conception has occurred, efforts should be made to maintain low SLE activity during pregnancy. In order to do this, the physician should monitor for rising SLE activity during pregnancy and promptly treat any SLE flare.
Women with lupus need to be counseled on the importance of contraception during active lupus. Dr. Clowse went on to explain her frustrations about practicing medicine in a state that provides abstinence-only education. A physician cannot presume that a woman in North Carolina has received a complete and accurate presentation on the steps necessary to prevent pregnancy. When counseled, many women were only familiar with abstinence—not a realistic option for a young married woman. Thus, physicians need to ensure that clear and accurate information is available on contraception options.
Once pregnant, the goal should be to maintain a low level of SLE activity, characterized as mild arthritis, rash, and mouth ulcers. While some women with mild SLE may be uncomfortable, this level of disease activity does not seem to have a significant effect on pregnancy. In contrast, high SLE activity (low platelets, active nephritis, severe arthritis, or rash) is associated with adverse pregnancy outcomes. In these situations, medications should be continued to prevent a flare.
Most studies agree that flares increase during pregnancy. Moreover, increased activity prepregnancy leads to increased activity during pregnancy. Thus, pregnancies should be monitored with frequent physician visits and lab testing, including urinalysis. Dr. Clowse emphasized, “You cannot assume that the obstetrician is following lupus.” SLE should be treated with hydroxychloroquine, azathioprine, and prednisone.
Novel Therapies for SLE
Richard A. Furie, MD, director of the Systemic Lupus Erythematosus and Autoimmune Disease Treatment Center at North Shore–Long Island Jewish Health System in Lake Success, N.Y., followed Dr. Clowse’s talk with a presentation on new drugs for SLE. He described the largest unmet needs for SLE to be severe extrarenal disease, lupus nephritis, damage prevention, and remission induction. He elaborated, “We do a terrible job with lupus nephritis … We need drugs to prevent damage.”
Unfortunately, he noted that, “doing lupus trials is very difficult.” This is because there is heterogeneity of manifestations that are further confounded by multiple background medications. Despite these challenges, there is currently unprecedented SLE clinical trial activity.
One therapeutic approach is a focus on the innate immune system and interferon alpha. Patients with SLE have elevated interferon alpha levels and serum from patients with SLE induces interferon gamma signatures. There is also evidence that antiinterferon alpha antibodies reduce SLE activity.
There have been two clinical trials to test type I interferon antagonists in patients with SLE. A phase I trial observed a reduction in interferon gene expression using a dose of 100 mg/week. A phase IIa trial noted a 40% reduction in interferon signature. Unfortunately, the reduction in interferon signature did not correspond with a clinical effect. Pharmaceutical companies have begun to target the interferon receptor (IFNAR). There are currently two trials underway: a phase I trial in scleroderma and a phase II study in SLE.
Dr. Furie explained that, “this is the era of lupus clinical trials.” He described studies using the B cell–directed therapies rituximab, ocrelizumab, epratuzumab, and belimumab. He concluded with a description of abatacept and its effect on lupus. While there are no conclusive data, the hope is that this heightened interest will result in improved treatment options for SLE.
Rheumatoid Arthritis: Treat to Target
Sergio Schwartzman, MD, associate attending physician at the Hospital for Special Surgery in New York City, described the initial 1958 diagnostic criteria for rheumatoid arthritis (RA), as well as the 1987 revised ACR classification criteria for RA. He then presented the newly established 2010 RA classification criteria and definition of remission. While acknowledging that they are imperfect, he explained that clinicians should “all be aware of these new definitions.” They allow for earlier disease recognition for clinical study and research and have implications for clinical practice.
Current RA disease measurement, while neither absolute nor perfect, allows for a quantitative baseline measurement. It also allows for a quantification of the benefits of targeted therapies. He explained that the key is to use a treatment strategy to advance therapy in a stepwise fashion while continuously measuring disease to achieve goal.
Outside Perspectives on Rheumatic Disease
Kenneth B. Gordon, MD, a dermatologist at the Northwestern University–Feinberg School of Medicine in Chicago, explained that it may be important to be more aggressive in the treatment of psoriasis, because psoriasis is associated with significant emotional and physical comorbid conditions as well as decreased quality of life. The effective treatment of psoriasis may be of benefit to patients beyond simply improving the appearance of their skin. The concept of the pathophysiology of psoriasis has continued to change and has provided researchers with new therapeutic targets. Dr. Gordon described the research in psoriasis therapy and explained that, “this story is going to change over the next few years.”
Dr. Cush described the talk by Greg Dumanian, MD, chief of plastic surgery also at Northwestern University–Feinberg School of Medicine as highly interesting. Dr. Dumanian presented many photographs and radiographic images of the hand. He reviewed the presentation and the physical exam findings of many common hand disorders that are seen by rheumatologists.
Michael P. Angarone, DO, clinical instructor in the division of infectious diseases at Northwestern University explained that rheumatic complaints are common in patients with HIV infections and that use of immune modulatory therapies is safe in this population. He described the challenges in the diagnosis and management of rheumatic complaints in HIV-positive patients. He also explained how screening for HIV infection in individuals with rheumatic complaints may help identify those individuals who are unaware of being infected.
Dr. Pullen is a medical writer based in the Chicago area.