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Denver Educational Seminar Highlights Need for Early AS Diagnosis
By Scott P. Edwards
Fall 2008 Issue of Spondylitis Plus Magazine
Nearly a year ago, researchers identified two genes, ARTS1 and IL23R, which increase the risk of developing ankylosing spondylitis. People carrying variants of these two genes, along with the genetic variant HLA-B27, are expected to have a one in four chance of developing spondylitis.
Speaking to a packed audience at a Spondylitis Association of America educational seminar in Denver in June, Dr. Michael Weisman, a Los Angeles rheumatologist who specializes in spondylitis, said the identification of these two genes should make early diagnosis of the disease easier for clinicians. Early diagnosis is important in terms of beginning appropriate therapies and preventing potentially debilitating deformities
These two new genes, in addition to HLA-B27, a powerful predisposing gene identified nearly 38 years ago, and inflammatory back pain, "will almost make the diagnosis of ankylosing spondylitis. The answer is, yes, these new genes are going to be helpful," said Dr. Weisman, director of the Division of Rheumatology at Cedars-Sinai Medical Center and professor of medicine at the David Geffen School of Medicine at UCLA.
Early diagnosis tricky but essential
The many different forms of the disease and our limitations on understanding how and when the disease begins make diagnosing spondylitis difficult. Dr. Weisman said a proper diagnosis typically includes classification (a set of criteria used to identify spondylitis patients unequivocally), genetic epidemiology, and symptomology.
The New York Classification Criteria for Ankylosing Spondylitis, developed in 1966, is the most widely used set of criteria for determining who has spondylitis. This system classifies the disease based on both clinical and radiological components. But, says Dr. Weisman, the system has limitations, primarily because it identifies only people who have late-stage disease or disease that has progressed beyond a certain point.
"When you classify patients," he said, "they have to absolutely have the disease, but that doesn't mean that people who have the disease may not make those criteria when you diagnose them. They may not be severe enough. It may not be fully manifest."
Clinicians can, he added, diagnose a patient before they meet classification criteria, so these criteria are not necessarily, in and of themselves, diagnostic.
"If you use classification criteria to diagnose patients, you're going to miss people, a whole lot of them who have not fully developed the features to be classified as having the disease," he said. "This is an extremely important issue because classification criteria have been misused as diagnostic criteria."
Susceptibility to AS is largely genetically determined. If one identical twin has AS, the other twin has a 63 percent chance of developing the disease. This compares to a 23 percent chance in fraternal twins (twins who are not genetically identical). The risk of AS in a sibling of someone who has the disease and is HLA-B27 positive is considerably higher than it is in an HLA-B27 individual in the community.
Genetic testing, says Dr. Weisman, can help to identify individuals who are at risk of developing AS; however, there are limits to this, as well. The discovery of the ARTS1 and IL23R genes make genetic testing much more accurate than simply testing for the genetic variant of HLA-B27.
If the prevalence of AS in the population is 0.4 percent, the prevalence will rise to 3.6 percent using HLA-B27 testing. If you test for ARTS1, the prevalence increases to 9.8 percent and, if you add IL23R testing to the other two, it increases to 23 percent.
"Now if you screen patients and find a population that has inflammatory back pain-let's say 10 percent; let's say you screen patients and with that screening tool, you come up with a 10 percent prevalence-if you apply just B27, the prevalence will be 50 percent. If you add the other two genes, the prevalence goes up to 90 percent. So these two new genes, if you add it to an inflammatory-back-pain population, you will almost make the diagnosis of ankylosing spondylitis," said Dr. Weisman.
Inflammatory back pain is key to diagnosis
The key to making a diagnosis of AS, however, is understanding what is inflammatory back pain. Inflammatory back pain, said Dr. Weisman, is back pain that awakens you in the middle of the night, improves with exercise and walking throughout the day, is worse in the morning and is associated with morning stiffness, and sometimes alternates from buttock to buttock. Mechanical back pain, on the other hand, usually does not awaken you and typically worsens during the day.
In an attempt to develop a diagnostic algorithm for AS, a European study conducted several years ago examined inflammatory back pain in both AS patients with back pain and non-AS patients with back pain. Using criteria such as morning stiffness, improvement with exercise, awakening in the second half of the night, and alternating buttock pain, the researchers found that inflammatory back pain was present in 81 percent of the AS patients compared to the control group.
"So," said Dr. Weisman, "inflammatory back pain is a pretty good way of telling the difference between AS and non-AS back pain." The recognition of inflammatory back pain will lead to a diagnostic algorithm for early diagnosis of AS, he added.
Another tool for diagnosing spondylitis is radiographic testing, or X-rays. But, says, Dr. Weisman, what kind of X-rays should be used? Who should do them? Who should interpret them?
MRI, or magnetic resonance imaging, uses a magnetic field and pulses of radio wave energy to make pictures of organs and structures in the body. This type of imaging gives different information than a standard X-ray and may show problems that cannot be seen with other imaging studies.
"An MRI is a completely different modality [than an X-ray]," said Dr. Weisman. "An MRI is actually using a magnetic field to measure inflammation of the molecules. An X-ray only shows you bones. An MRI shows you soft tissues and tendons and ligaments and fluid."
Further, he said, an accurate diagnosis may not be possible because subtle disease changes over time cannot be detected using conventional X-rays. While results may be ambiguous early in the disease process, MRI is better suited, over the long haul, to identify these changes.
Yesterday and Today
Advances in diagnostic techniques have created an old-world vs. new-world view of AS. The old-world view said that there was a long period of back pain and then, at some point, X-ray changes took place and an individual was diagnosed with spondylitis. Dr. Weisman said this really was not a diagnosis of spondylitis, but actually radiographic sacroiliitis. This is inflammation of one or both of the sacroiliac joints, which connect the lower spine to the pelvis, that shows up on an X-ray and is a prognostic factor for AS.
"The new-fashioned way of looking at the disease," he said, "is that there's a genetic predisposition, there's an environmental trigger-and we don't know what it is-and there's the onset of symptoms that take place for a long period of time before patients get X-ray changes. This is our new paradigm of the disease over time."
This new way of thinking about AS and the resulting changes in treatment, however, leads to several questions: do anti-TNF therapies alter the natural history of the disease and improve prognosis? Even with the identification of IL23R and ARTS1, do we completely understand the genetic risk for the disease?
Anti-TNF therapies have been proven to reduce inflammation, said Dr. Weisman, which can be measured with MRI and blood tests, but do they have an impact on fusion over time? These therapies are drugs that block the action of tumor necrosis factor (TNF), which causes the inflammation associated with AS and other autoimmune disorders.
"In studies that have been done so far, the measuring tools that have been used have not shown that anti-TNF drugs have had an impact on the rate of change, of bony change," he said. Two potential reasons exist: one, the fusion that takes place in AS is independent of any anti-TNF action (that is, these drugs do not control the process of bone change that leads to fusion) and two, other pathologic mechanisms are causing bone changes that not affected by anti-TNF drugs.
While these drugs do treatment inflammation but not bone changes, Dr. Weisman considers them to be a "boon patients with ankylosing spondylitis."
What is the SAA doing?
The Spondylitis Association of America is actively involved in helping physicians make early diagnoses of AS through a research study to develop a screening tool that identifies people at risk for the disease.
In this case, the tool is actually a questionnaire that will help to differentiate back pain caused by AS from other causes of back pain. At the conclusion of the two-year study, which began in 20[00?], the questionnaire will be available on the Internet for those searching for the cause of their pain.
An individual will answer the questionnaire and a score will be generated in real time that states the likelihood of that person having AS or not. Information on the disease and instructions on where to seek help will also be provided. Individuals with high-risk scores can see their physician and obtain further testing, such as genetic testing for the HLA-B27, IL23R and ARTS1 variants and MRI.
"Ultimately, the screening tool will help to identify new cases, greatly improve early diagnosis, encourage care-seeking among patients who learn that they are at risk for AS, provide useful information to patients and physicians, and help raise awareness about AS," said Dr. Weisman, who is the study's principal investigator.
"Shining a light" on early diagnosis
Ankylosing spondylitis is often diagnosed late and under-treated, with traditional therapies providing only symptomatic relief. An earlier diagnosis of the disease based on inflammatory back pain, imaging features, and genetic testing should, said Dr. Weisman, provide a "window of opportunity" to make therapy more definitive. Early diagnosis is important in terms of being able to identify patients before they develop the changes that occur in the spine that limit activity. Diagnosing patients when they fulfill classification criteria is too late, he added, because their joints have already been damaged.
"Early diagnosis [of AS] is close to being made with the development of assessment for inflammatory back pain and the new genes," Dr. Weisman said. "At the very least, it's going to bring people out of the wilderness into a place where you can shine a light on it and treat it and, hopefully, treat it effectively."