As we celebrate the 50th anniversary of the discovery of HLA-B27’s relation to ankylosing spondylitis (AS), I want to take you back in time and shed light on the impact of HLA-B27 on the field of rheumatology, both in the past and, as we will see, for the present and future for AS patients.
The story begins in the early days when AS and RA (rheumatoid arthritis) were considered as one disease; however, this perception was limited to the United States. One man, Walter Bauer, played a significant role in this misclassification. Bauer was the chief of the rheumatology section at the Massachusetts General Hospital (MGH) in Boston from the 1930s to the 1950s. In his influential paper published in 1939, he stated that “there was little justification for considering AS patients as suffering from a separate disease entity.” He considered AS to be just the axial piece of RA, and hence the term “rheumatoid spondylitis” was coined. This idea influenced many residents at MGH, who then agreed mightily with Bauer’s classification and went on to run other rheumatology programs throughout the United States.
Interestingly, in Europe at the same time, it was well known among rheumatology circles that AS and RA were two different conditions. Nevertheless, even in the late 1950s, Bauer himself recognized some differences between the two diseases in the book he co-authored with Dr. Charles Short. He noted that there was a small group of patients who had an earlier age of onset, were predominantly males, and had fewer rheumatoid nodules, yet he still did not consider them as having a separate disease.
Also, during this time, other advancements were taking place in the field of rheumatology. Rheumatoid factor, an important biomarker for RA, was discovered in the laboratory of Eric Waller in 1940. This factor was found to be an antibody twenty years later, revealing the autoimmune nature of RA. However, even these advancements did not significantly impact the classification bias that AS was part of RA.
It wasn’t until 1971 that Eric Bywaters published a pivotal paper discussing various rheumatologic conditions, including AS. He highlighted that most patients with chronic polyarthritis in the general population were seronegative, indicating a lack of rheumatoid factor positivity. Bywaters stated that AS was a separate entity, along with other conditions such as psoriasis, ulcerative colitis, Crohn’s disease, and connective tissue disorders. Despite this recognition, AS remained intertwined with RA in the United States due to the powerful influence of Walter Bauer and his trainees.
However, in 1973 a breakthrough occurred that would unmistakably change the course of AS diagnosis and understanding once and for all. Carl Pearson, ironically one of Bauer’s former residents at MGH, along with transplant immunologist researcher colleagues at UCLA, discovered and published the relationship between HLA-B27 and AS. This discovery was groundbreaking and held immense promise for the field of rheumatology especially in the USA where the old biases still hung on.
The initial hope was that HLA-B27 testing could secure a definitive diagnosis for AS, complemented by x-rays, to differentiate it from RA. Additionally, researchers believed that this discovery would lead to a comprehensive understanding of AS’s onset, pathogenesis, and treatment options. It was an exciting time for rheumatologists like me, as we anticipated significant advancements resulting from this finding.
However, as time went on, it became evident on a practical level that HLA-B27 testing was expensive and not accessible to everyone. Furthermore, interpreting X-rays proved challenging due to the variations in techniques. Amid these limitations, two astute clinicians from Stanford, Andrei Calin and James Fries, decided to develop a clinical method of diagnosing AS as an alternative to expensive and complex genetic testing. They developed a series of questions to differentiate between AS and other back pain conditions.
The questions they developed were simple yet effective. They asked about the duration of discomfort, the presence of back stiffness especially in the morning, the age at which the symptoms were first noticed, their speed of onset, and the relationship between back pain and exercise or rest. These questions formed the basis of the inflammatory back pain test, which was a significant step forward in diagnosing AS.
In their study, Calin and Fries compared a small number of AS patients, who were HLA-B27 positive, with other patients experiencing back pain but without AS, who were HLA-B27 negative. They discovered that five distinct characteristics could clearly distinguish AS from other chronic back pain conditions: onset at an age younger than forty, gradual and insidious onset over three months, morning stiffness, and improvement with exercise. These findings formed the foundation of the inflammatory back pain diagnostic tool.
The development of the inflammatory back pain test was a game-changer for the diagnosis of AS. It provided a more accessible and practical method of identifying AS patients, as it relied on clinical assessments rather than costly laboratory tests. This meant that more individuals with AS could be accurately diagnosed and receive appropriate treatment.
So, how is the inflammatory back pain test used today to decide how many people in the US have AS? Thanks to the collaboration and expertise of my colleague, John Reveille, MD, and the support of SPARTAN (Spondyloarthritis Research and Treatment Network), we were able to implement in the general population the questions related to inflammatory back pain and back pain in general. We wanted to determine the frequency of AS and inflammatory back pain along with HLA-B27 positivity throughout the United States. This had never been done before on such a large scale.
To achieve this, we utilized data from the National Health and Nutrition Examination Survey (NHANES), which included over 5,000 patients. The results were fascinating. We found that the prevalence of chronic low back pain in the United States was approximately twenty percent, regardless of the age at onset. This defied the usual bias that back pain was more prevalent in older individuals.
In addition to assessing chronic back pain, we also focused on identifying inflammatory back pain. We found that around five to six percent of the population exhibited symptoms consistent with inflammatory back pain. This was a significant finding as it allowed us to establish standards for differentiating among regular back pain, chronic back pain, and inflammatory back pain.
Moreover, we discovered that there were some differences in the prevalence of inflammatory back pain and HLA-B27 positivity among different ethnicities. Interestingly, when we tested HLA-B27 frequency in the general population aged 20-69, we found that it was 6.1%. However, what was particularly intriguing was that the frequency of HLA-B27 positivity decreased with age. This suggested a potential association between HLA-B27 and mortality, leading to intriguing questions regarding public health and the relationship between HLA-B27 and lifespan.
Building on these findings, we sought to explore further questions. Did everyone in the United States, including women and children, possess HLA-B27? How could we address the issue of heterogeneity in spondyloarthritis? Did HLA-B27 or other genetic testing provide insights into the disease? And what about the relationship between HLA-B27 and mortality? These were important areas of research that required further investigation. So, fifty years after the discovery of HLA-B27 and AS, exciting new questions are being asked, and the legacy of HLA-B27 continues.
One highly influential study very recently published used latent class analysis (which is an unbiased approach to see if certain parts of SpA fit together without preconceived ideas) to assess underlying associations within the heterogeneous group of very early patients suspected to have spondyloarthritis. This study drew upon two separate cohorts from different countries in Europe. By analyzing the data, they identified four distinct classes: axial disease with male predominance, abnormal imaging, and HLA-B27 positivity; inflammatory back pain with peripheral disease, female associations, and negative testing for HLA-B27; an at-risk group (those with a family history, no symptoms, and HLA-B27 positivity), and a group without spondyloarthritis at all. This analysis demonstrated that the marked heterogeneity in disease phenotypes (which we recognize clinically) are variably associated with HLA-B27, and definite gender differences do exist among patients with SpA.
Additionally, an observational cross-sectional study conducted by the ASAS (Assessment of Spondyloarthritis International Society) group examined HLA-B27 testing results in patients with peripheral spondyloarthritis. Interestingly, they found an absence of an association between HLA-B27 and peripheral structural damage in these patients. This study, and others like it, have found that HLA-B27 is associated with the axial (spine) part of SpA, and less so the peripheral arthritis part. This further highlighted the complexity and variability associated with different phenotypes of the disease and where HLA-B27 and other testing is connected. Maybe this genetic discovery has created more questions than answers, so there is more work to do.
One intriguing area of research is the relationship between HLA-B27 and mortality. Several studies have suggested that HLA-B27 positivity might be associated with increased mortality. However, the reasons behind this association are still not fully understood. It is challenging to determine whether the increased mortality is directly related to the presence of HLA-B27 itself or the chronic low back pain often associated with the condition, or a combination of both factors. Some studies have shown that chronic low back pain itself is a risk factor for mortality, suggesting that there may be other contributing factors at play.
Further research is needed to delve deeper into the relationship between HLA-B27 and mortality. One study conducted by Jesse Walsh, MD examined HLA-B27 testing in a veteran population, with results showing a higher mortality rate among HLA-B27 positive individuals. However, when the data was analyzed, separating those with spondylitis from those without, the difference in mortality rates was not statistically significant. These findings suggest that mortality may be more closely associ-ated with the presence of spondylitis rather than HLA-B27 positivity alone.
Another study conducted in France examined HLA-B27 prevalence in a community-wide sample of individuals. Although the results showed a difference in age-related prevalence of HLA-B27, it was not statistically significant. Researchers speculated that environmental factors and historical events, such as deprivation during World War II, might have influenced the findings. However, more research is needed to confirm these associations.
When considering the mortality aspect, we must also remember that AS and chronic low back pain can have significant impacts on an individual’s overall well-being and quality of life. Living with a chronic condition can lead to additional health challenges and affect mental health. Therefore, it is crucial to provide comprehensive care that addresses both the physical and emotional aspects of living with AS.
As we reflect on the past 50 years since the discovery of HLA-B27, we have made remarkable progress in understanding and managing patients with ankylosing spondylitis. HLA-B27 has played a vital role in diagnosing AS early before damage has occurred, and along with advances in MRI we now can identify patients early in their course and prescribe truly life-changing medications to relieve pain and hopefully avoid damage. Recent research using HLA-B27 as a tool has now permitted us to identify specific phenotypic expressions of the disease. It has allowed us to differentiate AS from other forms of back pain and has helped guide treatment decisions.
However, we also recognize that there is still much more to learn. The complexities of AS and its relationship with HLA-B27 require ongoing research and exploration. We need to investigate the influence of other additional genetic factors, such as the recently discovered associations between other HLA alleles and peripheral disease expression in SpA patients. Additionally, studying the impact of environmental factors and the interplay between genetics and disease severity can provide further insights into the possibility of uncovering prevention strategies.
The discovery of HLA-B27 has had a profound impact on the field of rheumatology, particularly in rescuing ankylosing spondylitis from being misclassified as a form of rheumatoid arthritis. While the initial promise of HLA-B27 as the essential diagnostic tool and the complete key to understanding disease pathogenesis has not been fully realized, it remains an extremely important component in the diagnosis, prognosis, and management decisions for AS. Through ongoing research, we continue to uncover new aspects of the disease, expanding our understanding and improving patient care.
As we move forward, it is essential to keep in mind that ankylosing spondylitis is a complex disease with varying manifestations and individual experiences. Each patient’s journey is unique, and a personalized approach to diagnosis, treatment, and support is crucial. By continuing to explore the intricate relationships among HLA-B27, other genetic discoveries, disease severity, and mortality, we can strive for a better future for individuals living with ankylosing spondylitis.
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