The science of medicine is both amazingly progressive and frustratingly imprecise. Let me explain from the perspective of someone who began studies in medical school five decades ago.
When I started my internship at Stanford Medical Center, MRI and PET scanning did not exist. Nor did biologics. Nor immuno- therapy, nor precision medicine for cancer. In medical school, you are taught that 50% of what you learn is incorrect. Of course, no one knows what part of what you learn will be shown to be incorrect. Progress in medicine is often two steps forward, one step back. A forward step would be the ability to make a highly effective vaccine against an emerging virus, COVID-19, in less than a year. A backward step might be our certainty that estrogen was a good thing for women to take after menopause to prevent heart disease, until we learned that the harmful effects might outweigh the benefits.
A landmark advance in our understanding of ankylosing spondylitis is the realization that a genetic marker, HLA-B27, markedly increases the likelihood to develop ankylosing spondylitis (AS). And with that insight first published in 1973, further, still unanswered questions have arisen such as: what is the mechanism that causes HLA-B27 to make it more likely to develop AS? Why doesn’t everyone who has the HLA-B27 gene develop AS?
Another major step forward in the history of understanding AS was the formulation of what are called the ASAS (Assessment of Ankylosing Spondylitis) criteria. When ankylosing spondylitis was first recognized as a disease, experts agreed that it could only be diagnosed if x-rays showed the presence of sacroiliitis. But later the ASAS group, which is mostly in Europe, astutely said that this makes no sense. Surely it takes time for the x-rays to show changes in the sacroiliac (SI) joints. Maybe some people have inflammation in the SI joints and they never develop changes that can be recognized by routine x-rays? Thus, the so-called ASAS criteria were developed and ankylosing spondylitis was renamed, axial spondyloarthritis. Non-radiographic axial spondyloarthritis is the subset of patients with axial spondyloarthritis who do not have definitive, x-ray evidence of sacroiliitis.
Quite a few studies performed prior to the ASAS criteria had shown that patients with ankylosing spondylitis who are HLA-B27 positive tend to have worse disease than those who are HLA-B27 negative. And one might assume that the same would hold true for axial spondyloarthritis. Not so fast though.
Since April, 2020, the SAA has made an effort to serve its membership by an ongoing survey as to how COVID affects spondyloarthritis. For example, are the medicines used to treat spondyloarthritis safe to take during the COVID pandemic? If you have spondyloarthritis and you develop COVID, will that affect the spondyloarthritis? Will your spondyloarthritis affect the severity of COVID?
In the course of collecting and publishing the data 1-3 that resulted from the survey, my colleagues and I stumbled across a most unexpected finding. The activity of axial spondyloarthritis is frequently measured by an instrument called BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), where Bath refers to Bath, England. We recently reported in an excellent scientific journal that patients in our survey who were HLA-B27 positive had lower BASDAI scores, meaning less disease activity, than those who are HLA-B27 negative 4. An excellent study relies on data that are collected from a random sample. But those who respond to a survey are not picked at random. It would be somewhat like doing a national political poll but relying only on the responses from people who live in California. Despite the potential bias of a survey, we think the results are real and meaningful—that HLA-B27 really is associated with less active disease. Here’s why:
In creating the ASAS criteria to diagnose axial spondyloarthritis, the experts decided that HLA-B27 would be a useful component of the diagnostic criteria. Accordingly, it is easier for a doctor to diagnose axial spondyloarthritis if you are HLA-B27 positive. Our survey results indicated that HLA-B27 negative people with mild back pain were rarely diagnosed with axial spondyloarthritis. But if you were HLA-B27 positive, mild back pain was often ascribed to inflammation in the SI joints. Our data did not distinguish between over diagnosing axial spondyloarthritis in HLA-B27 positive patients versus under diagnosing the condition in HLA-B27 negative patients. Indeed, both are likely to be true.
The art of making a diagnosis is unfortunately not 100% accurate nor precise. Doctors can be subject to cognitive bias just as we all might suffer from biases related to accent, race, height, weight, sex, or gender. A positive test for HLA-B27 could bias the doctor toward attributing back pain to spondyloarthritis. Conversely, a negative test for HLA-B27 could unconsciously bias a physician against making a diagnosis of spondyloarthritis for a patient with mild, chronic back pain.
My colleagues and I concluded that HLA-B27 could introduce a cognitive bias in making a diagnosis for patients with mild back pain. And now it will be up to time and additional studies to determine whether this observation is one of the “facts” that doctors in training should forget or retain. While we believe it is a step forward, only posterity will determine if it could be a step back.
Full article available here: https://www.nature.com/articles/s41598-021-91829-5
- Rosenbaum JT, Hamilton H, Weisman MH, Reveille JD, Winthrop KL, Choi D. The Effect of HLA-B27 on Susceptibility and Severity of COVID-19. J Rheumatol. 2020.
- Rosenbaum JT, Hamilton H, Choi D, Weisman MH, Reveille JD, Winthrop KL. Biologics, spondylitis and COVID-19. Ann Rheum Dis. 2020;79(12):1663-1665.
- Rosenbaum JT, Weisman MH, Shafer C, Aslanyan E, Howard RA, Ogle K, Hamilton H, Reveille JD, Winthrop KL, Choi D.. Correspondence on ‘Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry’. Ann Rheum Dis. 2021.
- Rosenbaum JT, Weisman MH, Hamilton H, Shafer C, Aslanyan E, Howard RA, Ogle K, Reveille JD, Winthrop KL, Choi D. HLA-B27 is associated with reduced disease activity in axial spondyloarthritis. Sci Rep. 2021;11(1):12331.
This research was supported by the Spondylitis Association of America. Abbvie has provided funding to the Spondylitis Association of America in support of this survey, but it did not participate in the design of the survey, the interpretation of results, or the writing of manuscripts. Web services were donated by Any-3 London. JTR receives support from the William and Mary Bauman Family Foundation, the Stan and Madelle Rosenfeld Family Trust, and the Grandmaison Fund for Autoimmunity Research.