Low Rate of Progression to Ankylosing Spondylitis Among Patients With Presumed Nonradiographic Axial Spondyloarthritis: Comment on the Article by Wang et al

To the Editor: In the recent report by Wang and colleagues on the progression of nonradiographic axial spondyloarthritis (SpA) to ankylosing spondylitis (AS) (1), it was concluded 1) that the rate of progression from nonradiographic axial SpA to AS is rather low, and 2) that the so-called “clinical arm” of the Assessment of SpondyloArthritis international Society (ASAS) classification criteria (2) may differ substantially from the so-called “imaging arm. ” As Wang and colleagues correctly state, recent studies have led to different numbers and conclusions (3,4). We contend that the conclusions drawn by Wang et al, made on the basis of data from the Rochester Epidemiology Project, are probably not justified, and this is not only because of the retrospective study design and the relatively small number of study subjects. The major factor to consider in a study like this is, of course, ascertainment: how likely is it that, on the basis of 10–20year-old data from medical records, one can identify a subgroup of patients with nonradiographic axial SpA, an entity which, at that point in time, was not known to exist? In selecting the study population the authors started with 1,009 individuals with chronic back pain plus those who underwent magnetic resonance imaging (MRI) for reasons other than back pain (n 5 1,142). If we assume a prevalence of axial SpA of 1–2% in the population, we would expect ;10 (at most, 20) patients in the latter group and 50 patients in the former group based on the assumption of a 5% prevalence in a primary care setting (5). This could be slightly higher because of the increased prevalence of HLA–B27 (16.7%) in that group. Altogether, one would have expected ;70 patients with axial SpA: approximately half with nonradiographic axial SpA and half with AS. Yet Wang and colleagues report having identified 122 patients, only 39 (32%) of whom had to be excluded because of established AS. Thus, there is quite a high probability that the study cohort was a somewhat artificial group of retrospectively assessed patients, in which we are not surprised that ultimately only 26% had progressed to a classification of AS according to the modified New York criteria (6). Most rheumatic diseases, including axial SpA, lack a gold standard, and therefore classification criteria are inappropriate for making a diagnosis (7). Major differences between classification and diagnostic criteria are, among others, 1) that the pretest probability of the disease of interest has to be known and taken into account when the diagnosis is made, 2) that positive findings of clinical parameters should be highly suggestive (compelling) for SpA (2,8), and 3) that other explanations for the presence of a parameter should have been actively excluded (differential diagnosis). The pretest probability of having axial SpA in a primary care setting has been estimated to be ;5% in patients presenting with chronic back pain (5). In the original ASAS study on the development of the new classification criteria, the sensitivity was 82.9% and the specificity 84.4% (2). In other studies, such as a recent one from The Netherlands in which patients had been referred because of possible axial SpA and in which the rheumatologist’s diagnosis was used as the gold standard, the sensitivity and specificity of the ASAS criteria were in a similar range (3). Interestingly, comparable sensitivities and specificities have been found when, in other diseases such as rheumatoid arthritis (RA) (9), classification criteria were tested against experts’ diagnoses. In the case of a pretest probability of 5%, the posttest probability of having axial SpA would not be higher than ;21% if the ASAS classification criteria are simply schematically applied (10). For the imaging arm in the study by Wang et al (1), MRIs were analyzed, most of which were “ordered for investigation of abdominal or gynecologic symptoms” and not because there was a suspicion of axial SpA. Thus, it is unlikely that the pretest probability among these patients exceeded 5%. Why HLA–B27 was tested at all in the individuals included in the clinical arm is not clear from Wang and colleagues’ report. However, a B27 prevalence of 17% in these individuals suggests a relatively low suspicion of axial SpA. However, if the ASAS criteria are applied in this group, even with a pretest probability of 10%, the posttest probability would not exceed 36% (10). In addition, we do not believe it is possible to determine whether a positive finding for a given parameter is highly suggestive of axial SpA, and it is also not possible to exclude other explanations for a positive finding without seeing and examining the patient, since positive findings have to be interpreted in the context of the overall clinical picture (11). For example, subchondral bone marrow edema may look rather similar in patients with axial SpA and in those with, for example, osteitis condensans, in which the cause of the bone marrow edema is mechanical stress rather than rheumatic inflammation (12). Thus, only 21–36% of the patients identified as having nonradiographic axial SpA in this study are likely to truly have a diagnosis of axial SpA. Only 28% and 43% of patients identified via the imaging arm and the clinical arm, respectively, of the ASAS criteria had a good response to nonsteroidal antiinflammatory drugs, according to Table 1 of Wang and colleagues’ report (1)—a rather unusual finding in patients with axial SpA. The reported age at onset of back pain is also relatively late, and the mean duration of followup relatively short, with a median of only 1 radiograph obtained during the course (information on the stage at which this was obtained is not provided). The fact that no difference in radiographic progression between male and female patients was found also raises a question on the selection process for this cohort. Finally, we would like to stress that we look at retrospective classification of patients more on a population basis than on the basis of a clinical study with low back pain as an entry criterion. No differentiation between low back pain—the most likely location of back pain in early axial SpA—and pain in other regions of the back was made in this study. A large number of patients had to be excluded in the study by Wang et al (1) because they had already reached the primary outcome, i.e., having AS. When considering the natural course of axial SpA it must be stressed that in several recent studies, 25–50% of patients with a relatively short disease duration (2–3 years) already fulfilled the modified New York crite-