Abstract
Objective
The long-term outcome of patients with non-radiographic axial spondyloarthritis (nr-axSpA) is unclear, particularly whether few or most progress to ankylosing spondylitis (AS). Our objective was to examine the progression to AS in a population-based inception cohort of patients with nr-axSpA.
Methods
The Rochester Epidemiology Project (REP) is a longstanding population-based study of health in the residents of Olmsted County, Minnesota. We searched the REP from 1985 to 2010 using diagnostic and procedural codes for back pain, HLA-B27 and pelvis magnetic resonance imaging, and performed detailed chart review to identify subjects who fulfilled the Assessment of Spondyloarthritis International Society classification criteria for axSpA but did not have AS. We followed these subjects from disease onset to March 15th, 2015, and used survival analysis to measure time to progression to AS.
Results
After screening 2151 patients, we identified 83 subjects with new-onset nr-axSpA. Over a mean follow-up of 10.6 years, 16 subjects progressed to AS. The probabilities of remaining as nr-axSpA at 5, 10, and 15 years were 93.6%, 82.7%, and 73.6%, respectively. Subjects in the imaging arm (n=18) progressed more frequently and rapidly than those in the clinical arm (n=65) (28% versus 17%; hazard ratio 3.50, 95% CI 1.15–10.6, p=0.02).
Conclusions
A minority (26%) of patients with nr-axSpA progressed to AS when followed for up to 15 years. This suggests that the classification criteria for nr-axSpA identifies many patients unlikely to progress to AS, or that nr-axSpA is a prolonged prodromal state, requiring longer follow-up to evolve to AS.
Spondyloarthritis (SpA) is a group of inflammatory conditions that primarily affect the axial skeleton, with ankylosing spondylitis (AS) being the prototypical disease. Radiographic sacroiliitis is the key component for classification of AS by the modified New York criteria (1). However, it may take up to 10 years from the onset of clinical symptoms to develop radiographic sacroiliitis of this degree, and delay in diagnosis and treatment may consequently occur (2, 3). The condition characterized by symptoms of AS but without radiographic abnormalities in sacroiliac joints was originally reported in HLA-B27 positive relatives of AS patients (4). More recently, this condition was termed as “pre-radiographic” spondylitis and proposed to be a precursor stage of AS (5). To facilitate earlier identification of patients, the Assessment of Spondyloarthritis International Society (ASAS) developed new classification criteria for axial SpA (axSpA) which include patients with clinical features of SpA who may or may not have radiographic sacroiliitis (6). Patients can be classified as axSpA either by being HLA-B27 positive and having two clinical SpA features (the “clinical arm” criteria), or by the presence of sacroiliitis on radiographs or magnetic resonance imaging (MRI) plus one clinical SpA feature (the “imaging arm” criteria) (6). Patients who fulfill axSpA criteria but who do not have radiographic sacroiliitis advanced enough to meet the modified New York criteria have been termed non-radiographic axSpA (nr-axSpA).
Cohorts of patients with nr-axSpA by ASAS criteria have greater clinical and genetic heterogeneity than cohorts of patients with AS, including a lower proportion of men and lower levels of systemic and spinal inflammation (3, 7–9). This clinical heterogeneity has raised questions about the prognosis of patients with nr-axSpA, and the degree to which the criteria identify patients who are likely to progress to AS or who may have a different outcome. This question has been addressed in two previous studies. A prospective longitudinal study reported that 11.6% of 95 patients with nr-axSpA progressed to AS in 2 years, whereas a population-based study of 20 patients reported that 20% progressed in 8 years (10, 11).
It remains unclear what proportion of patients with nr-axSpA progress to AS, and over what time frame. In addition, the long-term prognosis of patients in the clinical arm of nr-axSpA has been questioned, because in the absence of sacroiliitis on imaging, some patients with fibromyalgia or mechanical back pain could be included (12). Cross-sectional studies have reported that patients in the clinical arm and those in the imaging arm were similar in most clinical features, disease activity, and disease severity (13, 14). However, the likelihood of progression to AS of patients in these two arms has not been compared. Furthermore, the lower proportion of men with nr-axSpA compared to AS has suggested that male gender may be a risk factor for radiographic progression, but this has not been examined in longitudinal studies (3, 8). To address these questions, a population-based longitudinal study that followed patients for 10 to 15 years is needed, given that the development of radiographic sacroiliitis is slow.
The Rochester Epidemiology Project (REP) is a unique medical linkage system, with access to the medical records of the population of Olmsted County, Minnesota and detailed recording of diagnoses, tests, and procedures since 1966 (15). In 2000 and 2010, 98% of Olmsted County residents, including 90,000 to 100,000 adults, agreed to participate in the REP (15). Therefore, the REP is ideal for population-based studies requiring long-term follow-up. Using the REP, we conducted a retrospective study to identify an inception cohort of patients with nr-axSpA and examine their progression to AS.
PATIENTS AND METHODS
Subject inclusion and exclusion criteria
We sought to identify an inception cohort of patients with nr-axSpA. Inclusion criteria were: 1. subjects were enrolled in the REP; 2. had new-onset back pain at age 16 to 45 and lasting more than 3 months, occurring between January 1st, 1985 and December 31st, 2010; 3. met criteria for either the imaging arm or the clinical arm of the ASAS criteria for axSpA (6). In addition, for the clinical arm, subjects were required to have at least one radiograph without sacroiliitis within 2 years prior to, or any time after, documentation of the occurrence of the second SpA feature. Subjects who had radiographic sacroiliitis within 2 years prior to and after a positive MRI were excluded from the imaging arm. We gave MRI evidence of sacroiliitis precedence, and therefore subjects who satisfied criteria for both arms were included in the imaging arm.
We excluded subjects who had back pain lasting less than 3 months, isolated neck pain, or physician visits for chronic back pain before 1985.
This study was approved by the institutional review boards of Mayo Clinic and Olmsted Medical Center.
Case ascertainment
To identify subjects who fulfilled criteria for the imaging arm, we searched for Olmsted County residents who had a pelvis MRI at age 16 to 45 between January 1st, 1997 and December 31st, 2010. We screened the MRI reports for sacroiliitis. Reports with “active sacroiliitis”, “osteitis”, “bone marrow edema” or “inflammatory lesions” were considered positive and MRI images were then reviewed by a rheumatologist (MMW) to confirm the presence of active sacroiliitis based on ASAS criteria (6). Pelvis MRIs were rarely available in the REP prior to 1997, so we did not extend our search to an earlier date.
To identify subjects who fulfilled clinical arm criteria, we searched for Olmsted County residents who met the inclusion criteria and had a procedural or diagnostic code for HLA-B27 testing.
Among patients who were identified as possibly having nr-axSpA based on the research codes in the REP, we then performed a detailed review of the full medical records of subjects who had either active sacroiliitis on MRI, or HLA-B27 and chronic back pain. Clinical information, including back pain characteristics, SpA features, radiographic and MRI reports, and medications, was collected through March 15th, 2015 to determine their eligibility and outcomes. SpA features were defined as described in the ASAS handbook (6). For inflammatory back pain, we used any of three criteria sets (Calin, Berlin, or ASAS) commonly used during the years of this study, or the treating rheumatologist’s determination. All subsequent and available radiographs of the pelvis, hips, lumbar spine or abdomen were reviewed, and radiographic sacroiliitis was graded using the modified New York criteria by a rheumatologist (MMW) who was blinded to clinical information. Intra-reader reliability was tested on 25 randomly selected radiographs scored several days apart and found to be high (kappa = 0.77 for specific grade; kappa = 1.0 for meeting modified New York criteria or not). If films were unavailable, we judged whether modified New York criteria were met based on descriptions in radiology reports.
Statistical analysis
We used survival analysis, with Kaplan-Meier curves and the log rank test, to measure time to progression to AS. For subjects in the imaging arm, time 0 was defined as the date of the first pelvis MRI demonstrating active sacroiliitis. For subjects in the clinical arm, time 0 was defined as the date when the second clinical SpA feature was recorded by a physician. AS was defined by the presence of bilateral grade 2, or unilateral grade 3 or grade 4, sacroiliitis on radiographs (1). The endpoint for analysis was the date of the first films demonstrating radiographic sacroiliitis of this degree. Subjects who did not have radiographic sacroiliitis of this degree during follow-up and had a clinic visit after March 15th, 2013, were considered as not having progressed to AS, and subjects whose last clinic visit was before March 15th, 2013, were considered lost to follow-up. Subjects who died, were lost to follow-up or had no events during the follow-up were censored on the date of death or last clinic visit. In a sensitivity analysis, we used the date of last negative radiograph as the time of censoring. Gender differences were compared using the t-test, Fisher’s exact test and Wilcoxon rank sum test, as appropriate. We used R programs (ver. 3.0.1) (R Foundation for Statistical Computing, Vienna, Austria) for all analyses.
RESULTS
Study cohort
We identified 1142 Olmsted County residents who had a pelvis MRI at age 16 to 45 between 1997 and 2010 (Figure 1). Most studies were ordered for investigation of abdominal or gynecological symptoms rather than musculoskeletal complaints. After review, we identified 26 subjects who had a pelvis MRI with active sacroiliitis. All the included pelvis MRIs were performed under a dedicated sacroiliitis protocol, except in one patient with inflammatory bowel disease, which was performed for gastrointestinal reasons. We identified 1009 Olmsted County residents who had a clinic visit for back pain at age 16 to 45 between 1985 to 2010 and who had HLA-B27 tested (Figure 1). Of these,168 subjects were HLA-B27 positive, among whom 136 subjects had back pain for more than 3 months. After detailed medical record review and application of inclusion and exclusion criteria, we identified 83 subjects with new-onset nr-axSpA.
Figure 1.
Flow diagram illustrating the process of inclusion and exclusion. Shaded boxes represent patients who were included in the cohort of non-radiographic axial spondyloarthritis.
Eighteen subjects were included in the imaging arm and 65 subjects were included in the clinical arm (6 of whom had a negative pelvis MRI and 59 of whom did not have a pelvis MRI). Their demographic and clinical features are presented in Table 1. The average age at inclusion was 33.3 ± 8.3 years. The mean follow-up of the entire cohort was 10.6 ± 5.6 years, with a significant shorter period in the imaging arm than in the clinical arm (6.4 years ± 2.9 vs. 11.8 years ± 5.9, p < 0.0001). Subjects in the clinical arm had 0 to 7 follow-up radiographs (median 1), whereas subjects in the imaging arm had 0 to 4 follow-up radiographs (median 1).
Table 1.
Demographic and clinical features of 83 subjects included in the non-radiographic axial spondyloarthritis cohort.
| Total (N=83) |
Imaging Arm (N=18) |
Clinical Arm (N=65) |
|
|---|---|---|---|
| Age at inclusion, years * | 33.3 ± 8.3 | 32.0 ± 9.1 | 33.7 ± 8.1 |
| Age at back pain onset, years * | 30.3 ± 7.9 | 28.7 ± 10.1 | 30.7 ± 7.2 |
| Length of follow up, years * | 10.6 ± 5.6 | 6.4 ± 2.9 | 11.8 ± 5.9 |
| Male (%) | 53 | 56 | 52 |
| HLA-B27 (%) | 90 | 56 † | 100 |
| Uveitis (%) | 25 | 17 | 28 |
| Arthritis (%) | 43 | 33 | 46 |
| Dactylitis (%) | 19 | 6 | 23 |
| Enthesitis (%) | 30 | 28 | 31 |
| History of psoriasis (%) | 11 | 17 | 9 |
| History of IBD (%) | 8 | 17 | 6 |
| History of reactive arthritis (%) | 11 | 6 | 12 |
| History of IBP (%) | 75 | 72 | 75 |
| History of smoking (%) | 35 | 39 | 34 |
| Family history of SpA (%) | 36 | 33 | 37 |
| Good response to NSAIDs (%) | 40 | 28 | 43 |
| Elevated inflammatory markers (%) | 36 | 39 | 35 |
| Methotrexate, ever (%) | 27 | 22 | 28 |
| Sulfasalazine, ever (%) | 23 | 17 | 25 |
| TNFi, ever (%) | 33 | 39 | 31 |
| Number of follow-up radiographs after inclusion (median (min, max)) | 1 (0, 7) | 1 (0, 4) | 1 (0, 7) |
IBD: inflammatory bowel diseases; IBP: inflammatory back pain; NSAIDs: non-steroidal anti-inflammatory drugs; TNFi: tumor necrosis factor-alpha inhibitors.
presented in mean ± standard deviation.
56% were found to be positive, with the rest being negative or unknown.
Progression to AS
At the end of follow-up, 16 subjects had progressed to AS. Subjects who progressed did so in a median of 5.9 years (range 2.7 – 11.8 years). Fifty-four subjects (65%) remained as nr-axSpA without progression, 11 subjects (13%) were censored due to loss to follow-up, and 2 subjects (2.4%) were censored due to death. The probabilities of remaining as nr-axSpA at 5, 10, and 15 years were 93.6% (95% confidence interval (CI) 88.3% – 99.2%), 82.7% (74.1% – 92.3%), and 73.6% (62.7% – 86.3%) respectively (Figure 2a). Progression to AS was significantly more frequent and faster among subjects in the imaging arm (28%, median time to AS 4.8 years) than those in the clinical arm (17%, median time to AS 6.8 years), with a hazard ratio of 3.50 (95% CI 1.15 – 10.60), p=0.02 (Figure 2b).
Figure 2.
Kaplan Meier curves of progression from non-radiographic axial spondyloarthritis to ankylosing spondylitis. a. Kaplan-Meier curve of entire cohort (solid line), with 95% confidence interval (shaded area); b. Kaplan-Meier curves for patients in the imaging arm (black line) and clinical arm (grey line). X-axis represents the years of follow-up; Y-axis represents the proportion remaining as non-radiographic axial spondyloarthritis. Numbers below the plot represent the number of subjects at risk at each time.
Because the pelvic radiographs were performed for clinical care rather than by protocol, we could have underestimated the development of radiographic sacroiliitis. To assess this potential, we did a sensitivity analysis using the date of last negative radiograph as the time for censoring. The probabilities of remaining as nr-axSpA at 5, 10, and 15 years were 89.6% (81.4% – 98.7%), 70.4% (57.0% – 86.8%), and 53.9% (38.3% – 75.8%), respectively (Figure 3a). Again, development of radiographic sacroiliitis was significantly more frequent and faster for subjects in the imaging arm compared to those in the clinical arm (p=0.0003) (Figure 3b).
Figure 3.
Kaplan Meier curves of progression from non-radiographic axial spondyloarthritis to ankylosing spondylitis using the last negative x ray as the time of censoring. a. Kaplan-Meier curve of entire cohort (solid line), with 95% confidence interval (shaded area); b. Kaplan-Meier curves for patients in the imaging arm (black line) and clinical arm (grey line). X-axis represents the years of follow-up; Y-axis represents the proportion remaining as non-radiographic axial spondyloarthritis. Numbers below the plot represent the number of subjects at risk at each time.
Gender associations
There were 44 men and 39 women (Supplemental table 1). Men tended to be younger than women (31.9 years ± 7.6 vs. 34.9 years ± 8.8, p=0.11), and also more likely smokers (43% vs. 26%, p=0.11). More women than men were ever treated with methotrexate (36% vs. 18%, p=0.08). Men had fewer follow-up radiographs (range 0–4, median 1) than women (range 0–7, median 1), p=0.07. Gender was not associated with radiographic progression. Twenty-three percent of men progressed with a median time to AS of 5.9 years, while 15% of women progressed with a median time of 6.3 years (hazard ratio 1.58, 95% CI 0.57 – 4.34, p=0.38) (Supplemental Figure 1a). No significant difference in progression was seen between men and women in the sensitivity analysis (p=0.37) (Supplemental Figure 1b).
DISCUSSION
Since the introduction of the ASAS criteria for ax-SpA, there has been considerable interest in whether patients identified as having nr-axSpA represent those with “early AS” or a group with a different etiology and prognosis (7). Few studies have examined the prognosis of these patients. A study of the German Spondyloarthritis Inception Cohort reported that 11.6% of 95 patients with nr-axSpA progressed to AS in 2 years (10). A small population-based study from Norway reported that 20% of subjects with nr-axSpA developed radiographic sacroiliitis in 8 years (11). Older studies that examined patients with undifferentiated SpA or “possible AS,” rather than those meeting the new ASAS criteria, reported that 24% to 42% of patients progressed to AS over 5 to 10 years (16–18). Low grade radiographic sacroiliitis, HLA-B27, and buttock pain were prognostic factors for progression to AS in these studies (17, 18). Comparisons among these studies are difficult because they included patients in different segments of the SpA spectrum. Additionally, these studies were limited by losses to follow-up of greater than 40%. Because they studied patients from rheumatology clinics, they likely overestimated the progression to AS. Our population-based study addressed many of these limitations in a cohort with a larger sample, longer follow-up, and low loss to follow-up rate. In our cohort, the probability of progressing to AS after 15 years was 26%.
Our study is the first to compare the prognosis of patients in the clinical arm and the imaging arm of nr-axSpA. We found that subjects in the imaging arm were 3.5 times more likely to progress to AS than subjects in the clinical arm. This finding suggests an important difference among the entities included in the nr-axSpA umbrella, one of which is much closer to “pre-radiographic” AS while the other represents a condition with a different prognosis. Previous studies have also identified MRI evidence of sacroiliitis as a marker of progression to AS (19). Cross-sectional studies of the Spondyloarthritis Caught Early (SPACE) cohort and DESIR cohort reported no major differences between patients in the two arms in most clinical features, disease activity, and disease severity, although patients in the imaging arm were more likely men, were younger with a longer disease duration, more often without an SpA family history, and had serum higher C-reactive protein levels (13, 14). Although clinical features may be similar between the two arms, our results indicate that the prognosis of these patients differs substantially.
In several cross-sectional studies that have compared patients with nr-axSpA to patients with AS, a notable finding has been a higher proportion of men with AS compared to nr-axSpA (3, 8, 9, 14). Men were also found to have a higher likelihood of MRI sacroiliitis (20). Therefore, male gender was proposed as a risk factor for radiographic progression. While we found a trend of more frequent progression to AS in men, the difference was not statistically significant, likely due in part to the size of our sample.
Our study has some limitations, mainly because of its retrospective design. Given the slow rate of progression to AS, only this study design was practical. First, the radiographs were taken for clinical indications. and therefore, we may have underestimated the development of radiographic sacroiliitis. The endpoint was determined by the timing of a positive radiograph, rather than the natural progression of the condition. Not all subjects in the imaging arm had subsequent radiographs to document development of radiographic sacroiliitis. Most subjects in the clinical arm had repeated films if they had persistent symptoms, or had no further investigations if their symptoms resolved. To investigate the impact of these actions on our estimates of progression to AS, we performed the sensitivity analysis using the date of last negative plain films as the time of censoring. The frequency of true progression is estimated to be between that in the main analysis and in the sensitivity analysis. Second, HLA-B27 testing and pelvis MRI were not universally obtained in patients with new-onset chronic back pain, but rather were ordered based on diagnostic needs. Similarly, some clinical features were not always explicitly documented in the clinical notes, such as response to NSAIDs or family history. We could have therefore omitted some patients who would have been included if this information had been available. It is difficult to predict how this might bias the results, if at all. Third, in a few early subjects for whom radiographs were not available, we based the presence of radiographic sacroiliitis on the radiologists’ reports. Because radiologists are more likely to underreport than over-report radiographic sacroiliitis, we may have underestimated the progression to AS in this small group of subjects.
In conclusion, in our population-based inception cohort of patients with nr-axSpA by ASAS criteria, 26% of subjects developed radiographic sacroiliitis after 15 years of follow-up. Subjects in the imaging arm progressed significantly more frequently than those in the clinical arm. Our results suggest either that the classification criteria of nr-axSpA identifies many patients unlikely to progress to AS, or that nr-axSpA is a prolonged prodromal state, requiring longer follow-up to evolve to AS. Some researchers, after careful review of the available evidence, have raised concerns on the performance of ASAS criteria, and proposed steps to improve their validity (21, 22). Further longitudinal studies are needed to evaluate clinical, laboratory and radiologic features with high predictive value for progression to AS.
Supplementary Material
Acknowledgments
This study was supported in part by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. It was made possible using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health under Award Number R01AG034676, and CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
The authors have no financial or commercial conflicts of interest related to this work.
Contributor Information
Runsheng Wang, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health.
Sherine E. Gabriel, Division of Rheumatology, Department of Internal Medicine, Mayo Clinic; Department of Health Sciences Research, Mayo Clinic.
Michael M. Ward, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health.
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