Our results showed that in the cohort of patients with a relatively long duration of AS symptoms, a considerable number (23.1%) of patients had ≥ 1 EAMs at baseline. During the follow-up period, the patients often developed new EAMs. We found that the presence of EAMs, AAU alone, and combined EAMs (≥ 2 kinds of EAMs) in patients with AS was significantly correlated with the duration of AS. However, we did not find the same correlation for IBD and psoriasis.
In the baseline cross-sectional analysis, the history of AAU was associated with longer disease duration and older age. Vertically, the new onset of AAU was also related to longer disease duration and higher disease activity index of AS at baseline. Furthermore, the new onset of EAMs was observed more in HLA-B27-negative patients than in HLA-B27-positive patients with AS, and this may be attributed to the effect of patients with IBD in the cohort on the overall new-onset EAMs. This is because in the cross-sectional study at baseline, we found that HLA-B27-negative patients had a relationship with the history of IBD. In patients with psoriasis, no such association was found. This reflects the difference in inflammation accumulation and exposure period, and the degree of inflammation exposure may be relatively higher in patients with AAU and combined EAMs. We also found that the new onset of EAMs and AAU were related to a long duration of AS (> 10 years). Patients with a long duration of AS (> 10 years) have a 1.15-fold higher risk of the new onset of EAMs and a 1.197-fold higher risk of the new onset of AAU than do patients with AS with a disease duration of ≤ 5 years; this is similar to the findings of a clinical study . Furthermore, we found that patients with a relatively HDA (ASDAS > 2.1) at baseline were more likely to develop any new-onset EAMs and AAU.
The risk of new EAMs in HLA-B27-positive patients with AS was small compared to that in HLA-B27-negative patients with AS. These findings were further confirmed using the Kaplan–Meier curve analysis. The risk of any new EAM in HLA-B27-positive patients with AS was 0.542 times higher than that in HLA-B27-negative patients. In patients with AS, HLA-B27 positivity may be a protective factor for new-onset EAMs. The risk of any new EAM in patients with AS with unstable disease control (HAD and VHDA, ASDAS > 2.1) was three times higher than that in patients with a relatively stable disease control (ID and LDA, ASDAS ≤ 2.1). In our study, the history of EAMs was not associated with peripheral arthritis and enthesitis, even in patients with IBD and psoriasis. This finding is contrary to that of Gaelle et al. , who reported that in patients without EAMs and those with psoriasis, there was a trend of increased joint swelling. The difference in the findings may be related to the ethnic differences in the subjects studied. A similar finding was also obtained in our previous study: in the CASPIC, the occurrence of peripheral arthritis and enthesitis was not related to the disease duration . Additionally, in the present study, in the univariate analysis, patients with AS with a history of TNFi treatment seemed to be more likely to develop new EAMs, but no such result was obtained in the multivariate analysis. This may be related to the higher proportion of patients with AAU (69.4%) among those with new-onset EAMs. In the CASPIC, tumor necrosis factor receptor fusion protein was the main target component of TNFi . It has been reported that the receptor fusion protein may induce AAU development [23, 24], explaining the result of our study. At the same time, we found that there was also new-onset AAU in patients with AS who used tumor necrosis factor monoclonal antibody (Supplementary Table S1). Our results are similar to a newly published cohort study of 175 patients with AS, which revealed that the receptor fusion protein does not elevate the risk of occurrence of uveitis compared with monoclonal TNF antibodies . Although there was no evidence that tumor necrosis factor monoclonal antibody may promote the occurrence of AAU in patients with AS, it was still worthy of clinical attention and further research.
Patients with AS are more likely to develop AAU, IBD, and psoriasis than the general population. It has been reported that the cumulative incidence rate of AAU in the general population is 0.2–1.0% . Furthermore, the prevalence of IBD is 0.01–0.5% and that of psoriasis is 0.3–2.5% in the general population [26, 27]. A meta-analysis of the results of 156 studies in more than 40,000 patients with AS showed that the prevalence rates of AAU, IBD, and psoriasis were 25.8, 6.8, and 9.3%, respectively . Ivette et al. showed that the prevalence rates of AAU, IBD, and psoriasis at baseline were 18.0, 6.9, and 4.1%, respectively . AAU is the most common EAM in patients with AS . In our study, the prevalence rates of AAU, IBD, and psoriasis at baseline were 16.7, 6.9, and 2.6%, respectively, comparable to those reported by Ivette et al. . In similar clinical studies, the prevalence of different EAMs in patients with AS or nr-axSpA in the DESIR cohort and GESPIC was comparable to that observed in our study [28, 29]. However, the prevalence of psoriasis was slightly lower in our study, which may be due to the difference in the race of the participants. Furthermore, previous studies have shown that the prevalence of AAU increased with disease duration in patients with AS [3, 30]. In a meta-analysis, the prevalence of AAU was related to the disease duration. In patients with AS with an average disease duration of < 10 and > 20 years, the prevalence rates of AAU were 17.4 and 38.5%, respectively . A systematic review of 1989 patients with SpA showed that the prevalence of AAU increased with the disease duration . This is similar to our finding in the CASPIC. At baseline, we found that the history of AAU and IBD was related to the prolongation of AS. However, in the multivariate analysis at baseline and follow-up longitudinal observation study, we found that only the occurrence of AAU was related to a long disease duration, whereas IBD did not show such a relationship. It should be noted that no such association with psoriasis was found in previous studies. This may be because psoriasis and IBD occurred before the onset or diagnosis of AS; however, this has not been proven. This is because EAMs are a part of the current criteria of axSpA and are considered helpful for the diagnosis of axSpA or AS [32, 33]. The relationship between AS and EAMs requires more attention in the future.
HLA-B27 is closely related to the pathogenesis of AS. Strong evidence supports that it is an independent risk gene for the pathogenesis of AS/SpA and that it is the strongest among all known HLAs . There is evidence to show that HLA-B27 and IBD have a strong correlation, but whether there is a difference between the prevalence of HLA-B27-positive and HLA-B27-negative patients is still unclear  . In a large-scale study, in 908 HLA-B27-positive and 90 HLA-B27-negative patients with AS, the relationship between HLA-B27 and IBD in patients with AS was analyzed ; 9% and 20% of the patients had IBD. This was confirmed in our study; HLA-B27-positive patients with AS had a greater risk of AAU occurrence and lower risk of IBD occurrence than the HLA-B27-negative patients. Our previous study results suggested a similar trend, but there was no statistical difference, which may be related to the small number of patients observed in the previous study (801 patients with AS) . Although there was no statistical difference, the proportion of patients with IBD was different (the incidence rates of IBD in HLA-B27-positive and HLA-B27-negative patients with AS were 2.4 and 3.1%, respectively). Its clinical significance is worthy of attention. We should also pay attention to the possibility of IBD development in HLA-B27-negative patients with AS if they have obvious intestinal symptoms.
In our study, we compared patients with AS with and without EAMs, in whom of EAMs was related to their family history of AS. Patients with AAU or IBD alone showed a relation to their corresponding family history (family history of AAU or IBD). Furthermore, in the longitudinal analysis of new-onset EAMs, we found that any new-onset EAM was related to disease activity (ASDAS) at baseline. Although our findings suggested a link between EAMs and disease activity of AS (ASDAS), it did not necessarily describe causal relationships. The presence of IBD or AAU may also be a manifestation of cumulative exposure to systemic inflammation. Alternatively, patients with IBD or AAU may show more inflammatory activity before its occurrence. Therefore, we should also evaluate the changes in imaging and activity score to determine whether HDA and persistent inflammatory activity are risk factors for EAMs.
This study has several limitations. First, at baseline, we recorded EAMs in patients with AS by asking their medical history and reviewing the medical records of previous related diagnosis and treatment. However, 29 patients could not clearly describe their previous medical history or provide the examination and medical records of diagnosis, which may have led to an underestimation of the prevalence of EAMs. It also highlights the importance of consultation and physical examination of EAMs in daily practice. This can be achieved through some simple inquiries with doctors and then determining whether to recommend the patient to the corresponding specialist for diagnostic examination. Second, because of the relatively long disease duration at baseline, many patients (327/1414, 23.1%) already had EAMs, and we could not include them in the subsequent survival analysis. Among some early cohorts [28, 29] including our study, there was no study in which EAMs or axSpA/AS appeared before the other. This should be further analyzed in collaboration with ophthalmologists, gastroenterologists, and dermatologists. Furthermore, our research was based on real-world data without intervening with patients. Therefore, many patients were lost during the follow-up, the possible reasons for which include a change in long-term residence, transfer of patients to a community hospital for follow-up, and other uncertain factors. We analyzed the baseline characteristics of patients who were lost to follow-up, with no statistical difference; therefore, we believe that there was no significant choice bias (Supplementary Table S2). Finally, we did not discuss the evaluation of imaging, changes in disease activity, and inflammatory markers in this study. This will be supplemented and discussed in our follow-up study.
Herein, we systematically described and analyzed the characteristics and new development of EAMs in Chinese patients with AS. In particular, the occurrence of AAU was positively related to the prolongation of AS duration. Furthermore, HLA-B27-negative patients were more likely to develop IBD. The occurrence of EAMs was related to the increase in disease activity (ASDAS) in patients with AS.