The analysis of gender differences in this large CBP cohort with short duration of complaints allowed us to conclude that, while females are the majority of patients in the original CBP population, males were twice as likely to be diagnosed with axSpA. At the moment of diagnosis of axSpA, males were younger and more often presented with HLA-B27 positivity and imaging abnormalities, including a higher prevalence of syndesmophytes, even though symptom duration was similar to female patients. However, the prevalence of most other SpA features was equally distributed between genders.
Although we noticed differences in disease presentation, the results of our study suggest that similar elements are relevant for the diagnosis of male and female axSpA patients. In fact, despite HLA-B27 positivity and imaging abnormalities being more common in male axSpA patients, they were significantly associated with diagnosing axSpA in both genders. We believe this is this first study to examine the possible relevance of different SpA features in making a diagnosis stratified for gender. This is the first report showing in a CBP cohort that males have a higher probability to be diagnosed with axSpA. Since all patients, suspected of axSpA or not, in our cohort underwent the same protocol (including extensive imaging), the gender difference cannot be attributed to differences in the diagnostic process.
Nevertheless, it is obvious that early axSpA does not have such a clear male gender skewing as r-axSpA, since female patients still represent nearly half of the axSpA population, as previously noted [15, 16]. This suggests that specific gender disparities (e.g. radiographic evidence of sacroiliitis) may become more apparent later in the disease course.
Our finding of male patients being younger at disease onset is in line with findings in the DESIR cohort [16]; considering the strict age span allowed by the inclusion criteria and given that males and females in our cohort had similarly short symptom duration, this likely reflects a true difference in the disease onset, rather than a better recognition of the disease in males. Previous reports on age of onset in male and female axSpA patients mainly concern longstanding disease, and some of them reported that males seemed to have an earlier onset [12, 23, 24]. The mechanism behind this is unclear and deserves further investigation.
The results of this study also confirm that imaging abnormalities are more frequently found in male axSpA patients, already at the beginning of the disease [15, 16, 24]. Moreover, we show that male sex is independently associated with positive imaging, both in terms of MRI inflammation and radiographic sacroiliitis. Remarkably, syndesmophytes were more common in males at baseline, showing that differences in radiographic damage between genders, which have been repeatedly observed in r-axSpA [7, 10, 11], can already be found in very early disease. Also, radiographic or MRI sacroiliitis was the most important item for diagnosis in women, and was significantly more common in both male and female axSpA patients compared to no-axSpA patients.
HLA-B27 was also more common in male axSpA patients, and the overall prevalence of HLA-B27 in axSpA patients in our study was similar to other early axSpA cohorts [25]. However, it has to be noted that in other axSpA populations, such as those of the clinical trials, where axSpA patients are included only if they fulfil ASAS criteria and not based solely on the rheumatologist diagnosis, often display higher percentages of HLA-B27+ patients [26, 27].
In studying the factors associated with sacroiliitis in patients with axSpA, a positive family history was protective of positive imaging even in univariate analysis. At present we have no clear explanation for this observation. Little is known about differences in axial spondyloarthritis between patients with and without a familial history. One study reported that familial ankylosing spondylitis was significantly milder than sporadic disease [28], while another found no difference in disease phenotype [29].
Although PROs were not the main outcome of our study, it is interesting to observe how, in line with data from the literature, female patients in our cohorts presented with a higher subjective disease burden [7, 10, 12, 13]. Unfortunately, our cohort lacks assessment of fibromyalgia, but the observation of female axSpA patients presenting with more extreme PROs than males suggests that fibromyalgia could have been a frequent co-morbidity for our axSpA patients, possibly influencing the degree of symptom complaint in females. Indeed, it has been described that about a third of axSpA patients could have a neuropathic pain component [30].
A clear limitation in our analysis is that our diagnostic models for axSpA do not truly reflect a normal diagnostic work-up in clinical practice, in which looking for—and excluding—other causes of CBP is pivotal. However, the validity of our observations derives from the fact that all of the information included in the model was available to the rheumatologist and was used at the moment of making the diagnosis (axSpA/no axSpA). On the other hand, rheumatologists certainly performed a diagnosis according to their background knowledge and beliefs, and therefore there could have been a tendency towards a specific interpretation of the results (e.g. women could have been under-diagnosed if the rheumatologists interpreted axSpA as a predominantly male disease). Finally, we cannot exclude that possible referral bias may have interfered with the proportion of males and females in the study population or with other results such as the nearly significant prevalence of psoriasis in females. Indeed, the reasons why GPs or medical specialists referred CBP patients to the rheumatologists is unknown, but they could have been more prone to refer a female CBP patient if SpA features (besides HLA-B27 and imaging) were already present or because they had worse symptoms, thus a channelling mechanism cannot be excluded. However, other cohorts have reported a higher frequency of CBP in females [31]; moreover, the male to female ratio in our axSpA population is in line with previous findings [15, 16].