This study was the first to investigate the clinical features and serial outcomes comprehensively according to sex in a large nationwide cohort of Korean patients with RA (KORONA). In Korean patients with RA, most comorbidities were more prevalent in men than in women, except for neoplasm and thyroid and nephrologic disease. However, RA-related health outcomes, the longitudinal change in the disease activity and the rate of achieving clinical remission over time were found to be worse in women RA.
At the baseline enrollment of our cohort, male patients showed a later disease onset and had a significantly higher incidence of large joint involvement at first RA diagnosis. The proportion of seropositive RA patients was not different between men and women, but RF titer was higher in men. The titer of ACPAs was not included in the analysis because of the various ACPAs immunoassays at each center. These presentation patterns of RA according to sex have been inconsistently reported in previous RA studies from other countries . In terms of disease activity and severity, women showed a high proportion of radiographic erosion on hand joints and higher scores of DAS28 and HAQ in our RA population. These results may or may not be consistent with previous studies. Earlier studies have reported a more severe disease among men than women in an RA cohort with long disease duration . However, a number of studies since the 2000s have demonstrated that men exhibit an overall mild disease activity than women. In a Dutch cohort study including patients with early RA (209 women and 123 men), women showed significantly higher DAS and worse radiographic joint destruction and physical disability (HAQ-DI). A Japanese large observational cohort study analyzing 4,823 RA patients also showed high DAS and worse HAQ in women, and the progression of disability was almost three times more rapid in women than in men . Similarly, a Swedish cohort study for early RA patients (538 women, 306 men) showed that women had higher DAS28 and HAQ scores overall, but women below 50 years of age had milder disease than those with older age and closer to that of men .
Besides the composite disease activity index, patient-reported outcomes (PROs) are also important aspects for the comprehensive assessment of RA patients. In our cohort, all subjective health-related outcomes, including VAS for patients’ global health, pain, fatigue and sleep disturbance as well as EQ-5D were worse in women than in men at baseline. In the QUEST-RA study, a large multinational database of RA patients, women have noted worse HAQ, pain, fatigue, and patients’ global VAS compared to men . In addition, women generally tend to report more severe symptoms and poorer scores on questionnaires of self-reported health-related items , and this trend is also evident and maintained during the follow-up period in our study. Hence, physicians who treat RA patients should take into account these sex-related differences when interpreting PROs.
In our study population, the prevalence and distribution of comorbidities were significantly different between men and women, although the comorbidities were grouped by system rather than by disease. Men with RA were more likely to have CV and pulmonary diseases including ILD, while women with RA were more likely to have thyroid, neoplastic, and nephrologic disease. Male predominance of ILD as an extraarticular manifestation of RA has been consistently reported. On the other hand, although CV risk is higher in men compared to women in the general population , a recent meta-analysis on cerebrovascular/CV risks in RA patients showed a similar increased risk between both sexes . The prevalence of major depression is about two-fold higher in women than in men and is reported as the most frequent RA comorbidity with a world-wide prevalence of 15% [26, 27]. However, the sexual disparity in the prevalence of depression was not observed in our RA population. Discrepancies in the sex distribution of comorbidities between previous reports and our study may be attributed to the differences in ethnic group and studied RA population (e.g., early vs. established).
As shown in Fig. 1 and the additional file 1 (Fig. S1), the baseline disease activity, PROs, and longitudinal progress in women were better than those in men in either a whole RA population or a subgroup with moderate to high disease activity at the time of enrollment. However, trends in ESR levels did not differ according to sex in the latter group. To investigate whether sex certainly influences the change of disease activity over time, we conducted GEE analyses with adjustment for within-patient correlation of data. The rate of change of DAS28 was significantly influenced by sex over time in our RA cohort. Our results are similar with the previous evidence by Jawaheer et al. , albeit the patient group of the study was DMARDs-näive at study entry. Other than sex, in the GEE analysis, high baseline DAS28 scores and long disease duration were also considered as significant factors – covariates already known to be unfavorable [29, 30]. Interestingly, the prescription of biologic DMARDs was an insignificant factor in GEE analysis, presumably because the percentage of biologic DMARD users was low in our RA population. Owing to the stringent reimbursement criteria for biologic DMARDs by the Korean health insurance system, the use of biologic DMARDs had been relatively restricted prior to 2014.
The disease process in RA patients may be related to various factors including sex. To identify associated factors for achieving remission, we conducted Cox regression analysis on achieving point remission as well as sustained remission in the population confined to patients with active disease at baseline enrollment. Women with RA achieved remission less frequently than men with RA despite a similar treatment of conventional synthetic DMARDs and more frequent use of biologic DMARDs, which are consistent with the results of previous studies. In early RA patients from the CORRONA registry and British early RA study (ERAS) cohort, male sex was found to be associated with sustained remission [31, 32]. Another study from Finland reported that men achieved remission more frequently than women regardless of the definition of remission. These sexual disparities may be the result of the differences in components of disease activity indices between men and women. For instance, DAS28-ESR is a composite index consisting of ESR and patients’ global health, and reference ranges for ESR vary according to age and sex . In addition, women were found to report more intense pain compared to men in the general population, leading to worse subjective assessment in women with RA as well [34, 35]. Indeed, the improvement in all PROs over 12 years was better in men with RA than in women with RA in a large-scale longitudinal survey . In the additional sensitivity analyses using CDAI and SDAI, other composite disease activity indices not including ESR, women were less likely to achieve CDAI as well as SDAI remission in our RA population. A recent study of two large RA cohorts by Maynard et al.  has shown that women had reduced rates of DAS28-ESR remission but similar rates of other disease activity measures such as DAS28-CRP, CDAI, or RAPID3 as well as objective radiologic MRI measures. In actual clinical practice, a DAS28-ESR of < 2.6 has been the most widely used definition of remission in patients with RA. Taken together, more objective indicators such as imaging studies would be more appropriate for judging remission in women with RA, and the development and investigation of sex-specific tools for assessing disease activity will be warranted in the future. In addition to sex, our study found that seropositivity, high baseline DAS28, high ESR, and long disease duration were unfavorable risk factors for achieving remissions. These factors are well-known poor prognostic factors for the management of RA .
The specific causes for sexual dimorphism in the disease pattern, comorbidities, and disease course in RA patients are unclear, but several explanations have been suggested. Differences in chromosome complement according to sex, including Y-chromosome genes in males and the dosage effect of X-chromosome genes, and gonadal hormones such as estrogen or androgen generate differential effects on immune function . A low muscle mass and a different female body composition can contribute to fragile joint mechanics to some extent. The avoidance of potential teratogenic DMARDs in women of childbearing age with RA might also be a factor affecting sex-related differences.
This study has several limitations. Firstly, most of the serial outcome variables are subjective items rather than objective assessments, such as radiographic joint damage on imaging studies. Secondly, a relatively high percentage of RA patients were lost during the follow-up periods. Moreover, a wide assessment interval (1 year) may not be able to capture a brief flare-up of RA disease activity. Lastly, there may be age-specific effects according to sex hormone status in female patients, but this study did not reflect that effect. Nevertheless, our study has some strengths. As we used a large-scale multicenter database for analysis, the external validity is better than those of studies based on single-center or regional data. In addition, our study is meaningful in that for the first time in Korean patients with RA, the sex-related differences were compared comprehensively in terms of clinical features and longitudinal clinical course. The KORONA data is still being updated, and it is expected that more confirmative results will be obtained in the near future as the number of follow-up patients increases.