Discussion
In our study, we assessed the presence of gender differences in clinical manifestations, autoantibody positivity, disease course, therapy and organ damage in a large monocentric cohort of Caucasian patients with SLE. As reported herein, we observed that the overall clinical expression of SLE was quite similar for both sexes, with no significant differences in major organ involvement and rate or severity of relapses. We also noted that, similar to previous observations, Caucasian men of our cohort had a higher prevalence of serositis,13–15 an older mean age at disease onset16 17 and a higher rate of smokers when compared with female counterparts.
Women had a higher prevalence of haematological abnormalities, higher cumulative exposure to AZA and higher cumulative dose of GCs at 5 years.
The higher use of AZA in women may be due to different needs related to gender: in women, indeed, disease onset usually occurs during childbearing age, and AZA is generally considered to be safe during pregnancy.
Univariate analysis also revealed that male sex was associated with greater damage accrual at 1 and 5 years, consistent with findings from large multiethnic inception cohorts such as Lupus in Minority Populations: NAture versus Nurture (LUMINA)17 and SLICC.18
However, unlike LUMINA,17 this study did not observe any significant difference in damage scores17 over the follow-up period. Generally speaking, damage accrual is influenced by genetic predisposition, age, lifestyle, comorbidities, disease severity and course, delay in diagnosis and treatment, type of organ involvement, GC use, adverse reactions to drugs and compliance of the patient.
In our cohort, the earlier damage accrual in men could be due to several factors, the first of which is older age at disease onset in men. Indeed, it is well known that in the general population, SDI items such as stroke, angina, myocardial infarction, valvular disease, renal impairment, cataracts, retinopathy, diabetes and malignancy are more common with increasing age. According to the results from the SLICC inception cohort,18 age has a non-linear effect on damage. Older patients may therefore have a greater sensitivity to inflammation and drug adverse effects due to reduced organ reserve.17
Another important possible contributor to early damage is smoking; indeed, in our cohort, there is a high frequency of smokers, especially among men.
Logistic regressions were performed to estimate the effect of sex on damage, controlling for age at onset, disease duration and smoking. The multivariate analysis confirmed that male sex is an independent predictor of damage at 5 years, but this association was no longer significant when late-onset patients were excluded. Therefore, the results suggest that age at disease onset is more strongly associated with damage than male sex in our cohort.
A lower median cumulative dose of GCs was also observed in men at 5 years; we could hypothesise that accelerated damage accrual could be due to less aggressive treatment approach. Interestingly, GC-related damage was similar in both groups.
Our results also did not confirm a higher risk of developing CKD17 19 20 and CV events17 19 20 in male patients. Interestingly, despite a higher prevalence of smokers among men, arterial CV events occurred at comparable rates, ages and disease durations in both sexes (see table 5), which is not the case for the general population.21 Noteworthy, women in the study had a significantly lower median age at their first CV event (46 (38–57) years) compared with the general population. According to the Italian National Institute of Health,22 the prevalence of acute myocardial infarction in the general adult population is 1.6% in men and 0.6% in women, while cerebrovascular accidents occur in 0.7% of patients, regardless of sex. Consistently with previous observations, in our cohort the prevalence of CV events was remarkably higher (11.76% in men and 8.81% in women). Systemic inflammation, indeed, promotes atherosclerosis and patients with SLE have an increased risk (9–50 folds) of developing CV events compared with the population of similar age without SLE, especially those aged 36–45 years.23–25
Also osteoporosis occurred at a similar rate in both sexes (17.4% vs 23.5%, p=0.6; male to female ratio 1:1.35), while in the general population, the ratio is 1:3.26 27 The aetiology of bone loss in SLE is multifactorial, including traditional osteoporosis risk factors (such as age and menopause), inflammation and drug-induced adverse effects.28 29
The high prevalence of osteoporosis in our male patients could be due to several factors: use of GCs, a well-known risk factor for secondary osteoporosis,30 older age at last visit, higher prevalence of smoking (50% of male patients with OP vs 26% of female patients), and a non-negligible presence of patients with androgen deficiency (5.6% of all men, 12% of those with OP).
Another interesting finding is that, unlike previous studies, we did not detect any difference in the presence of anti-dsDNA31 32 and other autoantibodies, including antiphospholipid (aPL) autoantibodies, between men and women.
Nevertheless, men had a higher rate of APS, suggesting that other factors, such as smoking, can play a crucial role in the pathogenesis of the syndrome in these cases.33 Indeed, in our cohort, 23 of 70 (32.85%) patients with APS were smokers (53.8% of men vs 20.1% of women). Additionally, men were older, and the role of atherosclerosis in arterial events cannot be excluded. Thus, the first limitation of this analysis relies on the fact that it is not easy to completely understand the real contribution of aPL to vascular events with respect to traditional CV risk factors.
Other limitations include the retrospective study design and the lack of information on the degree of patient’s adherence to the treatments, which may influence damage progression.
Moreover, due to the small subgroup of male patients, the possibility of committing a type II statistical error could not be excluded. Furthermore, this is an observational study in a tertiary referral centre for SLE, a limitation in the generalisability of the results cannot be excluded. Therefore, selection bias cannot be ignored. We tried to reduce the possible impact using a propensity analysis and repeating the elaboration after eliminating the late-onset group from the sample.
Our study has several strengths. Patients in our cohort have a homogeneous ethnic and geographical background. Moreover, the prospective collection of data, the long-term follow-up time and the completeness of the clinical data due to a good adherence to routine visits should be considered. Moreover, evaluation of clinical outcomes at 1, 5 and 10 years, permits limitation of potential bias due to a different disease duration and follow-up.
In conclusion, we have described a large Caucasian population focusing on sex and gender differences in disease course, therapy and damage. Our findings suggest that, in Caucasians, men and women have a more similar disease course than expected.
However, male patients displayed higher prevalence of APS and earlier damage accrual probably due to the later disease onset. These data highlight the importance of an intensive follow-up, prevention and treatment of complications in this category of patients, especially in the first years of disease.