1. Introduction
Psoriatic arthritis (PsA) is an immune-mediated musculoskeletal disease that affects both the joint and the enthesis. It affects men and women equally, although differences have been found in phenotype, impact, and response to treatment [
1,
2]. In fact, multiple joint involvement is more common among women, in contrast with men, who are more commonly affected by axial presentations, which are associated with positive HLA-B27 values and greater radiological damage [
3,
4,
5]. As for cutaneous manifestations, most studies report more frequent onychopathy in men [
6]. Differences between the sexes have also been found with respect to the frequency of onset of specific comorbid conditions. Anxiety and depression affect up to 30% of patients with PsA, and, in line with the general population, these conditions are more frequent among women [
7,
8]. Similar data have been reported for fatigue and insomnia [
4,
9], whose greater frequency in women can act as a confounder owing to their potential effect on specific clinical manifestations of PsA, such as pain. Thus, women perceive pain as being more intense, a finding that has been associated with these comorbid conditions or with concomitant fibromyalgia. Irrespective of the origin, the more intense pain perceived by women leads to greater scores in measures of disease activity (most of which include pain as a domain) and to reduced efficacy and persistence of the treatments administered [
10,
11,
12,
13]. Despite the potential presence of other pathophysiologic mechanisms that account for greater intensity in the perception of pain, most studies continue to accept the presence of these confounders—anxiety, depression, and fibromyalgia—as the only explanation. Therefore, few data have been reported on whether a mechanism underlying sex and independent of confounders. Sex hormones clearly play a role in these mechanisms. Models based on male mice show that spinal microglial cells are associated with persistent hypersensitivity to pain, probably via the Toll-like receptor 4 (TLR4), which depends on testosterone [
14]. Estrogens and progestogens, on the other hand, seem to exercise a dual pronociceptive and antinociceptive effect [
15]. The hormone leptin is secreted mainly by adipose tissue, stimulated by ovarian sex hormones, and inhibited by testosterone; therefore, its blood levels are higher in women [
16]. Together with its metabolic function, leptin intervenes in the proinflammatory response by triggering the production of cytokines such as TNF alpha and IL-6, stimulating differentiation between Th1 and Th17 cells [
17,
18,
19], and contributing to abnormal pain processing [
20].
Therefore, the objective of our study was to evaluate the association between demographic and clinical characteristics and sex-related comorbidities in a cohort of patients with PsA.
4. Discussion
Many studies have addressed sex differences in patients with PsA, although these are aimed more at describing the phenotype than at investigating the causes underlying the differences. We found sex to be associated with the presence of specific clinical manifestations; in most of the subjective variables, the association was with disease activity and functioning. Higher leptin concentrations, while not directly associated with obesity, may have intervened in the perception of pain among women.
In most previous studies, the clinical presentation differed between the sexes, mainly in the greater frequency of axial disease affecting men [
3,
5]. Consistent with previous reports, we found a greater presence of axial disease, defined according to the degree of radiological damage. Furthermore, Eder et al. [
3]found that male sex was associated not only with more frequent axial presentation, but also with greater radiological damage. However, these results were not confirmed in recent studies in Turkish and Chinese populations [
39,
40]. In contrast with data reported by Queiró et al. [
5], our results are similar to those from various cohort studies [
3,
39,
40], which did not reveal more frequent polyarticular presentation in women. As for other clinical manifestations, enthesitis was more common among women than among men. These results are consistent with those from the cohorts CORRONA [
41]and ASAS [
42]. However, most studies report no association between sex and the predominance of enthesitis. These differences can be explained by the various methods of measurement applied [
39,
40]. As in other studies, we found no association between sex differences and dactylitis or severity of psoriasis [
3,
4,
5,
39,
40].
We recorded greater disease activity and poorer functioning in patients with peripheral manifestations. These findings are consistent with those of Orbai et al. [
43], whose multinational study covered 14 countries. With respect to disease activity, the findings are also consistent with the data obtained from the Turkish cohort using DAS28, although not with those reported for functioning [
39]. As for axial presentations, we found differences in disease activity but not in functioning. These results are consistent with those reported by Nas et al.[
44] for a study population comprising patients with axial PsA. In the ASAS cohort, significant differences were found in activity and functioning, although the study population was not separated according to whether the patients had axial or peripheral manifestations [
42].
Disease impact was also greater in women, consistent with data reported by
Gossec et al. [
4].
As for comorbidity, we did not find statistically significant differences in BMI between the sexes. Some previous studies report greater BMI in women [
39,
42], possibly because of the inclusion criteria more than the presence of any real sex differences. Serum leptin levels, such as those adjusted for BMI, were higher in women. In physiological terms, this hormone is predominant in women; however, to our knowledge, differences have not been studied in patients with PsA [
16]. In our study population, we found that leptin levels adjusted for BMI were associated with perception of pain. Eder et al. [
3] found no differences between leptin levels and the number of active joints (r: 10; p=0.05). In a further study, these authors did not examine the association between intensity of pain and leptin levels [
45]. A recent study of patients with rheumatoid arthritis found an association between leptin levels and pain, although the authors did not analyze the results by sex[
46]. This association has also been found in other diseases, such as arthrosis [
47]. Animal models have revealed a cellular link between the effects of leptin on the spinal column and the extrasynaptic NMDAR-nNOS–mediated cellular mechanism underlying neuropathic pain [
48].
As for axial manifestations, Hernández-Breijo et al. [
49] studied a cohort of patients with axial spondyloarthritis and reported an association between response to treatment with TNF inhibitors and baseline leptin levels. We found no correlation between axial disease activity and the leptin/BMI ratio. This observation could be explained by the small number of patients included.
Although we excluded patients with fibromyalgia, anxiety, and depression, the scores on the questionnaires associated with these conditions, either directly or indirectly, were higher in women. Moreover, they affected various items on the DAPSA for both sexes. Anxiety and depression have been associated with increased disease activity, especially in terms of the subjective components of the instrument [
38]. However, the fact that they more frequently affect women, irrespective of whether they have PsA, means that they must be considered confounders and not a sex-associated characteristic of the disease. Furthermore, these comorbid conditions affected the subjective variables of disease activity for both sexes, although they were more frequent in women. As for sleep quality, while this can be considered to be closely linked to anxiety and depression, a recent study by our group found an association between sleep quality and disease activity, irrespective of these conditions [
9]. To our knowledge, no other studies have previously associated sleep quality with sex in PsA.
Our study is limited by its cross-sectional design, and although it is not possible to establish causal relationships, in the case of the association between leptin/BMI ratio and intensity of pain, the association favors the effect of leptin on intensity and not the reverse. Studies with other characteristics could better consolidate the effect of higher leptin concentrations in women in more pronounced disease activity, without considering their role in obesity. Our study was also limited by the fact that we did not investigate women’s hormonal status, even though secretion of leptin is known to be associated with estrogen production. Lastly, while there is a direct correlation between BMI and leptin secretion, BMI may not be the best marker to accurately reflect adiposity leading to greater leptin secretion.
Despite its limitations, our study is the first, to our knowledge, to address the role of leptin, a hormone whose secretion is closely linked to sex, as a possible cause of the difference in disease activity observed in women with PsA.
Author Contributions
Conceptualization, C.M. and E.T.; methodology, C.M. and E.T.; statistical analysis, C.M.; data acquisition, C.M., C.C., C.H and M.I; data interpretation, C.M., E.T,L.G.M, C.C.,C.H.,M.I. and A.M.; writing—original draft preparation, C.M. and E.T.; supervision, C.M, E.T.. All authors have read and agreed to the published version of the manuscript.
Table 1.
Demographic, clinical, and disease-related characteristics of patients with psoriatic arthritis.
Table 1.
Demographic, clinical, and disease-related characteristics of patients with psoriatic arthritis.
Total |
n=203 |
|
mean ± standard deviation or number (%) |
Years of education |
11.0 ± 7.0 |
Smoking status |
|
Smoker |
53 (26) |
Former smoker |
93(46) |
Non-smoker |
57 (28) |
Pack-years |
20.0 ± 19.8 |
Conventional synthetic DMARDs |
153 (75) |
Methotrexate |
105 (52) |
Sulfasalazine |
38 (19) |
Leflunomide |
10 (5) |
tsDMARDs |
4 (2) |
bDMARDs |
55 (27) |
TNF inhibitor |
34 (17) |
Other |
17 (8) |
Failure of tsDMARDs or bDMARDs, N (%) |
28(50) |
Clinical form |
|
Peripheral |
|
Mixed |
166(82) |
Axial |
31(15) |
Polyarthritis |
6(3) |
Dactylitis |
20(9.9) 41(20.2) |
mMASES |
1.4 ± 2.0 |
PASI |
1.2 ± 7.7 |
FACIT-Fatigue |
35.8+11.3 |
DAPSA* |
14.9 ± 7.4 |
Pain VAS* |
4.5 ± 2.7 |
Activity VAS* |
4.0 ± 2.6 |
TJC* |
3.7 ± 2.4 |
SJC* |
1.7 ± 1.8 |
C-reactive protein (mg/dL) |
0.8 ± 1.0 |
HAQ* |
0.6 ± 0.6 |
ASDAS-CRP** |
1.7 ± 0.8 |
BASFI** |
3.5 ± 2.8 |
PsAID-12 |
3.4 ± 2.1 |
BMI (kg/m2) |
27.0 ± 4.4 |
Leptin (ng/dL) |
16.8 ± 18.9 |
Leptin/BMI |
0.5 ± 0.6 |
HADS anxiety |
5.7 ± 3.7 |
HADS depression |
4.1 ± 3.6 |
ISI |
8.1 ± 4.7 |
Table 2.
Demographic, clinical, and disease-related characteristics of patients with psoriatic arthritis by sex.
Table 2.
Demographic, clinical, and disease-related characteristics of patients with psoriatic arthritis by sex.
Variable |
Women (n=95) |
Men (n=108) |
P |
Age* |
54.2 ± 10.2 |
55.0 ± 12.3 |
0.4 |
Years of education* |
11.5 ± 4.9 |
10.7 ± 5.10 |
0.5 |
Years since onset* |
9.5 ± 6.2 |
10.4 ± 7.7 |
0.2 |
Smoking status (%) |
|
|
0.001 |
Smoker |
33 (35) |
20 (18) |
Former smoker |
31 (33) |
62 (57) |
Non-smoker |
31 (32) |
26 (24) |
Smoking, pack-years |
15.7 ± 14.2 |
23.3 ± 21.8 |
0.1 |
ts DMARDs or bDMARDs, N (%) |
26 (25.2) |
33 (28.7) |
0.5 |
Failure of tsDMARDs or bDMARDs, N (%) |
16 (64) |
12 (38.7) |
0.06 |
Clinical presentation, N (%) |
|
|
|
Peripheral |
88 (92) |
78 (72) |
Mixed |
7 (8) |
24 (22) |
0.001 |
Axial |
0 (0) |
6 (6) |
Polyarthritis (yes/no) (%) |
8/87 (8) |
12/90 (11) |
0.4 |
Dactylitis (yes/no) (%) |
12/83 (12.6) |
24/84 (22.2) |
0.07 |
Enthesitis |
2.2 ± 2.4 |
0.7 ± 1.2 |
0.001 |
PASI* |
1.1 ± 1.7 |
1.3 ± 1.7 |
0.2 |
FACIT-F |
32.7 ± 11.2 |
38.5 ± 10.8 |
0.001 |
CRP (mg/dL)* |
0.8 ± 1.1 |
0.8 ± 0.9 |
0.4 |
Pain VAS * |
5.2 ± 2.5 |
3.9 ± 2.8 |
0.001 |
Activity VAS * |
4.4 ± 2.4 |
3.6 ± 2.8 |
0.03 |
SJC * |
1.6 ± 1.7 |
1.7 ± 1.8 |
0.7 |
TJC * |
4.2 ± 2.5 |
3.2 ± 2.3 |
0.02 |
DAPSA |
16.4 ± 7.1 |
13.4 ± 7.5 |
0.001 |
ASDAS-CRP* |
2.4 ± 0.8 |
1.5 ± 0.7 |
0.02 |
HAQ-DI* |
0.8 ± 0. 5 |
0.5 ± 0.5 |
0.001 |
BASFI* |
4.9 ± 2.5 |
3.0 ± 2.8 |
0.95 |
PsAID-12 |
4.0 ± 2.1 |
3.0 ± 2.1 |
0.001 |
BMI (kg/m2) |
26.7 ± 5.2 |
27.3 ± 3.5 |
0.06 |
Leptin (ng/mL) |
26.4 ± 22.6 |
8.4 ± 8.6 |
0.001 |
Leptin/BMI |
2.4 ± 0.8 |
1.5 ± 0.7 |
0.001 |
HAS-A |
6.9 ± 3.8 |
4.7 ± 3.2 |
0.001 |
HAS-D |
4.9 ± 3.4 |
3.4 ± 3.5 |
0.004 |
ISI |
9.3 ± 4.9 |
7.0 ± 4.3 |
0.001 |
Table 3.
Correlation between DAPSA components and leptin levels, HADS, and ISI in women.
Table 3.
Correlation between DAPSA components and leptin levels, HADS, and ISI in women.
|
CRP |
VAS pain |
VAS activity |
TJC |
SJC |
Leptin/BMI |
r: 0.0 p=0.8 |
r: 0.2 p<0.02
|
r: 0.1 p=0.1 |
r: 0.0 p=0.5 |
r: 0.1 p=0.1 |
HADS-A |
r: 0.0 p=0.8 |
r: 0.1 p=0.09 |
r:0.2 p<0.03 |
r: 0.0 p=0.9 |
r: 0.0 p=0.9 |
HADS-D |
r: 0.1 p=0.1 |
r: 0.2 p<0.005
|
r: 0.2 p<0.02 |
r: 0.1 p=0.08 |
r: 0.2 p<0.04 |
ISI |
r: 0.0 p=0.9 |
r: 0.35 p<0 .001
|
r: 0.1 p=0.1 |
r: 0.2 p<0.01 |
r: 0.2 p<0.04 |
Table 4.
Correlation between the components of DAPSA and leptin levels, HADS, and ISI in men.
Table 4.
Correlation between the components of DAPSA and leptin levels, HADS, and ISI in men.
|
CRP |
VAS pain |
VAS activity |
TJC |
SJC |
Leptin/BMI |
r: 0.02 p=0.7 |
r: 0.07 p=0.46 |
r: 0.0 p=0.47 |
r: 0.02 p=0.7 |
r: 0.06 p=0.5 |
HADS-A |
r: -0.0 p=0.3 |
r: 0.37 p<0.001 |
r: 0.1 p=0.2 |
r: 0.0 p=0.3 |
r: 0.0 p=0.7 |
HADS-D |
r: -0.1 p=0.2 |
r: 0.4 p<0.005 |
r: 0.1 p=0.06 |
r: 0.0 p=0.3 |
r: -0.1p=0.8 |
ISI |
r: -0.7 p=0.4 |
r: 0.51 p<0.001 |
r: 0.36 p<0.001 |
r: 0.30 p<0.01 |
r:-0.0 p=0.5 |