INTRODUCTION
Sjögren’s syndrome (SS) is a chronic, slowly progressive autoimmune disease characterized by lymphocytic infiltration of exocrine glands resulting in dry mouth (xerostomia) and dry eyes (xerophthalmia). The syndrome has unique clinical features, from organic autoimmune exocrinopathy to systemic disease (1). Lungs, kidneys, thyroid gland, muscles, heart, nervous system and skin can be affected and symptoms of fatigue, depression, cognitive disorders, pain and mild arthritis are present (2). A small but significant number of patients develop lymphoma (1). The condition can be primary or secondary — as part of some other autoimmune event (3). The prevalence of primary Sjögren’s syndrome (pSS) is ~ 0.5–1%, while secondary SS (sSS) develops in 5–20% of patients with other autoimmune diseases (1). Women develop SS significantly more often than men; the gender difference ranges between 9:1 and 19:1. Average age at first diagnosis of pSS is 56 years old. However, the first symptoms may appear several years before diagnosis (4). Some studies indicate that the gender ratio and age distribution depend on the ethnicity and geographical area of the researched population. SS rarely occurs in children, and the onset has been described as early as the fifth year of life (3). Most patients with SS have symptoms related to impaired salivary gland function. Patients mostly complain of difficulty swallowing food, altered sense of taste, burning sensation in the mouth and more frequent occurrence of cavity. Oral candidiasis stands out as another complication of xerostomia (5). Ocular involvement is the second main manifestation of SS (3). Almost three-quarters of pSS patients present with signs or symptoms of extraglandular disease, but only approximately 25% of pSS patients develop moderate or severe extraglandular disease (6). SS is associated with various respiratory symptoms. The most typical manifestations are chronic interstitial lung disease (ILD) and tracheobronchial disease. The most common manifestation of ILD is nonspecific interstitial pneumonia with fibrosis (NSIP). Tracheobronchial disease is common and is characterized by diffuse lymphocytic infiltration of the airways. It can appear in the form of bronchial hyperreactivity, bronchiectasis, bronchiolitis or repeated respiratory infections (7).
It is important to emphasize the association of SS with other autoimmune diseases, especially with primary biliary cholangitis (PBC) and Hashimoto’s thyroiditis. PBC and SS are described as autoimmune epithelitis in which apoptosis in both cases may be a key element to explain the organic immune-mediated injury of biliary epithelium and epithelium of exocrine glands. Antimitochondrial antibodies in the serum of patients with
SS detected by indirect immunofluorescence highly predict the development of PBC during a five-year follow-up period (8). Various studies have established the coexistence of SS and autoimmune thyroid diseases (AITD) and pointed to the fact that both diseases are characterized by the presence of lymphocytic infiltrates, especially CD4+ T lymphocytes and activation of B cells. The presence of specific chemokines, such as CXCL10, have been described in AITD as markers of an inflammatory response leading to tissue destruction and consequent hypothyroidism, while in SS it has been shown that glandular epithelial cells produce CXCL9 and CXCL10, thereby contributing to the damage of the salivary glands (9).
The development of B-cell non-Hodgkin’s lymphoma is the main complication of the disease and can occur in 5–7% of patients with SS, usually within 10 years of diagnosis (6). In one study, an almost sevenfold higher risk of developing lymphoma was found in SS patients compared to the healthy population (10).
A meta-analysis of observational cohort studies showed that pSS is characterized by an almost one and a half times higher risk of cardiovascular diseases, including coronary artery disease, acute coronary syndrome, angina pectoris, ischemic heart disease and cerebrovascular disease, compared to control subjects (11).
The goals of this paper were to examine the differences in clinical manifestations and comorbidities between men and women with SS treated at UHC Split and to compare the results of our study with results from the available literature.
SUBJECTS AND METHODS
The conducted research is retrospective, observational and cross-sectional. Data from outpatient clinics, inpatient facilities and day hospitals of the Division of Rheumatology and Clinical Immunology of the Department of Internal Medicine, Split University Hospital Centre were used. All patients older than 18 years of age who were registered at the Division of Rheumatology and Clinical Immunology from January 1st, 2010 to December 31st, 2020, and who had at least two visits, examinations or hospitalizations at the Division during the follow-up period. As an inclusion criterion, we used the diagnosed SS according to the 2016 ACR/EULAR criteria. By inspecting the patients’ medical history, we collected data on age, gender, clinical manifestations and comorbidities. From the clinical manifestations, we took into account the following: the existence of cutaneous manifestations, vasculitis, lymphoma, haematological and immunological manifestations, involvement of the joints, nervous system, kidneys, lungs and gastrointestinal system. From the group of comorbidities, we recorded the following: cardiovascular diseases, hypertension, degenerative diseases of the spine, hypothyroidism, diabetes (DM), dyslipidemia, systemic infections, associated neoplasms and accompanying autoimmune diseases (rheumatoid arthritis – RA, systemic lupus erythematosus – SLE, systemic sclerosis – SSc).
We made a basic division of SS into pSS and sSS, whereby we described each SS with an additional diagnosis of SLE, RA or SSc as secondary. We singled out the overlap syndrome as a separate category and evaluated it when it was prominent in the clinical findings. In the cardiac involvement variable, we included diseases of the pericardium, myocardium, endocardium, heart valves and coronary blood vessels, as well as heart rhythm disorders. Under haematological manifestations we included anaemia, leukopenia and thrombocytopenia, and under immunological manifestations we included polyclonal hypergammaglobulinemia, IgA and IgG immunodeficiency, common variable immunodeficiency, monoclonal gammopathy and monoclonal gammopathy of undetermined significance (MGUS). The study was approved by the Ethics Committee of UHC Split.
Statistical processing
The collected data were entered into a computer database, using the SPSS 20 software for Windows (IBM, New York, USA). We used the χ 2 test, Fisher’s test, Fisher-Freeman-Halton test, univariate logistic regression, Firth univariate logistic regression and multivariate logistic regression. A P-value of less than 0.05 was considered as statistically significant. Data are presented as absolute values, percentages, OR odds ratio and 95% confidence intervals 95% CI).
RESULTS
The research included 317 patients with SS. The median age of the subjects was 64 (min-max: 19–89). We divided the subjects into 3 groups according to age: < 59, 59–69, > 69. Out of the total number of subjects there were 17 (5.4%) men and 300 (94.6%) women.
Table 1 shows that there was no statistically significant association of clinical manifestations with gender. Nevertheless, it is worth emphasizing that the most common cutaneous manifestations were Raynaud’s phenomenon (RP) (15%), discoid lupus (11%), erythematous cutaneous manifestations (8%) and alopecia (7%). The share of other recorded cutaneous manifestations is shown in Figure 1.
Likewise, in the category of nervous system diseases, which we divided into central and peripheral nervous system, the prevalence of central nervous system involvement (epilepsy, demyelinating diseases, cerebrovascular disease, condition following meningoencephalitis, CNS vasculitis, central vertigo, extrapyramidal disorders, cerebrovascular insult, headache) was 5.7%, and the share of peripheral neuropathies was 7.6%.
From the data shown in Table 2, it can be seen that men have a higher frequency of lung diseases, vasculitis, lymphoma and primary SS, while women have a higher incidence of hypothyroidism.
Our results indicate a significant association between vasculitis and the male gender, with the proportion of vasculitis being 4 times higher in men than in women. The most common form is cryoglobulinemic vasculitis with a prevalence of 29%, followed by leukocytoclastic vasculitis (17%) and CNS and systemic vasculitis (12%). Nodular and urticarial vasculitis had the lowest incidence (6%).
The frequency of lung diseases is 2.7 times higher in men than in women. Figure 2 shows the share of different lung diseases, of which we single out interstitial lung disease as the most represented entity. It should be emphasized that pulmonary fibrosis was the most common form of ILD with a 40% incidence, followed immediately by idiopathic interstitial pneumonia with a 20% incidence and sarcoidosis with a 16% incidence, while the fewest recorded cases were bronchiolitis obliterans with organized pneumonia (8%).
Table 2 also shows that the proportion of lymphoma is 8.8 times higher in men than in women, while the chance of lymphoma is 10.5 times higher in men than in women. All lymphomas evaluated in the study were non-Hodgkin’s lymphoma.
Out of a total of 89 cases of diagnosis of hypothyroidism, all 89 were diagnosed in women, so the proportion of women with hypothyroidism was 29.7%, and taking into account the men in our sample it was 0%. Thus, by the resulting calculation, it can be concluded that the chance of hypothyroidism is 14.8 times higher in women than in men.
We also analysed clinical manifestations and comorbidities in relation to three age groups (<59, 59–69 and > 69) because these three age groups are adjusted according to gender. Out of the clinical manifestations, haematological manifestations including thrombocytopenia were statistically significantly different between age groups (Table 3).
The attached table shows that the chance of occurrence of haematological manifestations in the group of patients aged 59–69 years old is 20% lower compared to the group of patients <59 years old (P= 0.206), while the chance of occurrence of haematological manifestations in the group of patients > 69 years old is by 40% lower compared to the group of patients <59 years old (P=0.02). Following the analysis of the prevalence of clinical manifestations, the chance of occurrence of thrombocytopenia in the group of patients <59 years is 14.6 times higher than in the group of patients 59–69 years old (P= 0.07), while the chance of occurrence of thrombocytopenia in the group of > 69 years old by 4.9 times higher than in patients 59–69 years old (P=0.31).
Although there was no statistically significant correlation in the prevalence of kidney diseases with gender (Table 1) and among the observed age groups, it is certainly important to point out that in the study we had a total of 41 (12.9%) patients with one of the diagnosed kidney diseases, of which one (5.9%) was a man, and 40 (13.3%) were women. Out of the 41 cases of kidney disease, there was one biopsy-confirmed tubulointerstitial nephritis (TIN) with renal tubular acidosis type I and one TIN with mesangio proliferative glomerulonephritis.
All significantly associated comorbidities with SS, shown in Table 4, were associated with age groups in a positive direction, i.e. with increasing age, the proportion of patients also increased, with the exception of APS, which in our cohort was recorded in 3.8% cases, which was negatively related to age groups. For this reason, when performing the logistic regression for these comorbidities, we used the group < 59 years old as the reference level. The probability of occurrence of APS in the group of patients aged 59–69 years old is 40% lower compared to the group of patients <59 years old (P=0.178), while the probability of APS in the group of patients >69 years old is 65% lower compared to the group patients <59 years old (P=0.0508).
Using multivariate logistic regression in which we took each of the observed clinical manifestations and comorbidities as dependent variables, and gender and age groups as independent variables, we confirmed the association of pSS with gender and age groups (Table 5, Figures 3 and 4).
From the presented results, it can be concluded that the probability of primary SS in the group of patients <59 years old is 2.1 times higher compared to the group of patients 59–69 years old (P=0.013). The chance of occurrence of primary SS in men is 8.7 times higher than in women (P=0.038). From the results of the multivariate logistic regression (Figures 3 and 4), it can be seen that in men, once they develop SS, it is usually pSS without other associated autoimmune diseases, in contrast to women who often already have a known diagnosis of RA or SLE which is often followed by sSS. In our study, the number of diagnosed sSS was 79, of which only one was male and 78 were female.
DISCUSSION
The main results of our research indicate the existence of obvious differences in clinical manifestations and comorbidities between men and women suffering from SS. With statistical significance, we proved that gender and lung diseases are related in our sample of subjects. The more frequent incidence of lung disease in men with SS was also confirmed by a study conducted by Swedish authors (12). Male gender is widely recognized as a risk factor for the development of interstitial lung disease. The reasons for such male dominance are poorly understood, however, they could be the result of higher seropositivity, exposure to environmental pollutants and more frequent smoking. Idiopathic pulmonary fibrosis is the most common form of interstitial lung disease detected in pSS and is more preventable in men (13, 14).
In the study, we also proved a significant association of lymphoma with gender. A study of almost 1,000 patients with pSS reported a higher incidence of lymphoma in men, while a study by Vasaitis et al. showed that men compared to women had a shorter average time from pSS diagnosis to lymphoma diagnosis (1 vs. 8 years) and more often had lymphoma localized in the salivary glands (56% vs. 29%) (12, 15).
Horvath et al. found that autoimmune thyroiditis is highly prevalent in women and, according to our study, no cases were found in men, in contrast to 7% occurrence in women (16). Such results are explained by the fact that systemic autoimmune diseases characteristically appear more often in women, which emphasizes the importance of female sex hormones in the pathogenesis of these diseases. Estrogen metabolites, especially their hydroxylated forms, increase the rate of B-cell differentiation leading to increased production of autoantibodies and activation of T-cells with consequent secretion of pro-inflammatory cytokines.
The study by Strikić Đula et al also testifies to the higher prevalence of thyroid disease in women in general. in which it was noted that women have a 47% lower chance of euthyroidism than men. In addition, women had 1.57 times the odds of antibody-positive euthyroidism, 2.1 times the odds of subclinical hyperthyroidism, 2.37 times the odds of clinical hypothyroidism, and 1.58 times the odds of subclinical hypothyroidism (17).
We showed a significant association between vasculitis and male gender, but the small number of men in the sample should be taken into account. A higher frequency of vasculitis in men was also recorded in a study in which men presented more often with La/SSB, Ro/SSA and ANA positivity, which resulted in higher immune activity (18). This increased response of the immune system could have contributed to the more frequent occurrence of vasculitis. This is supported by the observations of Scofield’s study, in which a connection was observed between the occurrence of vasculitis and certain immunological changes, such as hypocomplementemia, cryoglobulinemia, and the presence of anti-Ro and La antibodies (19).
The most common observed cutaneous manifestation was RP, which was present in a total of 22 (7%) patients and with a higher frequency in women. Here we also included patients who were diagnosed with CREST syndrome. In other studies, this prevalence was up to 33% (20, 21). The different geographical areas where the research was conducted could explain this difference in results. It is known that a colder climate can exacerbate the development of RP along with other risk factors, such as emotional stress. A higher frequency of RP in women was also proven in the studies of Brandt et al. and Horvath et al. (2, 16). Sex hormones are considered to play an important role in the pathogenesis of RP, whereby the incidence of RP-like vasospastic reactions increases with oestrogen administration and in the preovulatory period (22).
In the study by Narváez et al. the prevalence of kidney diseases in pSS was 9%, where 38 cases out of 39 were in women, according to the results of our research (23). It should be emphasized that our study included patients with pSS and with sSS that developed as part of some other autoimmune disease. We emphasize this especially in the analysis of kidney diseases, where certainly a good part of the total kidney disorders can be attributed to the primary disease, for example SLE, in which sSS developed, and kidney involvement is a consequence of lupus nephritis. To determine the true prevalence of kidney involvement in pSS, while excluding the influence of associated diseases, such as SLE, it is necessary to perform kidney biopsy more often.
In the Sjögrenser study, which included 437 patients with pSS, the prevalence of gastrointestinal complaints was 16.2% (24). Gastritis was the most recorded (29.5%), which was also the case in our study, but with an even higher percentage (48.6 %). Atrophic gastritis appears to be age-related as its incidence increases with age, which may explain the different research results. Under gastrointestinal diseases, we also classified PBC, of which there were four in total, and all PBCs were diagnosed in women.
Numerous sources report CNS involvement in pSS with a frequency of 2–5% (25, 26). Similar results were shown by our research, in which the prevalence of CNS involvement was 5.7%, of which all forms of CNS involvement were also diagnosed in women. The same observations were made by the study of Ramírez Sepúlvedo et al. (18). Peripheral neuropathies are a more common form of neurological manifestations in pSS and occur in 5–15% of cases (27). In a cohort study in which there were 400 patients with pSS, a frequency of peripheral neuropathies of 7% was recorded, which is almost equal to the result of our research, where this incidence was 7.6% (28).
In the analysis of haematological manifestations in relation to age groups, we found a statistically significant association between thrombocytopenia and age. The more frequent incidence of thrombocytopenia at a younger age was also proven by the study by Maria Ramos-Casals et al. which was conducted on a Spanish cohort (29). In her research, Ro/La positive patients were recognized at a younger age with a higher frequency of positive diagnostic tests (parotid scintigraphy, salivary gland biopsy), enlarged parotid glands, more frequent extraglandular manifestations (Raynaud’s phenomenon – RP, arthralgias, arthritis, vasculitis, kidney involvement and peripheral neuropathy) and cytopenia (leukopenia and thrombocytopenia) and positive immune markers (ANA, RF and cryoglobulins) in univariate analysis (29).
Out of the comorbidities that we observed in the research, namely cardiovascular diseases, hypertension, degenerative diseases of the spine, diabetes, dyslipidemia and associated autoimmune diseases (RA, SLE, SSc), all of them occurred significantly more often in older patients. In addition to age, which is one of the key risk factors for the development of the above-mentioned conditions, the characteristics of SS, including inflammation and specific treatment, which contribute to the development of concomitant diseases, also stand out. In a study by Pérez-De-Lis et al. it was found that elevated levels of CRP in patients with pSS may contribute to a higher frequency of atherosclerotic cardiovascular damage, and glucocorticoid therapy was clearly associated with a higher prevalence of cardiovascular risk factors, especially diabetes, hypertension and hypertriglyceridemia (30).
In our study, APS showed a negative correlation with age groups, i.e., with increasing age, the proportion of patients decreased. In a Brazilian study, the frequency of APS in patients with pSS was 3%, which is in accordance with our results (3.8%). Prolonged lupus anticoagulant (LAC) in pSS is a predictor of stroke and deep vein thrombosis, especially in young patients (31). This is consistent with our observations where APS occurs more often in younger age groups with statistical significance.
CONCLUSION
The results of our research indicate the existence of obvious differences in clinical manifestations and comorbidities between women and men suffering from SS. Lung diseases, lymphoma and vasculitis occurred many times more often in men than in women, in contrast to hypothyroidism, which is significantly associated with the female gender. All cases of PBC and CNS involvement were recorded in women, while pSS was significantly associated with male gender and younger age. Thrombocytopenia and APS also had a higher incidence in younger age groups. The probability of developing SS is lower in men than in women, but men who develop SS are more likely to have a more severe form of the disease.
Conflict of interest statement: The authors declare no conflict of interest.
REFERENCES / Literatura
31. Pasoto SG, Chakkour HP, Natalino RR, Viana VST, Bueno C, Lianza AC i sur. Lupus anticoagulant: a marker for stroke and venous thrombosis in primary Sjögren’s syndrome. Clin Rheumatol. 2012;31:1331–8.
Table 1 Distribution of patients by age groups and type of clinical manifestations that did not differ significantly between the genders
Tablica 1. Raspodjela bolesnika prema dobnim skupinama i vrsti kliničkih manifestacija koje se nisu statistički značajno razlikovale među spolovima
Legend / Legenda: GI system = gastrointestinal system / gastrointestinalni sustav. aχ 2-test, bFisher’s test / Fisherov test. Data are presented as absolute value and percentage / Podatci su prikazani kao apsolutna vrijednost i postotak.
Figure 1 Proportion of different cutaneous manifestations in Sjögren’s syndrome patients
Slika 1. Udio različitih kožnih promjena u bolesnika sa Sjögrenovim sindromom
Table 2 Distribution of Sjögren’s syndrome patients according to type of disease and clinical manifestations where a significant difference between the genders was proven.
Tablica 2. Raspodjela bolesnika prema vrsti kliničkih manifestacija gdje je nađena značajna razlika među spolovima
Legend/ Legenda: SS = Sjögren’s syndrome / Sjögrenov sindrom. aχ2-test, bFisher’s test / Fisherov test, cFisher-Freeman-Halton test, dlogistic regression / logistička regresija, eFirth logistic regression / Firth logistička regresija. Data are presented as absolute value and percentage / Podatci su prikazani kao apsolutna vrijednost i postotak
Legend/ Legenda: COPD / KOPB = chronic obstructive pulmonary disease / kronična opstruktivna plućna bolest
Figure 2 Proportion of certain lung diseases in Sjögren’s syndrome patients
Slika 2. Udio pojedinih plućnih bolesti u bolesnika sa Sjögrenovim sindromom
Table 3 Odds ratio (OR) with 95% confidence interval for clinical manifestations significantly associated with age groups.
Tablica 3. Omjer izgleda (OR) uz 95-postotni interval pouzdanosti za kliničke manifestacije koje su statistički značajno povezane s dobnim skupinama
Legend / Legenda: OR = odds ratio / omjer izgleda. dlogistic regression / logistička regresija, eFirth logistic regression / Firth logistička regresija
Table 4 Odds ratio (OR) with 95% confidence interval for comorbidities significantly associated with age groups.
Tablica 4. Omjer izgleda (OR) uz 95-postotni interval pouzdanosti za komorbiditete koji su značajno povezani s dobnim skupinama
Legend / Legenda: DM= diabetes mellitus / šećerna bolest; RA= rheumatoid arthritis / reumatoidni artritis; SSc = systemic sclerosis / sistemska skleroza ; SS= Sjögren’s syndrome / Sjögrenov sindrom ; APS= antiphospholipid syndrome / antifosfolipidni sindrom. d logistic regression / logistička regresija
Table 5 Results of multivariate logistic regression between Sjögren’s syndrome, age and gender.
Tablica 5. Rezultati multivarijantne logističke regresije između primarnog Sjögrenova sindroma, dobi i spola
Legend / Legenda: SS = Sjögren’s syndrome / Sjögrenov sindrom.* reference level / referentni nivo, ** logistic regression / logistička regresija, *** for the group <59 years / za skupinu < 59 godina
Age /Dob < 59 g.: N pSS=9; Age / Dob > 69 g.: N pSS=3; Age / Dob 59 – 69 g.: N pSS = 4
0 = absence of pSS in one male of the age group > 69 years / odsustvo pSS kod jednog muškarca iz dobne skupine > 69 godina (diagnosis / dijagnoza: sSS)
Legend / Legenda: N = number /broj ; pSS = primary Sjögren’s syndrome / primarni Sjögrenov sindrom ; sSS = secondary Sjögren’s syndrome / sekundarni Sjögrenov sindrom
Figure 3 Distribution of primary Sjögren’s syndrome (pSS) according to the age groups among males
Slika 3. Raspodjela bolesnika s primarnim Sjögrenovim sindromom (pSS) u muškaraca prema dobnim skupinama
Age / Dob < 59 yrs. of age /god.: N pSS=74; Age / Dob > 69 yrs. of age / god.: N pSS= 60; Age / Dob 59–69 yrs. of age /god.: N pSS= 54
0 = absence of pSS in a certain number of women in all age groups / izostanak pSS-a kod određenog broja žena u svim dobnim skupinama (diagnosis /dijagnoza: sSS and / i syndrome overlap)
Legend/Legenda: pSS = primary Sjögren’s syndrome / primarni Sjögrenov sindrom ; sSS = secondary Sjögren’s syndrome / sekundarni Sjögrenov sindrom
Figure 4 Distribution of primary Sjögren’s syndrome (pSS) according to age groups among females
Slika 4. Raspodjela bolesnika s primarnim Sjögrenovim sindromom u žena prema dobnim skupinama