The aim of this retrospective, single-centre study was to investigate the clinical and laboratory features and disease outcomes of 547 patients diagnosed with primary Sjögren’s syndrome (pSS) between 1975 and 2010. The patients were followed up for
With a prevalence of 0.2%–1.4%, primary Sjögren’s syndrome (pSS) is one of the most common chronic, slowly progressing systemic autoimmune diseases; its main symptoms are keratoconjunctivitis sicca and xerostomia. The extremely various clinical picture is characterized by multiple extraglandular manifestations (EGMs) and associated diseases. This disease affects predominantly middle-aged women, the gender ratio being 9-10 to 1; however, both distributions by age and by gender show geographical and ethnic differences [
Based on its prevalence and clinical variety, pSS is high on the list of systemic autoimmune diseases; however, there are only few publications on factors influencing mortality. According to the available literature data, geographical characteristics, ethnic groups, number of patients, studied aspects, and follow-up periods show significant differences. The applied classification criteria (particularly in studies performed before 2002) are not coherent in studies, making the comparison difficult. Investigations focusing on defining risk factors predisposing to development of lymphoproliferative diseases (LPD) are reported in several studies [
A long-term follow-up study called attention to frequent concomitant occurrence of LPD, glomerulonephritis, and hypocomplementemia, as well as cutaneous vasculitis and mixed cryoglobulinemia. The mortality was twofold higher compared to normal population, and hypocomplementemia, mixed cryoglobulinemia, and purpuras were considered as adverse prognostic factors [
Davidson et al. emphasized the high incidence of thyroiditis with hypothyreosis in patients with seronegative pSS and the role of certain serological abnormalities (antinuclear antibody (ANA) or rheumatoid factor (RF) positivity) in increased tendency to progression toward rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). They have confirmed that the risk for LPD is increased in pSS patients with parotidomegaly, lymphadenomegaly, and antibody positivity to Sjögren’s syndrome-specific nuclear and cytosolic antigens (anti-SS-A/-SS-B) [
In a large population of pSS patients, after solid tumours, the second most common cause of death was LPD, which manifested before the diagnosis of pSS in 40% of cases. An unfavourable histological finding was considered to be the most powerful predictor of mortality, and other listed factors included lymphadenopathy, palpable purpura, parotidomegaly, low complement 4 (C4) levels, and positivity for RF and ANA. The establishment of a “high-risk” or “type I autoimmune epithelitis” risk group was recommended in patients with parotidomegaly, palpable purpura, seropositivity for anti-SS-A or anti-SS-B, or hypocomplementemia, who are at high risk of developing an LPD. Additionally, it has been noted that LPD tends to develop concomitantly with glomerulonephritis and peripheral neuropathy [
Studies described differences also in the geographic variation of disease. An investigation in Asia revealed that unlike other geographical areas, the onset of pSS occurs earlier (at 30–39 years of age) in China; the percentage of patients with systemic symptoms is significant, above 90%. The incidence of lung and kidney involvement, pericarditis, myositis, and pancreatitis is high, while the chance for developing Raynaud’s phenomenon is minimal. Thyroiditis was recorded in one third of patients. Infections, especially pneumonia, accounted for more than 60 percent of deaths. Mortality caused by liver insufficiency was manyfold higher than that of cardiovascular or cerebrovascular origin. Pulmonary artery hypertension (PAH), interstitial lung disease, liver cirrhosis, and consistently high immunoglobulin M (IgM) levels were indicated as mortality risk factors [
The purpose of our retrospective study was to assess the clinical and laboratory features and the disease outcomes of 547 pSS patients. We evaluated the influence of the main disease features on the time of diagnosis and mortality ratios.
The Division of Clinical Immunology of the University of Debrecen is one of the largest tertiary referral centers in Hungary for systemic autoimmune diseases. In the present study, we collected all the patients who were diagnosed and followed up regularly with primary Sjögren’s syndrome between 1975 and 2010 at our center. From the whole group of these 1094 patients, we gained a random sample by using a systemic sampling method. After arranging their name in alphabetical order, we selected every second patient for the analyses. Consequently, the final population of our retrospective study consisted of 547 (487 women and 60 men, gender ratio = 8 to 1) patients with pSS. Before 2002, Fox RI criteria [
During follow-up visits, EGMs, associated diseases, and immunoserological characteristics were recorded. Immunoserological tests were performed at the Regional Immunology Laboratory of the University of Debrecen and included the measurement of ANA, RF, antibodies against extractable nuclear antigen (ENA), anti-SS-A, anti-SS-B, anti-DNA, anti-thyroglobulin (TG), anti-thyroid peroxidase (TPO) antibody, serum immunoglobulin, cryoglobulin, and complement levels. The quantitative measurement of autoantibodies (anti-ENA, anti-SS-A/-SS-B, anti-CCP, anti-TG, anti-TPO, ANA, RF, and anti-DNA) was performed with enzyme-linked immunosorbent assay (ELISA) technique. Immunoglobulin levels and complement activity were determined with turbidimetry and nephelometry techniques and haemolysis test in sheep red blood cell suspension, respectively. The presence of each element and its changes in time were monitored in the whole study population. Data were evaluated by comparing well-defined subgroups (women/men, glandular/EGM, presence/absence of associated diseases, presence/absence of immunoserological differences, and patients alive at the end of the study/deceased over time).
The SPSS version 20.0 (SPSS Inc., Chicago, IL, UDA) was used for statistical analysis. To analyze the distribution of the data, Kolmogorov-Smirnov test was used. In cases of normal distribution, we determined
Survival time and rate were assessed using Kaplan-Meier estimator. Chi-square test and Fisher’s exact test were used to discriminate between patient groups; we used Cox regression model to predict poor outcome of the disease. For comparison among patient and control groups, standardized mortality ratios (SMRs) were calculated. Differences were considered statistically significant at
The demographic characteristics of patients’ groups are demonstrated in Tables
The mean age of patients determined at the time of diagnosis and the average follow-up period.
Subgroup | Mean age at the time of diagnosis of pSS (years) | Follow-up period (years) |
---|---|---|
Male ( |
47.55 ± 12.051 | 11.47 ± 6.113 |
Female ( |
49.99 ± 11.366 | 11.41 ± 6.342 |
|
|
|
Alive ( |
49.14 ± 11.249 | 11.41 ± 6.240 |
Deceased ( |
55.35 ± 12.038 | 11.49 ± 7.035 |
|
|
|
EGM ( |
48.97 ± 11.273 | 12.07 ± 6.408 |
Glandular ( |
52.48 ± 11.751 | 9.04 ± 5.331 |
|
|
|
Percentages of sex and clinical characteristics in patient groups stratified by age.
Age at diagnosis years | Patients’ number | Female | Male | Glandular | EGM | ||||
---|---|---|---|---|---|---|---|---|---|
Number | % | Number | % | Number | % | Number | % | ||
0–29 | 27 | 23 | 85,19 | 4 | 14,81 | 6 | 22,22 | 21 | 77,78 |
30–39 | 70 | 58 | 82,86 | 12 | 17,14 | 10 | 14,29 | 60 | 85,71 |
40–49 | 154 | 136 | 88,31 | 18 | 11,69 | 26 | 16,88 | 128 | 83,12 |
50–59 | 183 | 169 | 92,35 | 14 | 7,65 | 39 | 21,31 | 144 | 78,69 |
60- | 113 | 101 | 89,38 | 12 | 10,62 | 36 | 31,86 | 77 | 68,14 |
Table
Frequency of clinical and immunoserological features during the disease course.
Clinical and serological features | Frequency (%) | Distribution according to gender ( |
|
|
---|---|---|---|---|
Female ( |
Male ( | |||
EGMs | ||||
Polyarthritis ( |
48.1 | 218 | 42 | <0.001 |
Raynaud's phenomenon ( |
39.9 | 213 | 5 | <0.001 |
Vasculitis ( |
25 | 126 | 11 | 0.203 |
Lymphadenopathy ( |
9.3 | 46 | 6 | 0.89 |
Myositis ( |
6.9 | 35 | 5 | 0.748 |
Lung fibrosis ( |
6.2 | 31 | 3 | 0.679 |
Renal manifestation ( |
5.5 | 26 | 3 | 0.912 |
Serositis ( |
5.3 | 29 | 1 | 0.169 |
Associated disorders | ||||
Thyroiditis ( |
13.9 | 77 | 0 | 0.001 |
Microscopic colitis ( |
3.5 | 17 | 3 | 0.436 |
LPD ( |
3.3 | 15 | 4 | 0.152 |
APS ( |
2.7 | 15 | 0 | 0.168 |
Autoimmune hepatitis ( |
1.6 | 10 | 1 | 0.840 |
Sarcoidosis ( |
1.5 | 6 | 2 | 0.201 |
ITP ( |
1.3 | 7 | 0 | 0.350 |
Serological positivity | ||||
ANA ( |
64.6 | 316 | 37 | 0.623 |
anti-ENA ( |
78.9 | 382 | 50 | 0.38 |
anti-SS-A ( |
76.9 | 372 | 49 | 0.359 |
anti-SS-B ( |
55.2 | 277 | 25 | 0.025 |
anti-DNA ( |
13.7 | 72 | 3 | 0.038 |
RF ( |
29.8 | 130 | 33 | <0.001 |
anti-CCP ( |
7.3 | 34 | 6 | 0.397 |
anti-TG ( |
8.8 | 48 | 0 | 0.011 |
anti-TPO ( |
18.5 | 101 | 1 | <0.001 |
Hypergammaglobulinemia ( |
69.6 | 338 | 43 | 0.719 |
Hypocomplementemia ( |
21.8 | 106 | 13 | 0.986 |
Cryoglobulinemia ( |
6.2 | 32 | 2 | 0.567 |
Time intervals between the diagnosis of the primary Sjögren’s syndrome and the onset of extraglandular manifestations and associated diseases.
Approximately, 55%–75% of pSS patients were positive for ENA, anti-SS-A, ANA, and anti-SS-B or had hypergammaglobulinemia. RF positivity and hypocomplementemia occurred in more than 20% of cases, while more than 10% of patients were anti-TPO and anti-DNA positive. Other tested parameters (anti-TG, anti-CCP, and cryoglobulin) were positive in 6–9 percent of cases (Table
During the follow-up period, 51 (46 women and 5 men) of our patients died. Mortality of the whole patient population was almost 9 percent, with no significant differences between genders. As to the distribution by age groups, we lost 36 (32 female and 4 male) and 15 (14 female and 1 male) patients, from the >60 year and 40–59 year age groups, respectively. When evaluating the causes of death, cardiovascular events (myocardial infarction, pulmonary embolism, and stroke) were the leading causes, being followed by solid tumours (bronchial, colorectal, and bladder carcinoma, as well as invasive ductal breast cancer and malignant melanoma). Various causes (infection, ileus, gastrointestinal bleeding, and suicide) also accounted for some deaths. Figure
Comparison of the causes of death between our patients’ data and the sex- and age-adjusted data on general Hungarian population.
Calculated mortality per 1,000 individuals per year was as follows: in the Hungarian population adjusted for age and gender ratios of the whole pSS population 7.821 (based on the data of the Hungarian Central Statistical Office from 2001 [
Standardized mortality ratios (SMRs) of pSS subgroups.
Standardized mortality ratios (SMRs) | |
---|---|
Whole pSS population ( |
1.32 |
Female patients ( |
1.49 |
Male patients ( |
0.65 |
Patients without EGMs ( |
0.51 |
Patients with EGMs ( |
1.62 |
Calculations were based on the data of the Hungarian Central Statistical Office from 2001 [
Median survival time in the whole population was 33.71 years. Patients with pSS, complicated from the time of diagnosis with EGM or associated diseases, could be characterized with significantly worse survival ratios. This was also valid in the case of early occurrence of polyarthritis, vasculitis, and LPD. Late occurrence of cryoglobulinemia (even years after the diagnosis of pSS) also impaired survival ratios significantly (Figures
Variations in survival times for parameters that are significantly impairing survival indicators compared to the average values of patients.
|
|
Survival time (year) | CI 95% | |
---|---|---|---|---|
Mean survival time for our patient with pSS | 33.71 | |||
Studied factor | ||||
EGM | 0.001 | NS | 26.949 | 23.907–29.991 |
Polyarthritis | <0.001 | NS | 27.554 | 23.844–31.263 |
Vasculitis | <0.001 | NS | 7.956 | 6.700–9.213 |
Associated disorder | <0.001 | NS | 14.283 | 10.962–17.603 |
LPD | <0.001 | NS | 4.000 | 4.000-4.000 |
Cryoglobulinemia | NS | 0.010 | 24.112 | 19.899–28.326 |
CI: confidence interval; NS: nonsignificant.
The Kaplan-Meier survival plots for the risk of death in patients subgroups with/without (a) extraglandular manifestations, (b) polyarthritis, (c) vasculitis, (d) associated disorders and (e) lymphoproliferative disease developed already at the time of diagnosis, or (f) cryoglobulinemia developed during the disease course.
Mortality risk in subgroups with significantly worse survival ratios increased 1.085–10.716-fold. An older age at the time of pSS diagnosis also increased the risk for death, numerically by 8.5 percent per year. The presence of vasculitis before the diagnosis of pSS resulted in the highest risk, while the lowest risk was associated with a younger age at onset of pSS (Table
Mortality risk in subgroups with significantly worse survival indicators, also taking into consideration the age recorded at the diagnosis.
Analysed variable |
|
Relative risk | CI 95% |
---|---|---|---|
Age at the diagnosis of pSS |
<0.001 | 1.085* | 1.049–1.121 |
Polyarthritis | 0.048 | 1.898 | 1.006–3.581 |
Vasculitis | 0.001 | 10.716 | 2.795–41.089 |
LPD | 0.005 | 5.172 | 1.652–16.192 |
Cryoglobulinemia | 0.038 | 2.331 | 1.048–5.185 |
In our retrospective study, we reported on research outcomes of 547 patients with pSS from one Hungarian clinical immunology centre. No other research on pSS patients with similar ethnical characteristics has been conducted in any East-Central European centre before. Compared to earlier publications, our pSS population was the third largest, but it was the first, when considering the patient proportion related to the whole population of the given countries [
In Greek publications, the proportion of female patients was high (women to men ratio = 16–22 : 1); in British and Chinese studies it follows internationally accepted rates, while, in Hungary, the proportion of men is higher than usual (women to men ratio = 8 : 1). The mean age of our patients at the time of pSS diagnosis is in line with the British values. In Southern Europe, the disease sets on 2–5 years later, while in China 8–10 years earlier [
In our study, we evaluated which EGMs and associated diseases, in which age groups, at what typical time intervals, and in what proportion occurred among our patients. The three leading EGMs were polyarthritis, Raynaud’s phenomenon, and vasculitis. The frequency of other EGMs ranged between 5% and 10%. When comparing our results to the literature data, we can conclude that, in the Hungarian population, the order of frequency for EGM is similar to what is seen in British people; the frequency of polyarthritis and vasculitis correlates with Chinese data, while that of Raynaud’s phenomenon and pulmonary fibrosis corresponds to Greek data. Lymphadenopathy and renal manifestations occurred in a lower proportion among our patients; the incidence of myositis was higher than in the literature, while serositis developed in an approximately similar proportion. With few exceptions, EGMs tend to precede the onset of systemic autoimmune disease, as if anticipating it. The newly defined characteristic manifestation time intervals of each EGM draw attention to the importance of cooperation with related professions in conditions predicting pSS. Significant gender differences were found for two EGMs: polyarthritis with the predominance in males and Raynaud’s phenomenon predominating in females. The presence of EGMs enabled an earlier establishment of the diagnosis.
During many decades of care activity, we concluded that certain associated diseases worsen the course of pSS; therefore, we decided to analyse them with the method applied for EGM. The most common associated disease in our patients was thyroiditis, while incidence of other associated diseases was below 3%-4% [
Differences in the prevalence of EGMs and associated diseases modifying the clinical picture, as compared to literature data, may be explained by the influence of different genetic, life style, and geographical factors. In 2002, we reviewed non-Hodgkin’s lymphoma (NHL) patients to describe its coexistence with autoimmune diseases. The most frequent autoimmune disease in the NHL group was pSS. This association can be explained by the dysregulation of apoptosis and increased levels of activated B-cells [
Significant gender differences were found for several serological factors. Anti-TG and anti-TPO positivity prevailed in females, while RF showed male predominance, in accordance with the observed clinical differences, and with the dominance of thyroiditis in women and polyarthritis in men. Cryoglobulinemia can be considered a highly relevant immunoserological abnormality, the emergence of which in the follow-up period of pSS significantly impairs survival ratios and increases mortality risk. In our previous reports, we concluded that cryoglobulinemia may play a more important role in the extraglandular features observed in SS associated with hepatitis C virus (HCV) than it does in pSS alone, although these manifestations also might be related to either the underlying SS or the HCV infection itself [
Summarizing our results, we concluded that pSS is composed of subgroups displaying a different clinical picture and mortality risk. During our work, we identified clinical and immunoserological features characterizing Hungarian patients. Based on significantly worse survival ratios and the concomitantly increasing mortality risk, pSS subgroups with polyarthritis, vasculitis, LPD, or cryoglobulinemia should be clinically classified as severe pSS. Consequently, we recommend the use of targeted diagnostic protocols for identifying patients with severe pSS. Moreover, close observation of cases associated with polyarthritis, vasculitis, LPDs, or cryoglobulinemia is also essential.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors thank Katalin Hodosi for her contribution to the statistical analysis.