PDF
ePub
Citation
Print
INTRODUCTION
Primary Sjögren’s syndrome (pSS) is a chronic systemic
autoimmune disease characterized by lymphocytic cell
infiltration of salivary and lacrimal exocrine glands, resulting
in functional impairment. However, the inflammatory
process can extend beyond the exocrine
glands and affect various non-exocrine organs such as the
joints, skin, lungs, kidneys, nerves, and small vessels
[1,2]. Although the prevalence or incidence of pSS is debated,
it has been considered a rare disease and a recent
meta-analysis reported a global worldwide prevalence of
0.06% [3,4].
A variety of extraglandular manifestations have been reported
in pSS patients and a large Spanish registry revealed
that 13% had a potentially life-threatening systemic
manifestation [5]. However, most pSS patients
have benign subjective conditions such as sicca symptoms,
arthralgias, and fatigue. In line with these findings,
pSS has not been associated with increased mortality
[6,7], even though it negatively affects health-related
quality of life [8-10].
To assess disease activity and outcome measures, the
European League Against Rheumatism (EULAR)
Sjögren’s syndrome disease activity index (ESSDAI) and
EULAR Sjögren’s syndrome patient reported index
(ESSPRI) have been developed [11,12]. The ESSDAI and
ESSPRI have now been validated as outcome measures
for pSS in many studies. These indices reflect 2 facets of
pSS: 1) benign but disabling subjective symptoms and 2)
systemic and potentially severe manifestations. The two
indices reportedly had good sensitivity to change in clinical
trials, although the change in the ESSPRI was smaller
than that in the ESSDAI [12]. The ESSPRI levels are reportedly
well-correlated with quality of life and functional
status [8,13]. Since the two indices are poorly correlated
with each other, each should be evaluated separately
and independently.
However, to our knowledge, no report has investigated
longitudinal ESSPRI changes in routine clinical practice
for pSS. Additionally, we do not know how many patients
obtain clinically meaningful ESSPRI improvement with
routine therapies. We evaluated temporal changes in the
ESSPRI and ESSDAI and clinical features associated with
favorable ESSPRI changes in Korean patients with pSS.
MATERIALS AND METHODS
Patients
Among 104 pSS patients enrolled in a previous study
[8], 63 had been followed by our rheumatology clinic and
41 were reevaluated between January 2015 and April
2016. The median follow-up period was 6.6 (4.9∼8.3)
years (range 3.5∼9.8 years). All patients met the 2002
American-European Consensus Group classification criteria
for SS [14], and all but 1 were females. Median age
was 49.0 (39.0∼57.0) years and the median duration of
sicca symptoms was 8.0 (3.0∼10.8) years at enrollment.
Eight (19.5%) had moderate-to-high disease activity status
and the most common extraglandular manifestation
was arthralgia/arthritis (31.7%). Baseline characteristics
are summarized in Table 1. This study was approved by
our institutional review board (IRB No. B-0506/
021-004) and written informed consent was obtained
from all participants.
Methods
At enrollment and follow-up, the ESSDAI, ESSPRI, and
EULAR sicca score (ESS) were calculated using a previous
definition [11,15]. Patients also completed questionnaires
and provided a visual analog scale (VAS) score;
the short-form 36 (SF-36) and Xerostomia Inventory (XI)
scores were determined, and patients were assessed for
dry eye, dry mouth, joint pain, myalgia, anxiety, depression,
fatigue, and global status. Demographic, clinical,
and laboratory variables were collected using medical records
review. Cumulative dose and prescription duration
of pilocarpine, glucocorticoids, and hydroxychloroquine
were calculated during the follow-up period. Satisfactory
refill adherence of pilocarpine was defined as dispensed
refills covering ＞75% of the follow up period.
Based on the definition proposed by the EULAR
Sjögren’s Task Force [16], pSS was classified according to
low (ESSDAI ＜5), moderate (5≤ESSDAI≤13), and
high disease activity (ESSDAI ≥14). Additionally, unsatisfactory
symptom status was defined as ESSPRI ≥5, and
minimal clinically important improvement was defined
as an increase in ESSPRI of ≥1 point or by 15%, or an increase
in ESSDAI of ≥3 points, as previously proposed
[16]. Based on temporal ESSPRI changes, pSS patients
were classified into favorable (F) or unfavorable (UF)
outcome subgroups. The F subgroup was defined as
showing an improvement in ESSPRI (from baseline
ESSPRI ≥5 to follow-up ESSPRI ＜5) or maintenance of
satisfactory symptom status (ESSPRI ＜5). The UF subgroup
showed worsening of ESSPRI (from baseline
ESSPRI ＜5 to follow-up ESSPRI ≥5) or maintenance of
unsatisfactory symptom status (ESSPRI ≥5).
Statistical analysis
Continuous variables are expressed as median with interquartile
range (25th to 75th percentile). Statistical
analysis was performed using the Mann–Whitney test for
continuous variables and Wilcoxon signed-rank test for
paired values. The chi-square test or Fisher’s exact test
was used for categorical variables. To identify clinical factors
associated with favorable outcome, multivariate models were created using the variables with a statistical
significance of p＜0.1 from the univariate analyses.
Statistical analysis was performed using IBM SPSS version
21 (IBM Co., Armonk, NY, USA); p＜0.05 was considered
significant.
RESULTS
Longitudinal changes in patient-oriented and laboratory measurements
The median daily dose of pilocarpine was estimated as
8.4 (2.8∼10.1) mg/day in the study subjects. During the
follow-up period, 17 patients (41.5%) showed satisfactory
refill adherence and 6 had never received
pilocarpine. Patients with satisfactory refill adherence of
pilocarpine showed a significantly higher age (55.0 [48.0∼
59.0] vs. 43.5 [36.0∼53.3] years, p=0.011) and baseline
ESS (6.33 [5.33∼8.50] vs. 5.67 [3.00∼7.33], p=0.033)
and ESSPRI (4.11 [3.17∼5.95] vs. 3.78 [2.85∼5.19],
p=0.014) levels (Table 2) than the those without satisfactory
refill adherence.
After a median 6.6 years of follow-up, ESSDAI scores
were not significantly changed but ESSPRI scores were
statistically marginally increased (p=0.047). The median
change was 0 (−1.0∼2.0) in ESSDAI and 0.6 (−0.8∼
2.0) in ESSPRI. Six (14.6%) patients showed clinically
important improvement based on ESSDAI, as did 11
(26.8%) based on ESSPRI, over a median of 6.6 years.
Follow-up VAS scores for dry eye or extraglandular manifestations
and physical or mental component summary
scores on the SF-36 were not significantly improved.
However, VAS scores for dry mouth (p=0.035) and XI
scores (p=0.010) were significantly decreased from
baseline. Moreover, VAS scores for patient global assessment
improved from 45 (20∼80) to 30 (10∼59) (p=
0.009).
The temporal changes in ESS (from 6.33 [5.33∼8.50] to
6.00 [5.00∼7.17]) and ESSPRI (from 4.11 [3.17∼5.95] to
5.33 [3.84∼6.84]) were not significant in patients with
satisfactory refill adherence of pilocarpine, although VAS
for sicca symptoms tended to decrease (from 80 [55.0∼
95.0] to 47.0 [33.5∼80.0] of oral dryness VAS, p=0.062;
from 70 [45∼70] to 50 [40∼80] of eye dryness VAS,
p=0.426).
Among laboratory variables, the levels of total immunoglobulin
G (IgG) were significantly decreased from
1,980 (1,710∼2,460) to 1,710 (1,530∼1,950) mg/dL (p＜
1.0×10−5). However, the magnitude of decrease in serum
IgG levels was not significantly correlated with patient-
oriented measures for sicca symptoms. Hemoglobin,
C-reactive protein, and complement levels showed a statistically
significant change, but these were not clinically
significant.
Comparison between favorable and unfavorable outcome groups
When pSS patients were stratified into F or UF subgroups,
17 patients (41.5%) showed a favorable outcome
over a median of 6.6 years and 4 of these had unsatisfactory
symptom status at baseline. In other words,
4/16 pSS patients (25.0%) with baseline unsatisfactory
symptom status achieved better symptom status during
the follow-up period (Figure 1). In patients with baseline
unsatisfactory symptom status, 5/16 (31.3%) exhibited
clinically meaningful improvement. However, in those
with baseline satisfactory symptom status, about half
(n=12/25, 48.0%) reported worsening of symptoms at
follow-up.
When F and UF outcome subgroups were compared, the
F subgroup had a significantly increased prevalence of
premenopausal status (p=0.025) or Raynaud’s phenomenon
(p=0.045), and greater tear production (the sum of
Schirmer’s test results in both eyes, p=0.049; Table 3).
Additionally, the F subgroup had significantly less severe
symptoms of dry mouth, dry eye, and depression at baseline
than the UF subgroup. Accordingly, the F subgroup
showed better baseline assessment using the ESS,
ESSPRI, and some domains of SF-36, including bodily
pain, general health, and vitality (all p＜0.05). At follow-
up, the F outcome subgroup had a significantly lower
ESSPRI (2.67 [2.00∼4.00] vs. 6.50 [5.42∼7.00], p
＜1.0×10−7) than the UF outcome subgroup. During the follow-up period, the F subgroup received a significantly
lower cumulative dose of pilocarpine (p=0.022) and glucocorticoids
(p=0.039), while more patients in the UF
subgroup took mucolytics (p=0.004) and nonsteroidal
anti-inflammatory drugs (p=0.012; Table 4). Additionally,
UF subgroup tended to have a higher refill adherence for
pilocarpine and a higher prevalence of central nervous
system acting drugs use.
We performed multivariate analysis after adjusting for
covariates such as menopause, Schirmer’s test results,
the presence of Raynaud’s phenomenon, VAS scores for
oral or eye dryness, depression, and fatigue, XI scores, initial
ESSPRI scores, several SF-36 scores, and medication
usage. But no significant predictive factor for favorable
outcome was found.
DISCUSSION
The current study is the first to investigate longitudinal
changes in patient-oriented outcome measures including
ESSPRI and SF-36 in Korean patients with pSS. In routine
care, after a median of 6.6 years, clinically meaningful improvement
in ESSPRI was observed in at most 25% of patients
with pSS. Moreover, there was no significant improvement
in quality-of-life measurements and subjective
assessments of xerophthalmia and extraglandular
symptoms, even though patient-derived measures for xerostomia
and patient global assessment were significantly
improved.
The number of published papers on pSS has grown exponentially
in the last several decades but longitudinal
patient-oriented outcomes have rarely been studied in patients
with pSS. It was reported that salivary secretory
function or sicca complaints in pSS were not markedly
changed over a period of about 10 years [17,18]. In
Swedish patients with pSS, symptoms of dry eye, dry
mouth, and fatigue and health related quality of life did
not change significantly over a period of 5 years [19]. In another longitudinal study on temporal changes, self-reported
fatigue levels were unchanged over a period of 5
years in Norwegian pSS patients [20]. Moreover, a recent
study using salivary gland ultrasound outcomes revealed
that abnormalities did not change significantly during a
follow-up of nearly 2 years [21].
The current study also found no clinically meaningful
changes in most patients with pSS; 85% and 73% did not
experience clinically important improvement in ESSDAI
and ESSPRI, respectively. Such stability of patient-oriented
outcome measures or symptoms suggests that the
current treatment modalities provide only very limited
efficacy. In the current study, ESSPRI was not significantly
reduced even in subjects with satisfactory refill
adherence of pilocarpine although there was a tendency
to decrease in VAS for sicca symptoms. It has been well
established that pSS patients have significantly impaired
quality of life and this may produce a floor effect.
However, unlike the abovementioned studies, our participants
reported significant improvement in xerostomia
and global assessment of SS during the follow-up period.
This can be explained by the finding that more patients
(34/41, 82.9%) had taken cholinergics in our study when
compared to previous studies (2/58 [4.4%] in the Swedish
study) [19]. Moreover, diagnosis and education during
regular visits can reduce the emotional impact of anxiety
and depression, although mental component scores in
the SF-36 were not improved.
Concerning laboratory parameters, we observed that
only serum IgG levels were significantly decreased during
the follow-up period. Theander et al. [19] previously reported
that serum IgG levels were not changed over a period
of 5 years, but Pertovaara et al. [18] reported that levels
significantly decreased after a median of 9 years.
Several treatments including abatacept and hydroxychloroquine
reportedly decreased the serum IgG levels in
pSS patients [22-24]. In the current study, 34 (82.9%) of
41 study subjects had taken hydroxychloroquine and 21
(51.2%) had received glucocorticoids during follow-up.
These treatments could reduce serum IgG levels. However,
the decrease in serum IgG levels was not associated with
subjective improvement of xerostomia in our study.
Although pSS patients have a higher risk of non-
Hodgkin lymphoma (NHL) than controls or patients with
systemic lupus erythematosus, most have relatively
chronic stable disease without rapid deterioration of exocrine
function or dramatic changes in extra-exocrine clinical
features [25-27]. Nevertheless, many researchers
have focused only on the risk factors for NHL that develop
in a small proportion of pSS patients (＜2%) [28,29].
Until now, no study has investigated predictive factors for
patient-oriented outcomes or longitudinal change in the prevalent symptoms. In this context, we divided our pSS
patients into favorable and unfavorable subgroups and
compared clinical features between the two subgroups.
In the current study, about 40% showed a favorable
course and even about 30% of pSS patients with baseline
ESSPRI ＞5 achieved clinically meaningful improvement,
although the F subgroup used less medication and tended
to have low prevalence of satisfactory refill adherence of
pilocarpine than the UF subgroup. Because of small sample
size, multivariate analysis did not demonstrate an independent
factor associated with favorable outcomes.
However, in univariate analyses, better patient assessment
of sicca symptoms and depression was associated
with favorable outcomes. Therefore, the psychological attitude
toward the disease or the background psychological
profile may be an underlying factor associated
with favorable outcomes, because ESSPRI is correlated
with the mental health subdimension of SF-36 or depression
[8,30].
Premenopausal status, the presence of extraglandular
manifestations such as Raynaud’s phenomenon, or residual
lacrimal gland function at diagnosis was also associated
with a favorable course. The prevalence of Raynaud’s
phenomenon was reported to be 16%∼35% in a large
case series of pSS patients, and Raynaud’s phenomenon
preceded the onset of sicca symptom in about half of pSS
patients [31,32]. Several studies showed that the age at
disease onset (defined as the first subjective experience of
glandular or extraglandular symptoms) does not influence
clinical features [33,34]. In the current study, disease
duration was comparable between F and UF outcome
subgroups. However, in a large Spanish cohort
study, younger-onset pSS showed a lower prevalence of
xerostomia and abnormal ocular findings [31].
Therefore, when considering the abovementioned findings
together, a higher prevalence of premenopausal
women in the F subgroup may suggest that early diagnosis
without severe exocrine impairment could be associated
with a favorable outcome in pSS. Unfortunately, we
know little about the natural history of pSS as well as the
transition from the preclinical phase into clinical disease.
pSS-related autoantibodies can be detected at a median of
4∼5 years before clinical diagnosis. In addition, immune-
meditated glandular injury is considered to progress
over several years and the delay between symptom
onset and final diagnosis has been reported to range from
3∼10 years [35,36]. Therefore, when the diagnosis of
pSS is made after the development of sicca symptoms, the
patient may already have irreversible exocrine dysfunction.
Moreover, delayed diagnosis could increase the psychological
distress caused by unexplained symptoms in pSS
patients [10]. Thus, diagnosis in the state with lower
scores on sicca symptoms or with residual exocrine function
could be important to improve patient-oriented outcomes
and to help decrease the local or systemic
complications.
Our study has several limitations. First, the rate of loss
to follow-up was high (about 60%). Those without symptomatic
improvement were more likely to be lost to follow-
up and the proportion of patients achieving clinically
meaningful improvement could be overestimated in this
study. However, we believe that the importance of early
diagnosis in pSS is not overemphasized. Second, the sample
size was inadequate for multivariate analysis. Hence,
a larger number of patients with pSS is needed for study.
Third, most patients had low-to-moderate disease activity
and did not have severe systemic manifestations.
However, the ESSDAI level (median 2.0) in our patients
was similar to that in the French Assessment of Systemic
Signs and Evolution in Sjögren’s syndrome (ASSESS) cohort
and in patients enrolled in a randomized clinical trial
of hydroxychloroquine (the JOQUER trial) [37]. Therefore,
our study subjects reflected general rather than unique
features of pSS patients.
CONCLUSION
In summary, our study showed that 27% showed clinically
important improvement in ESSPRI over a median of
6.6 years and 40% showed a favorable course based on
ESSPRI in routine care. Favorable patient-derived outcome
was associated with some clinical features, including
premenopausal status, greater lacrimal flow, and fewer
sicca or depressive symptoms at baseline.
XML Download