Impaired functional status in primary Sjögren's syndrome

Authors


Abstract

Objective

Several studies have demonstrated that primary Sjögren's syndrome (SS) is associated with reduced productivity; however, the impact of primary SS on daily function is not fully understood. This study aims to assess the physical function of primary SS patients and determine the relationship between the functional impairment experienced by primary SS patients and disease activity, patient-reported symptoms, and quality of life.

Methods

Sixty-nine primary SS patients from a specialist clinical service were assessed for their functional ability (Improved Health Assessment Questionnaire [HAQ]), dryness, pain, and overall primary SS–related symptom burden; systemic disease activity; levels of fatigue, daytime somnolence, anxiety, and depression symptoms; quality of life; and systemic inflammation (erythrocyte sedimentation rate, C-reactive protein [CRP] level). Data were compared to 69 healthy volunteers matched for age and sex.

Results

Primary SS patients experienced greater functional impairment than controls (Improved HAQ total scores: mean ± SD 24 ± 25 for primary SS versus 9 ± 19 for controls; P = 0.0002) across all domains of activity. In primary SS, functional impairment was significantly associated with physical fatigue (P < 0.0001, R2 = 0.3), pain (P < 0.0001, R2 = 0.3), depression (P < 0.0001, R2 = 0.3), total symptom burden (P < 0.0001, R2 = 0.3), systemic disease activity (P = 0.002, R2 = 0.15), quality of life (P < 0.0001, R2 = 0.3), dryness (P = 0.002, R2 = 0.12), daytime somnolence (P = 0.02, R2 = 0.08), anxiety score (P = 0.03, R2 = 0.07), and CRP level (P = 0.04, R2 = 0.06). Only CRP level is independently associated with functional impairment (β = 0.38, P = 0.025).

Conclusion

Primary SS patients experience significant functional disability compared to age-matched healthy controls. Impaired function is associated with reduced quality of life and symptoms such as pain, fatigue, and depression, as well as disease activity, illustrating the importance of optimal management of all aspects of the disease.

Introduction

Primary Sjögren's syndrome (SS) is a relatively common autoimmune rheumatic disease affecting 0.3–0.5% of the adult population (1). Several studies in Europe and the US have demonstrated that there is a significant loss of productivity among primary SS patients, with fatigue being an important predictor (2–5). We have recently shown that liver-transplant recipients and patients with primary biliary cirrhosis (PBC) or chronic fatigue syndrome (CFS) have significant impairment of their functional capacity, which is independently associated with fatigue, orthostatic symptoms, and daytime somnolence (6–8). Although it is increasingly recognized that patients with primary SS experience significant symptoms of fatigue (9), autonomic dysfunction (10, 11), and excessive sleepiness, in addition to sicca symptoms, the overall impact of these symptoms upon their functional ability is poorly understood. In this study, we quantified functional ability in a cohort of clinically well-characterized primary SS patients in a large teaching hospital in the northeast of England, using a well-validated comprehensive physical function assessment tool. Furthermore, we explored the interrelationship between functional ability and systemic disease activity, patient-reported outcome measures, and potentially relevant clinical and laboratory parameters.

Significance & Innovations

This is the first study to systematically examine the functional status and the predictors of functional ability of patients with primary Sjögren's syndrome (SS).

We showed that primary SS patients have reduced capacity to carry out a wide range of everyday activities.

Functional disability in primary SS correlates strongly with fatigue, depression, pain, disease activity, and impaired health-related quality of life.

We propose that the development of a multidisciplinary management program to maximize physical function in primary SS should be explored.

Significance & Innovations

  • This is the first study to systematically examine the functional status and the predictors of functional ability of patients with primary Sjögren's syndrome (SS).

  • We showed that primary SS patients have reduced capacity to carry out a wide range of everyday activities.

  • Functional disability in primary SS correlates strongly with fatigue, depression, pain, disease activity, and impaired health-related quality of life.

  • We propose that the development of a multidisciplinary management program to maximize physical function in primary SS should be explored.

Methods

Subjects.

Primary SS patients (n = 98) were identified from an existing database of all patients attending a dedicated primary SS clinic (as of December 31, 2010) run by one of the investigators (W-FN), providing care to the majority of primary SS patients referred to the hospital. All patients were invited to participate in this study, and 69 (70%) patients agreed to be participants. All primary SS participants fulfilled the American–European Consensus Group classification criteria (12). Informed consent was obtained from all participants according to the principles of the Helsinki Declaration. All clinical and laboratory data were collected prospectively at recruitment. Each primary SS participant was matched case by case, by age (within 2 years) and sex, to an existing community healthy cohort established by an author (JLN) (6–8) and consisting of 145 subjects who had completed the Improved Health Assessment Questionnaire (HAQ; formerly the Patient-Reported Outcomes Measurement Information System HAQ). Ethical approval was granted by the North West Research Ethics Committee.

Functional ability assessment.

The Improved HAQ (13) consists of 20 questions that ask the respondents to rate their ability to perform daily activities on a 5-point scale, where 0 = without any difficulty and 4 = unable to do. These questions are divided into 8 domains of physical function: dressing, arising, eating, walking, hygiene, reach, grip, and activity. The highest scoring question in each domain is used as the domain score. The total Improved HAQ score = ([mean domain score] × 25). Higher scores indicate greater functional impairment.

Other assessments of primary SS patients.

The following data were collected for all primary SS subjects: European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI; measures overall burden of symptoms), EULAR sicca scale (measures overall severity of dryness), Profile of Fatigue, Epworth Sleepiness Scale (measures daytime sleepiness), Hospital Anxiety and Depression Scale (measures anxiety and depression), Orthostatic Grading Scale (measures orthostatic intolerance), and EuroQol-5 domain (measures health-related quality of life). Further details, including references on these instruments, are provided in Supplementary Appendix A (available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658). Additionally, levels of systemic inflammation were assessed using C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR).

Data analysis.

The Kolmogorov-Smirnov test was used to determine whether data were normally or non-normally distributed. Parametric data are presented as mean ± SDs, and group comparisons were made using unpaired t-tests. Nonparametric data are presented as the median (25th, 75th percentile values), and comparisons were made using the Mann-Whitney test. Univariate analysis was performed using Spearman's and Pearson's tests for parametric and nonparametric data, respectively. Multivariate analysis was performed using the log rank test. A statistically significant result was considered when P values were less than 0.05. All analyses were performed using Prism 3.0 or SPSS (version 11) software.

Results

Patient characteristics.

The clinical characteristics of the patient cohort are summarized in Table 1. The mean ± SD age of primary SS patients (n = 69) and controls (n = 69) was 60 ± 13 years (64 women) and 62 ± 11 years (64 women), respectively. Of the primary SS cohort, 91.3% were positive for anti-Ro or anti-La antibodies, with a median disease duration of 6.9 years (interquartile range [IQR] 2.3–12.0 years). The median ESSDAI score was 3.0 (IQR 1.0–7.0), and the mean ± SD ESSPRI score was 5.4 ± 2.1. These parameters and other clinical features are similar to the UK primary SS registry (UKPSSR) cohort of more than 600 primary SS patients from 30 centers (14), suggesting that our cohort is representative of primary SS patients in the UK (see Supplementary Table 1, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

Table 1. Demographic, clinical, and laboratory features of the primary SS cohort*
CharacteristicValue
  • *

    SS = Sjögren's syndrome; MSG = minor salivary glands; IQR = interquartile range; ESSDAI = European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; VAS = visual analog scale; ESSPRI = EULAR Sjögren's Syndrome Patient Reported Index; HADS = Hospital Anxiety and Depression Scale; ESS = Epworth Sleepiness Scale; OGS = Orthostatic Grading Scale; EQ-5D = EuroQol 5-domain; TTO = time trade-off.

  • Presence of disease activity in any ESSDAI domains except glandular domain alone.

  • Two patients had paraproteinemia; 3 others had faint monoclonal band but no quantifiable paraproteins.

Age, mean ± SD years60 ± 13
Sex, no. 
 Male5
 Female64
SSA/SSB positivity, no. (%)63 (91.3)
MSG biopsy, no. (%)13 (18.8)
Disease duration, median (IQR) years6.9 (2.3–12.0)
ESSDAI score, median (IQR)3.0 (1.0–7.0)
Disease activity in individual organ domain, no. (%) 
 Constitutional8 (11.6)
 Lymphadenopathy5 (7.2)
 Glandular12 (17.4)
 Articular20 (29.0)
 Cutaneous6 (8.7)
 Respiratory2 (2.9)
 Muscular2 (2.9)
 Peripheral nervous system3 (4.3)
 Central nervous system0 (0)
 Hematologic7 (10.1)
 Biologic41 (59.4)
 Renal2 (2.9)
 Evidence of systemic manifestation49 (71.0)
IgG, median (IQR)16.6 (12.5–20.4)
CRP level, mean ± SD mg/dl5.8 ± 2.4
ESR, median (IQR) mm/hour22 (10.0–46.8)
Lymphoma, no. (%)5 (7.2)
Paraproteinemia, no. (%)2 (2.9)
Other malignancies, no. (%)2 (2.9)
Disease damage, median (IQR) physician VAS (range 0–10)4.0 (2.0–5.0)
ESSPRI score, mean ± SD (range 0–10)5.4 ± 2.1
Dryness, mean ± SD EULAR sicca score (range 0–10)6.0 ± 2.5
Physical fatigue, mean ± SD (range 0–7)3.9 ± 1.5
Mental fatigue, mean ± SD (range 0–7)2.9 ± 1.8
Overall fatigue, mean ± SD (range 0–100)54.6 ± 25.8
Pain, median (IQR) (range 0–10)5.0 (2.0–7.0)
Anxiety, median (IQR) HADS8.0 (5.0–12.0)
Depression, median (IQR) HADS4.0 (2.0–8.0)
Daytime sleepiness, mean ± SD ESS7.8 ± 5.0
Orthostatic intolerance, median (IQR) OGS3.0 (1.0–5.0)
Health-related quality of life, median (IQR) EQ-5D 
 TTO (range −1.0 to 1.0)0.73 (0.52–0.80)
 VAS (range 0–100)60.0 (50.0–70.0)

Functional capacity significantly reduced in primary SS patients.

The mean ± SD total Improved HAQ score for the primary SS group was 2.5 times higher than that of the age- and sex-matched healthy controls (24 ± 25 versus 9.3 ± 19; P = 0.0002) (Figure 1A). Primary SS patients also scored higher compared to controls in all individual domains, indicating that primary SS patients have reduced physical ability/functioning across a wide spectrum of daily activities (Figure 1B). In total, 20 (29%) primary SS patients reported no functional impairment (compared to 36 [52%] healthy controls; P = 0.02), and the median scores for each domain were relatively low. In comparison to primary SS patients without functional disability, functionally impaired primary SS patients reported higher levels of physical fatigue, pain, depressive symptoms, and total symptom burden (see Supplementary Table 2, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

Figure 1.

A, Improved Health Assessment Questionnaire (HAQ) scores of primary Sjögren's syndrome (PSS) patients and controls (Ctrl) and B, the individual domain scores for PSS patients and for controls. * = P < 0.05; ** = P < 0.01; *** = P < 0.001; **** = P < 0.0001.

Relationship between functional capacity and clinical features of primary SS.

To further explore the relationship between functional ability and other clinical features of primary SS, we performed a correlation analysis (Table 2). There were strong correlations between Improved HAQ total score and fatigue, pain, overall symptom burden, systemic disease activity, dryness, depression, and health-related quality of life. There were also weak but statistically significant correlations between Improved HAQ score and daytime sleepiness, symptoms of anxiety, mental fatigue, and CRP level. There was no significant correlation between functional ability and age, disease duration, ESR, or orthostatic intolerance.

Table 2. Univariate analysis of the relationship between Improved HAQ total score and various clinical features of primary Sjögren's syndrome*
Instrument usedPR2
  • *

    HAQ = Health Assessment Questionnaire; EULAR = European League Against Rheumatism; VAS = visual analog scale; ESSPRI = EULAR Sjögren's Syndrome Patient Reported Index; ESSDAI = EULAR Sjögren's Syndrome Disease Activity Index; OGS = Orthostatic Grading Scale; ESS = Epworth Sleepiness Scale; HADS = Hospital Depression and Anxiety Scale; EQ-5D = EuroQol 5-domain; TTO = time trade-off.

  • Statistically significant.

Age0.50.0006
Fatigue profile  
 Physical< 0.00010.37
 Mental0.020.08
 Overall< 0.00010.25
Dryness, EULAR sicca score0.0040.12
Pain, VAS< 0.00010.36
Overall symptom burden, ESSPRI< 0.00010.41
Systemic disease activity, ESSDAI0.0010.15
Systemic inflammation  
 C-reactive protein0.040.06
 Erythrocyte sedimentation rate0.150.03
Disease duration, years0.290.02
Other symptoms  
 Orthostatic intolerance, OGS0.070.05
 Daytime somnolence, ESS0.020.08
 Anxiety, HADS0.030.07
 Depression, HADS< 0.00010.29
 Health-related quality of life  
  EQ-5D VAS< 0.00010.28
  EQ-5D TTO< 0.00010.47

Since the ESSDAI scores correlated with the Improved HAQ scores, we explored whether disease activity in any particular systemic domain(s) is/are associated with functional impairment (see Supplementary Table 3, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658). Interestingly, there was a significant association between disease activity in the articular domain and the Improved HAQ score (P < 0.001, R2 = 0.25). The median (IQR) Improved HAQ score was significantly higher in primary SS patients with extraglandular manifestations (defined as disease activity in any ESSDAI domain except the “glandular” domain) than those without (median 23.4 [IQR 0–40.6] versus median 6.3 [IQR 0–15.6]; P = 0.006) (Supplementary Figure 1, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

To determine whether any of the parameters observed as associating with the Improved HAQ total score were independently correlated with increasing functional impairment, we conducted a multivariate analysis. Only CRP level (P = 0.025, β = 0.38) was independently associated with the Improved HAQ total score.

Discussion

To our knowledge, this is the first study to systematically examine the functional status of primary SS patients using a validated instrument and to determine the predictors of physical function in primary SS. Our data demonstrated that primary SS patients have reduced capacity to carry out a wide range of everyday activities compared to age- and sex-matched healthy controls. Our data also revealed that functional impairment in primary SS is associated with many, but not all, of the key clinical features of primary SS, as well as reduced health-related quality of life. The strong correlation between fatigue and functional disability is in common with that observed in PBC, CFS, and post–liver transplantation (6–8), highlighting the need for more effective management of fatigue in these conditions. In contrast to patients with PBC or CFS, functional impairment in primary SS does not correlate with orthostatic symptoms (7, 8). The correlation between disease activity in the articular domain and the Improved HAQ scores suggests that optimal management of articular symptoms in primary SS may improve physical function. The independent association between functional disability and CRP level may indicate that systemic inflammation is a contributory factor to functional ability. However, the data should be interpreted with caution, as only 11 of 69 primary SS patients had abnormal CRP level (>5 mg/dl) results (of which 1 [5%] of 20 primary SS patients without functional disability versus 10 [20.4%] of 49 primary SS patients with functional impairment had abnormal CRP levels). It is also noteworthy that nearly 30% of the primary SS patients experienced no functional disability.

There are several potential limitations of this study. First, physical function was assessed using a self-report questionnaire, which may be susceptible to reporting bias by the respondents. However, the Improved HAQ has been fully validated and shown to be sensitive to change (15). Furthermore, we have recently shown that primary SS patients have a low tendency to overreport symptoms (16). Therefore, the functional impairment reported by the primary SS group is likely to be genuine. Second, only 70% of the invitees participated in the study; therefore, our data may be skewed due to selection bias. However, the clinical parameters of the primary SS group in this study are similar to the UKPSSR cohort. Furthermore, there was no difference in the mean ± SD ESSDAI score, ESSPRI score, ESR, or CRP levels, which are routinely measured in the clinic, between the participants and nonparticipants (4.71 ± 5.1 versus 4.1 ± 3.7, 5.4 ± 2.1 versus 5.5 ± 1.7, 31.6 ± 25.1 versus 25.5 ± 25.5, and 5.8 ± 2.4 versus 5.1 ± 0.4, respectively; P > 0.05 for all group comparisons). These observations suggest that our findings are unlikely to be a consequence of selection bias.

Due to differences in routine clinical services, minor salivary gland (MSG) biopsies are historically less frequently performed in the UK compared to other developed countries; therefore, our cohort may bias toward seropositive patients and hence more severe disease. It would be interesting to compare our data with primary SS cohorts from other countries, where MSG biopsies are more frequently carried out. Finally, only cross-sectional data are available for this study; information on short- and long-term changes in physical function of primary SS patients, especially in response to different treatments, will be invaluable.

In conclusion, we have shown that patients with primary SS have significant functional impairment. Assessment for functional disability and associated clinical features should therefore be considered as part of routine care for primary SS patients, and future research directed toward the development of effective rehabilitation regimens to maximize physical function is warranted.

AUTHOR CONTRIBUTIONS

Study conception and design. Newton, Elliott, Mitchell, Ng.

Acquisition of data. Hackett, Newton, Elliott, Lendrem, Foggo, Edgar, Mitchell, Ng.

Analysis and interpretation of data. Hackett, Newton, Frith, Elliott, Lendrem, Mitchell, Ng.

Acknowledgements

We would like to thank all the patients and healthy volunteers who have participated in this study.

Ancillary