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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Objective

The European League Against Rheumatism (EULAR) Sjögren's Syndrome (SS) Disease Activity Index (ESSDAI) and the EULAR SS Patient-Reported Index (ESSPRI) were recently developed. We aimed to determine whether patients' symptoms differed between patients with and without systemic involvement and if the disease-specific indices correlated with each other in primary SS.

Methods

Fifteen French centers included 395 primary SS patients in the Assessment of Systemic Signs and Evolution in Sjögren's Syndrome Cohort. At enrollment, physicians completed the ESSDAI, the SS Disease Activity Index (SSDAI), and the Sjögren's Systemic Clinical Activity Index (SCAI), and patients completed the ESSPRI, the Sicca Symptoms Inventory, and the Profile of Fatigue and Discomfort. All scores were compared between patients with and without systemic involvement. Correlations between scores of systemic activity and patients' symptoms were obtained.

Results

At enrollment, 120 (30.4%) patients had never experienced systemic complication and 155 (39.2%) patients and 120 (30.4%) patients had, respectively, only past or current systemic manifestations. Past or current systemic patients had higher levels of symptoms, except dryness. The ESSDAI did not correlate with the patient-scored ESSPRI (rho = 0.06, P = 0.30), whereas the SSDAI and the SCAI, which include subjective items, did correlate (rho = 0.28 and 0.25, respectively; P < 0.0001 for both).

Conclusion

Alterations of common patient-reported outcomes are present in all patients with primary SS, including those with systemic complications. However, patient symptoms and systemic complications are 2 different facets of primary SS. Therefore, the use of both systemic and patients' indices, such as the ESSDAI and ESSPRI, are useful. Since these 2 facets weakly overlap, one should identify which of both components is the main target of the treatment to test, when designing clinical trials in primary SS.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Primary Sjögren's syndrome (SS) is a systemic disorder characterized by lymphocytic infiltration and progressive destruction of exocrine glands. The inflammatory process extends beyond the exocrine glands and can potentially affect any organ. As a result, clinical features can be divided into 2 facets: 1) benign but disabling patient symptoms such as dryness, pain, and fatigue that affect almost all patients and 2) systemic potentially severe manifestations that affect 20–40% of patients.

Two disease activity indices have been recently developed by a European League Against Rheumatism (EULAR) SS task force for evaluation of both disease facets: the EULAR SS Disease Activity Index (ESSDAI) ([1]) for systemic features and the EULAR SS Patient-Reported Index (ESSPRI) for patients' symptoms. These indices have never been compared to the other existing tools for real life patients ([2]), i.e., the SS Disease Activity Index (SSDAI) ([3]), the Sjögren's Systemic Clinical Activity Index (SCAI) ([4]), the Profile of Fatigue and Discomfort (PROFAD), and the Sicca Symptoms Inventory (SSI) ([5, 6]).

Since no data exist on the relationship between systemic features and patients' symptoms in primary SS, we aimed to examine whether common patients' symptoms differed between patients with and without systemic complications. We also analyzed whether the different disease-specific indices of patients' symptoms and of systemic activity correlated with each other and whether the subjective measures of dryness correlated with the objective measures.

Box 1. Significance & Innovations

  • Evaluation of systemic activity did not correlate with the level of patients' symptoms.
  • Evaluation of patients' symptoms with the European League Against Rheumatism (EULAR) Sjögren's Syndrome (SS) Patient Reported Index is therefore complementary to evaluation of systemic features with the EULAR SS Disease Activity Index.
  • When designing a trial in primary SS, one should identify which of the two components is the main target of the treatment to test.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Patients.

The Assessment of Systemic Signs and Evolution in Sjögren's Syndrome Cohort is a national multicenter prospective cohort that was set up in 2006 and supported by a French Ministry of Health grant. The primary objective of this cohort was to identify valuable predictive factors of systemic complications and lymphoma in primary SS during a 5-year prospective followup. The study was approved by the Ethics Committee of Hôpital Bichat and the “Commission Nationale Informatique et Libertés” in 2006. Fifteen tertiary centers for autoimmune diseases (rheumatology and internal medicine departments) included 395 consecutive primary SS patients, fulfilling American-European Consensus criteria ([7]) between May 2006 and July 2009. All patients gave their informed written consent. A standardized paper clinical report form (CRF) was prospectively completed by participating clinicians. This CRF included, among other information, classic demographic, biologic, and histologic (focus score) data of primary SS.

Measurement.

Physician outcome measures.

At enrollment, physicians completed the ESSDAI, the SCAI, and the SSDAI and assessed systemic disease activity with a physician global assessment (PhGA) scale (0–10). Also, physicians evaluated separately the severity of patients' symptoms on a scale of 0–10 (PhGA of patient symptoms).

Patient-centered measures.

All patients completed the ESSPRI (mean score of 0–10 numerical scales for pain, fatigue, and dryness features, including oral, ocular, and global dryness), the SSI, the PROFAD questionnaires, and a 0–10 patient global assessment (PGA).

Objective measures of dryness.

At enrollment, objective measures of dryness included Schirmer's test dye scores of both eyes, which were considered abnormal if ≤5 mm in 5 minutes and unstimulated salivary flow (USF), which was considered abnormal if ≤0.15 ml/minute.

Definition of systemic involvement.

Systemic involvement was defined as the presence or a past history of arthritis, myositis, purpura, and peripheral or central nervous system, pulmonary or renal involvement, or B cell lymphoma. All these items had been prospectively collected in a standardized way in the CRF. Raynaud's phenomenon was not considered as a systemic involvement.

Patients were divided into 3 groups: 1) nonsystemic patients who had never experienced systemic complication, 2) past systemic patients who had experienced systemic complication(s) but are currently not active, and 3) current systemic patients with currently active systemic complication(s). Patients with both past and current systemic complications were included in the current systemic patients group.

Statistical analyses.

Continuous data are presented as medians with interquartile ranges (IQR). We used nonparametric tests to analyze continuous variables, despite the large number of patients, because the distribution of data was uneven. Severity of each symptom and disease-specific scores were compared between patients with and without systemic involvement. The Wilcoxon's test was used to compare continuous data, and the chi-square or Fischer's exact test, when appropriate, was used to compare nominal data. Correlations were studied with Spearman's rank test. Rho correlation coefficients between scores of systemic activity and patient's symptoms were obtained and ranged from 0 (no correlation) to 1 (perfect correlation). For all statistical analyses, a P value less than 0.05 was considered statistically significant. All statistical analyses involved use of SAS, release 9.1, and R, release 2.2.1, statistical software packages.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Patient characteristics.

Characteristics of the 395 patients with primary SS are summarized in Table 1; 93.6% of patients were women, the median age was 58 years (IQR 51–67 years), and median disease duration was 5 years (IQR 2–9 years). Of the 395 patients, 59.2% of patients were anti-SSA positive and 33.5% were anti-SSB positive. One-third of the patients had never experienced a systemic complication, whereas 155 (39.2%) and 120 (30.4%) had, respectively, a past history or current presence of systemic manifestations at enrollment.

Table 1. Characteristics of the 395 primary SS patients and comparisons between systemic and nonsystemic patients*
 All patients (n = 395)Nonsystemic patients (n = 120)Past systemic patients (n = 155)PaCurrent systemic patients (n = 120)Pa
  1. Values are the median (interquartile range), the number (percentage), or the number/total number (percentage) unless indicated otherwise. SS = Sjögren's syndrome; ESSDAI = European League Against Rheumatism (EULAR) SS Disease Activity Index; SCAI = Sjögren's Systemic Clinical Activity Index; SSDAI = SS Disease Activity Index; PhGA = physician's global assessment; ESSPRI = EULAR Patient-Reported Index; SSI = Sicca Symptoms Inventory; PROFAD = Profile of Fatigue and Discomfort; PGA = patient's global assessment.

  2. a

    Scores were compared to those of patients without systemic involvement using Wilcoxon's test.

Demographic characteristics      
Age, years58 (51–67)58 (50–67)59 (51–67)0.7059 (52–68)0.23
Female/male, %93.6/6.494.1/5.995.5/4.50.6190.7/9.30.32
Disease duration, years5 (2–9)4 (2–8)5 (2–10)0.116 (2–10)0.11
Decreased salivary flow162/327 (47.5)50/99 (50.5)58/120 (48.3)0.7554/108 (50.0)0.94
Schirmer's test <5 mm208/340 (61.2)67/104 (64.4)79/134 (58.9)0.3962/102 (60.8)0.59
Focus score ≥1318/352 (87.8)93/108 (86.1)126/143 (88.1)0.9298/109 (89.9)0.93
Anti-SSA positive antibodies228 (59.2)77/116 (66.4)84/152 (55.3)0.0767/117 (57.3)0.15
Anti-SSB positive antibodies129 (33.5)46/116 (39.6)50/152 (32.9)0.2533 (28.2)0.06
Physician outcome measures      
ESSDAI (0–127)2 (0–7)2 (0–3)2 (0–4)0.198.5 (5–13.5)< 0.0001
SCAI (0–78)5 (4–8)5 (3–6)5 (4–8)0.027 (4–10)< 0.0001
SSDAI (0–21)1.5 (0–2)0 (0–1)1 (0–2)0.0021 (0–2)< 0.0001
PhGA (0–10)2 (2–4)2 (2–4)2 (2–3)0.992 (2–5)0.0004
Patient-centered measures (0–10)      
ESSPRI5.7 (4–7)5.0 (3.7–6.3)5.7 (4.0–7.3)0.0015.7 (4.0–7.0)0.07
SSI4.9 (3.2–6.5)4.7 (3.3–6.0)5.0 (3.3–6.9)0.365.1 (3.1–6.5)0.76
PROFAD4.6 (3.0–6.0)3.9 (2.5–5.2)5.0 (3.2–6.1)0.0054.7 (3.5–6.7)0.002
Global dryness6 (4–7)5 (3–7)6 (4–7)0.415 (3–7)0.97
Pain5 (2–7)4 (2–7)6 (3–7)0.015 (3–7)0.049
Fatigue6 (4–8)6 (4–8)7 (5–8)0.087 (4–8)0.40
PGA5 (3–7)5 (3–6)5 (3–7)0.045 (4–7)0.11

The different disease activity scores were obtained with no missing data in 389 (98.5%) patients for the ESSDAI, 389 (98.5%) patients for the SSDAI, and 287 (72.7%) patients for the SCAI. For patients' scores, full data were obtained in 356 (90.1%) patients for the ESSPRI, 344 (87.1%) patients for the SSI, and 345 (87.1%) patients for the PROFAD.

Comparison of systemic and nonsystemic patients.

Physician's outcome measures.

Current systemic patients had significantly higher systemic disease activity scores (SSDAI, SCAI, ESSDAI, and PhGA) than patients having never experienced systemic complications (Table 1). However, past systemic patients had also significantly higher SCAI and SSDAI scores than nonsystemic patients despite having no current systemic involvement. By contrast, ESSDAI scores in this group of past systemic patients, i.e., currently inactive, was not different from nonsystemic patients and was significantly lower than in current systemic patients (Figure 1). In addition, the SSDAI score was not able to discriminate currently active patients from inactive past systemic patients (median 1 [IQR 0–2] in both groups; P = 0.24). SCAI scores also significantly differed between previously active patients and currently active patients but, contrary to ESSDAI scores, the range of scores widely overlap between these 2 groups (Figure 1).

image

Figure 1. Distribution of systemic scores in nonsystemic, past, and current systemic patients. ESSDAI = European League Against Rheumatism Sjögren's Syndrome (SS) Disease Activity Index; SCAI = Sjögren's Systemic Clinical Activity Index; SSDAI = SS Disease Activity Index; PhGA = physician's global assessment.

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Patient-centered measures.

Both current and past systemic patients had higher scores of pain, PROFAD, and ESSPRI compared to nonsystemic patients, whereas dryness and SSI scores did not differ between groups (Table 1). However, no significant difference was observed in any scores between current and past systemic patients (P = 0.27–0.59).

Links between systemic and patients' scores.

ESSPRI was strongly correlated with PGA (rho = 0.73) and PROFAD (rho = 0.71). In addition, ESSPRI scores were more correlated with PGA (rho = 0.73) than other patients' scores. The PhGA of patient's symptoms was more correlated with its evaluation of disease activity (rho = 0.56) than with the patient's evaluation of symptoms (rho = 0.41). The ESSDAI did not correlate with ESSPRI or any other patient scores (Table 2), whereas the SSDAI and SCAI had moderate but significant correlations with all patients' scores, particularly the PROFAD (rho = 0.28 and 0.35, respectively).

Table 2. Correlation between primary SS disease-specific outcomes measures assessing systemic activity and patients' symptoms*
 SSIPROFADPGAPhGA of patient symptomsPhGAESSDAISSDAISCAI
  1. SS = Sjögren's syndrome; SSI = Sicca Symptoms Inventory; PROFAD = Profile of Fatigue and Discomfort; PGA = patient global assessment; PhGA = physician global assessment; ESSDAI = European League Against Rheumatism (EULAR) SS Disease Activity Index; SSDAI = SS Disease Activity Index; SCAI = Sjögren's Systemic Clinical Activity Index; ESSPRI = EULAR SS Patient-Reported Index.

ESSPRI        
Spearman's rho0.550.710.730.390.180.060.280.25
P< 0.0001< 0.0001< 0.0001< 0.00010.00090.30< 0.0001< 0.0001
SSI        
Spearman's rho1.000.550.470.270.100.020.170.18
P < 0.0001< 0.0001< 0.00010.060.720.00230.0036
PROFAD        
Spearman's rho 1.000.660.300.140.080.280.34
P  < 0.0001< 0.00010.010.17< 0.0001< 0.0001
PGA        
Spearman's rho  1.000.410.210.070.270.24
P   < 0.0001< 0.00010.17< 0.0001< 0.0001
PhGA of patient symptoms        
Spearman's rho   1.000.560.140.330.24
P    < 0.00010.01< 0.0001< 0.0001
PhGA        
Spearman's rho    1.000.340.330.21
P     < 0.0001< 0.00010.0003
ESSDAI        
Spearman's rho     1.000.270.25
P      < 0.0001< 0.0001
SSDAI        
Spearman's rho      1.000.39
P       < 0.0001

Taking the 75th percentile of the distribution of the ESSDAI (ESSDAI >7) and ESSPRI (ESSPRI ≥7) to define, respectively, patients with high disease activity and with high levels of symptoms, we found that only a minority of patients having a high level of symptoms also had a high level of disease activity and vice versa. Effectively, among 94 and 89 patients having a high level of disease activity and of symptoms, respectively, less than 30% (n = 26) of patients had both a high level of symptoms and disease activity.

Correlations between subjective and objective measures of dryness.

Global dryness (0–10 numerical scale) did not correlate with Schirmer's dye score (rho = −0.05) and had low correlation with USF (rho = −0.20). Schirmer's score and USF did not correlate with each other (rho = 0.11). Even when they were related to the same domain, subjective and objective dryness were weakly correlated (rho = −0.24 for Schirmer's test and ocular dryness and rho = −0.38 for USF and oral dryness).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

This study is the first to compare all existing disease-specific indices in a large cohort of primary SS patients. The results showed that patients with systemic complications of the disease seemed to experience more from their disease, as reflected by their higher scores of patient-reported outcomes. In addition, we found that correlations and overlap between systemic activity scores and patient symptoms were low and even nil for the ESSDAI, reflecting the fact that these 2 components are different facets of the disease. Lastly, the ESSDAI seemed to be the most valuable score for distinguishing currently active patients from inactive nonsystemic or past-systemic patients.

Patients with systemic complications of the disease have higher levels of symptoms as reflected by higher pain and PROFAD and ESSPRI scores, but similar levels of dryness, compared to those without any systemic complications. Despite having recovered from their systemic complications, past systemic patients kept the same high level of these symptoms as current systemic patients. Thus, the impact of the disease is present in most of the patients with primary SS and is more profound in patients with systemic complications ([8]). Since patients' symptoms did not correlate with the ESSDAI, this high level of symptoms seems to reflect more of a higher perceived disease burden than a marker of disease activity in these more severe patients currently having or having previously experienced systemic complications. This supports the interest of using ESSPRI and other patient-reported outcomes in both groups of patients with and without systemic complications. However, these results also suggest that patients' scores are possibly less sensitive to change than systemic scores in systemic patients, reinforcing the interest of the use of a systemic score to detect improvement of patient status. This is particularly crucial when assessing the effects of immunosuppressive therapy.

The main result of this study is that systemic disease activity measures did not correlate (as for the ESSDAI) or poorly correlate (as for the SCAI and SSDAI) with patient-centered measures, reinforcing the need for evaluation of both these disease facets separately. The discrepancies between ESSDAI scores and other systemic scores are probably linked to the fact that the SSDAI and the SCAI include subjective items that are related to frequent patient symptoms, such as fatigue, but also, for the SCAI, symptoms of pain that are sometimes not necessarily due to disease activity but rather to fibromyalgia-like symptoms. Similar results have been found in systemic lupus erythematosus (SLE), where some activity indices that include patient-derived assessments, such as the British Isles Lupus Assessment Group ([9, 10]) and the Systemic Lupus Activity Measure ([11]), were more sensitive to patient-assessed changes ([12, 13]) than the SLE Disease Activity Index (SLEDAI) ([14]), including only objectively assessed manifestations. In addition, we found that the wider range of value of the ESSDAI seems to make it more able to discriminate between currently active patients and inactive patients with previous systemic complications, as compared to the SSDAI, which did not, and the SCAI, which seemed to perform worse. This result is also likely to be due to these subjective items, since we found that the level of patient symptoms did not improve in past systemic patients and was higher than in nonsystemic patients. Also, we observed a high rate of missing data with the SCAI score compared with the ESSDAI and SSDAI scores, probably reflecting the relative complexity of this score.

Correlation between PhGA of patient's symptoms and PGA was low, reflecting the fact that the physician could hardly appraise the impact of the patient symptoms ([15, 16]). This reinforces the idea that these symptoms had to be assessed by the patients themselves ([17]). In addition, the PhGA of patients' symptoms and of disease activity had a stronger correlation, suggesting that, no matter how the question is phrased, the physician implicitly incorporates his own opinion into the assessment of both systemic activity and patient symptoms.

As previously shown, we observed very low correlations between objective and subjective measures of dryness ([6, 18]), suggesting that these objective measures probably imperfectly reflect the perceived symptoms. In addition, these objective measures have been shown to be poorly sensitive to change ([19, 20]). Minor salivary gland examination was not mandatory at study entry but could have been done previously. Therefore, it was not possible to assess a possible association between histologic patterns and subjective or objective measures of dryness or phenotypic characteristics ([21]). Thus, assessment of patient's symptoms is complementary to objective assessment of dryness. In the future, these measures have to be evaluated in longitudinal studies in order to determine which ones are the more sensitive to change and thereby improve outcome assessment of patients' symptoms in primary SS.

In conclusion, alterations of common patient-reported outcomes are present in most of the patients with primary SS and are particularly important in those with systemic complications. This supports the interest of using ESSPRI and other patient-centered measures in both groups of patients with and without systemic complications. Our results clearly show that patients' symptoms and systemic complications are 2 different facets of primary SS, with no correlation between the ESSDAI and the ESSPRI. In addition, our results suggest that the wide range of values of the ESSDAI make it the most able to discriminate between active and inactive patients. Therefore, the use of both the ESSDAI and the ESSPRI are necessary and complementary to completely assess disease activity and symptoms of primary SS patients. Since these 2 facets of the disease poorly overlap, one should define which component of the disease is the main target of the treatment to test when designing clinical trials in primary SS.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Seror had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Seror, Gottenberg, Devauchelle-Pensec, Dubost, Sibilia, Ravaud, Mariette.

Acquisition of data. Seror, Gottenberg, Dubost, Le Guern, Hayem, Fauchais, Goeb, Hachulla, Hatron, Larroche, Morel, Pedriger, Puéchal, Rist, Saraux, Sene, Vittecoq, Zarnitsky, Labetoulle, Mariette.

Analysis and interpretation of data. Seror, Gottenberg, Goeb, Sibilia, Ravaud, Mariette.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

The authors thank Frederic Desmoulins, Karine Inamo, Stanie Gaete, Djilali Batouche, Mickael Randrianandrasana, Isabelle Pane, Gabriel Baron, and the Centre de Ressources Biologiques de l'Hôpital Bichat.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES
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