Objectives To describe primary Sjögren’s disease (SjD) patients presenting no or low level of dryness and to compare them with SjD patients with oral or ocular dryness features.
Methods All patients diagnosed with SjD according to AECG or ACR/EULAR criteria in our tertiary reference centre were included. Patients with high or low subjective symptoms or objective signs of dryness were compared.
Results Overall, 509 patients were included for the comparison of patients with high (n=456) or low (n=53) level of subjective dryness and 472 for the comparison of patients with (n=359) or without (n=113) high objective dryness. Compared with patients with subjective dryness, patients without high subjective dryness were significantly younger (median 49 (39–62) years vs 58 (47–67) years, p<0.01), diagnosed earlier (median time from first symptoms to diagnosis 2 (0.5–4.5) years vs 4 (1–9.25), p=0.0056), more frequently anti-SSA positive ((83% vs 64%, p=0.008) and had less focal sialadenitis in minor salivary gland biopsy (69% vs 83%, p=0.02).
The patients without high level of objective dryness (n=113) were also younger (51 (41–60) vs 58 (47–67) years, p<0.001) and were more frequently anti-SSA positive (79% vs 63%, p=0.002).
In both groups, no difference was observed regarding disease activity.
Conclusions Among the patients with SjD, those without high subjective or objective dryness features had a younger profile, a faster diagnosis which may result from a more acute onset, were more frequently anti-SSA positive than patients with high dryness features.
- Sjogren's syndrome
- autoimmune diseases
Data availability statement
Data are available upon reasonable request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
To date, no study has evaluated the clinical presentation of patients with Sjögren’s disease (SjD) with absence or very low level of dryness.
WHAT THIS STUDY ADDS
This study shows that patients with SjD without high level of symptoms of dryness are younger and have an earlier diagnosis.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Physicians must be aware that the diagnosis of SjD should not be ruled out in patients with no or low dryness features, especially in case of early onset.
Primary Sjögren’s disease (SjD) is a systemic autoimmune disease affecting approximately 60 individuals per 100 000 individuals with a predominance in middle-aged women.1 The most frequent symptoms are dry eyes and/or dry mouth but extra-glandular manifestations are possible in almost 30%–50% of the patients.2 Extra-glandular systemic manifestations are polymorphous and can affect almost any organ, among them B-cell lymphoma is the most feared.2 In the current ACR/EULAR classification criteria,3 an entry criterion must first be met, which can be either ocular or oral dryness or at least one systemic feature or biological marker of activity according to the EULAR Sjögren’s disease Activity Index (ESSDAI) score.4 Then, the diagnosis can be made based on scoring including specific markers: anti-Ro/SSA antibodies, focal lymphocytic sialadenitis and objectives measures or dryness: that is, abnormal ocular staining score (OSS)/Van Bijsterveld score (VBs), Schirmer’s test or salivary flow (online supplemental table 1).
Thus, it is now possible to classify patients as SjD without objective or subjective dryness, which was not the case in the previous widely used AECG criteria, requiring at least one objective or subjective criteria of dry mouth or dry eyes.4
To date, no study has focused on SjD patients presenting without or with low level of dryness. The aim of the study was to compare SjD patients with and without high level of dryness to determine whether a specific clinical presentation can be identified in these patients.
Patients and methods
The ‘Paris-Saclay’ cohort is a prospectively collected cohort including all patients participating to a multidisciplinary diagnostic session dedicated to SjD-suspected patients, in the Department of Rheumatology, Bicêtre Hospital, French National and European Referral Center for Rare Systemic Autoimmune Diseases, Paris-Saclay University. In this study, all patients from the ‘Paris-Saclay’ cohort diagnosed with SjD according to AECG or ACR/EULAR criteria and recruited between 1999 and 2020 were included. To focus on primary SjD, patients with a secondary SjD (ie, with associated auto-immune disease) were excluded.
The following data were collected: age, sex, patient medical history, age at onset of SjD symptoms and at diagnosis, disease duration, ESSDAI score at diagnosis, Schirmer’s test, OSS or VBs, unstimulated whole salivary flow (UWSF), parotid gland enlargement, extra-glandular involvement, Visual Analogue Scale (VAS) for ocular and mouth dryness, pain and fatigue. Biological and immunological features were collected: anti-Ro/SSA, anti-La/SSB, anti-DNA, labial minor salivary gland biopsy focus score. Disease activity was assessed using the ESSDAI,4 and patient symptoms using the EULAR Sjögren’s disease Patient Reported Index (ESSPRI).5
Patients without dryness features were defined as follows:
Subjective dryness: patients were considered without high level of subjective dryness if both VAS for dry eyes and dry mouth were ≤30/100. This threshold was chosen because is the threshold usually used to define low level of symptoms, for example, for the pain VAS. This threshold is much below the patient acceptable symptom state, which is for example for ESSPRI of 50/100. Since they cannot be classified as having or not subjective dryness, patients with missing values on VAS for dry eyes or dry mouth were excluded from the analysis comparing patients with or without high level of subjective dryness.
Objective dryness: patients were considered without high objective dryness if having both a Schirmer’s test above 5 mm/5 min and an UWSF rate above 0.1 mL/min. Since they cannot be classified as having or not objective dryness, patients with missing values on Schirmer’s test or UWSF were excluded from the analysis comparing patients with or without high objective dryness.
As sensitivity analysis, to define objective dryness we additionally used results of the OSS or VBs, when available. In this sensitivity analysis, patients were classified as having high level of objective dryness if they had any of the following abnormal test: Schirmer (≤5 mm/5 min), UWSF (≤0.1 mL/min), OSS (≥5) or VBs (≥4).
Data were expressed as median (IQR) for continuous variables and number (%) for categorical variables.
Patients with and without high level of dryness features were compared using Mann-Whitney U test for continuous variable and χ2 test, or Fisher’s exact test when appropriate, for qualitative variables. Statistical analyses were performed on GraphPad Prism V.8.4.0. A p value <0.05 was considered statistically significant.
Among the 646 patients with SjD identified in the ‘Paris-Saclay’ cohort database, 509 patients were included for the comparison of patients with (n=456, 89%) or without (n=53, 10.4%) high subjective dryness and 472 for the comparison of patients with (n=359, 76%) or without (n=113, 23.9%) high objective dryness (figure 1). Patients excluded from the analysis for missing data were not different from included patients (online supplemental table 2). Of note, among the 113 patients with no high objective dryness, only 17 (15%) also had no or low subjective dryness. Also, among the 53 patients with no or low subjective dryness, 33 (62.3%), actually had high objective dryness.
Comparison between patients with high and low subjective dryness
Compared with patients with subjective dryness (table 1), patients without high subjective dryness were younger (median 49 (39–62) years vs 58 (47–67) years, p=0.0026) and were diagnosed faster (median time from first symptoms to diagnosis 2 (0.5–4.5) years vs 4 (1–9.25), p=0.0056). Most frequent symptoms at presentation were arthralgia (57%), parotid swelling (25%), fatigue (21%), Raynaud’s syndrome (13%) and peripheral nerve involvement (6%) (online supplemental data 4). They were more likely to be anti-Ro/SSA positive (83% vs 64%, p=0.008) but less likely to have focal sialadenitis in minor salivary gland biopsy (69% vs 83%, p=0.02). There was no difference in overall disease activity measured by the ESSDAI, or anti-La/SSB positivity (32% vs 34%, p=0.26). They had more frequent peripheral nervous system involvement (median 5/48 (10.4%) vs 11/443 (2.5%) p=0.01) and higher level of IgG (median 15.1 g/L (12.3–17.3) vs 13 g/L (10.2–17) p=0.03). Nevertheless, patients with high subjective dryness reported also a higher level of fatigue (median fatigue VAS: 6.5/10 vs 4.7/10, p=0.0005), and had more frequently a chronic cough (24.2% vs 9%, p=0.01) than patients without high subjective dryness.
Comparison between patients with and without objective dryness
Patients without high objective dryness, compared with those with objective dryness (table 2), were also younger (51 (41–60) vs 58 (47–67) years, p=0.0005) and were more often anti-Ro/SSA positive (79% vs 63%, 0.002). However, there was no difference in disease activity (median ESSDAI (IQR): 2 (1–6) vs 2 (0–4), p=0.1), frequency of anti-La/SSB positivity (31% vs 37%, p=0.14) or focal sialadenitis in minor salivary gland biopsy (77% vs 79% p=0.56). Patients with high level of objective dryness had higher levels of subjective dryness (median ocular dryness VAS: 5.7/10 (2.5–8) vs 4.9/10 (1.7–7.1), p=0.019; median oral dryness VAS: 7/10 (4.8–8.8) vs 5.8/10 (3.4–7.5), p=0.0012). In a sensitivity analysis adding OSS or VBs scores to classify patients, patients with no or low objective dryness were also significantly younger, had more frequent anti-Ro/SSA positivity and had a higher ESSDAI score (online supplemental table 3).
Patients without high subjective and objective dryness (n=17, online supplemental data 5), were even younger (median 42 (36–50) years), have high disease activity (ESSDAI 4 (2–7)) and were always anti-Ro/SSA positive (100%).
In this large monocentric cohort of well phenotyped SjD patients, we observed that only 10.4% of patients did not report high level of subjective dryness, while almost 23.9% did not have objectively assessed high level of dryness, with a quite low overlap between both. Absence of dryness symptoms is uncommon in reported studies: in a cohort of 125 patients with SjD, only 10% had no subjective ocular dryness and 6% no subjective oral dryness, 39% had a Schirmer’s test above the diagnostic threshold and 33% a normal UWSF.6 In another cohort of 352 patients with SjD, 19% had no subjective ocular dryness and 10% no subjective oral dryness.7
Our patients without high subjective or objective dryness were younger and had a shorter time from first symptoms to diagnosis, reflecting probably a more acute onset. They also were more frequently anti-Ro/SSA positive and for patients without subjective dryness less frequently focus score positive. This suggests the presence of at least two endotypes of the disease: patients with severe dryness, more frequently focus score positive and patients with lower dryness, who are younger and more frequently anti-Ro/SSA positive.8 There was no difference in anti-La/SSB positivity between these two endotypes. An alternative explanation might be that their presenting symptoms, high frequency of arthralgia (88%), prompted the clinician to search earlier for autoantibodies (online supplemental data 5) in patient without objective or subjective dryness.
A few studies have shown that absence of dry eye and/or mouth was associated with an earlier age of onset of the disease,9 10 consistent with our findings showing that patients without high level of sicca syndrome were younger and had a shorter time to diagnosis. The influence of age-related hormonal imbalance is known to promote ocular dryness.11 Age being a risk factor for dryness, it may also be a confounding factor explaining this higher prevalence of sicca syndrome in older patients.12 It can be hypothesised that there are several clinical presentations of the disease, or that the disease evolves over time with an increased risk of dryness as patients get older. To support the latter hypothesis, one could imagine a progressive atrophy of the salivary glands related to the autoimmune disease or to age-related changes. Also, it has been reported in a large series of 12 753 patients, that patients diagnosed younger had more frequent systemic involvement such as: lymphadenopathy, constitutional, cutaneous and haematological involvements and that patients without objective dryness features were younger and had a more systemic disease.10 However, a limitation of our study is that our data are transversal, and we cannot exclude that some patients without initial dryness features will develop dry eye and/or mouth later.
We observed a very low overlap between objective and subjective evaluation of dryness, since only 15% of patients with no or low objective dryness, also had no or low subjective dryness, whereas more than two-thirds of the patients having no or low subjective dryness, actually, had high level of dryness when assessed objectively. Poor correlation between signs and symptoms regarding dryness features have been described in general population13 and in SjD.14 15 In SjD, one of the hypotheses to explain these discrepancies, may be related to the quite high frequency of corneal neuropathy that may alter corneal sensitivity and prevent patients from experiencing subjective symptoms.16 17 There are several types of corneal neuropathy in these patients, and it has been shown that it can take the form of hypoesthesia or hyperalgesia.18 19 According to these two subtypes of nerve sensitivity abnormalities, corneal neuropathy can further reduce tear production and thus worsen objective sicca syndrome and paradoxically reduce the perception of dryness,20 or induce neuropathic corneal pain with even a paradoxical tear reflex when the lacrymal gland is not yet too much impaired.19
Subjective dryness was associated with chronic cough that might be explained by dryness of the upper airways, since we did not observe more frequent lung involvement in patients with high dryness features. Subjective dryness was also associated with a higher level of other SjD cardinal symptoms such as fatigue and pain, and thus ESSPRI, while objective dryness was mainly associated with a higher level of pain. Interestingly, a previous series of 688 patients, reported that fibromyalgia, anxiety and depression symptoms were significantly more frequent in patients with high level of subjective dryness (not linked to objective features), possibly explaining this association with fatigue and pain.14
One of the limitations of this study is the relatively little number of patients with low or no dryness features, despite a large number of patients included. However, this is inherent to the nature of the SjD, where dryness is a hallmark and affects the vast majority of patients. Our results highlight that this patient phenotype is probably infrequent. However, such patients exist and deserve a particular attention since having a higher risk of systemic complications. Our results also underline the relevance of the more recent ACR/EULAR classification criteria, able to detect them more easily, and allowing conducting clinical studies, particularly randomised controlled trials (RCTs), including these patients. Effectively, it has been shown that patients who met the ACR/EULAR criteria but not the AECG criteria had fewer dryness features and more systemic complications.6 Our results underline the importance of defining outcome measure taking into account both systemic and symptomatic involvement and in particular dryness.
This study is the first to evaluate the clinical profile of patients with SjD with no or low dryness features, defined either subjectively or objectively. It revealed that among patients with SjD, those without high level of subjective or objective dryness features were younger and had a shorter time than patients with dryness features. Thus, physicians should be aware that the absence of dryness should not rule out the diagnosis of SjD, especially in young patients.
Data availability statement
Data are available upon reasonable request.
Patient consent for publication
This study involves human participants and was approved by Comité de Protection des Personnes (IRB Paris Sud #00-17). Participants gave informed consent to participate in the study before taking part.
Contributors AK collected data, conducted statistical analysis and wrote the manuscript. AK, RS, GN and XM designed the study. RS and GN conducted statistical analysis. XM, FD, EB, ML, CLP and AR served as scientific advisors, critically reviewed the study proposal. All authors provided care for study patients. AK and RS are garantors, they accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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