Radiological Imaging of the Lacrimal Gland in Sjogren’s Syndrome: A Systematic Review and Meta-Analysis

Abstract

Purpose

To critically appraise the evidence on the ability of the lacrimal gland ultrasonography (USG) or magnetic resonance imaging (MRI) to differentiate between Sjogren’s syndrome and non-Sjogren’s syndrome/healthy controls.

Methods

A systematic review and meta-analysis (based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines) of online literature search was performed using PubMed, Scopus, and Cochrane databases. Cohort studies comparing the imaging features of the lacrimal glands of Sjogren’s syndrome with a control group were included. Quantitative synthesis was performed using the RevMan (Version 5.4.1).

Results

Six studies used USG as an imaging technique, and three used MRI for the lacrimal gland imaging. The lacrimal gland affected with Sjogren’s syndrome shows glandular heterogeneity on USG and MRI. Heterogeneity on USG had 6.18 times higher odds of the lacrimal gland being involved with Sjogren’s syndrome (95% CI, 3.31–11.55). Gland hyperechogenicity cannot reliably differentiate the glandular involvement in Sjogren’s syndrome. There is insufficient data for analysis on the gland size, hypoechoic areas, fibrous bands, and increased lacrimal artery resistance in Sjogren’s syndrome patients. Of the three MRI-based studies, reduced apparent diffusion coefficient and heterogeneity were the characteristics of Sjogren’s syndrome. Clinical parameters such as dry eye symptomatology and Schirmer values had variable associations with USG or MRI parameters. Ultrasonography parameters were no different between dry eye versus no dry eye in Sjogren’s syndrome patients, whereas small-sized glands had low Schirmer on MRI-based studies.

Conclusion

Glandular heterogeneity on USG is significantly associated with lacrimal gland involvement in Sjogren’s syndrome patients. However, the role of radiology in predicting lacrimal gland involvement is unclear as the evidence is insufficient and heterogeneous.

Introduction

Sjogren’s syndrome is an autoimmune disease affecting the lacrimal and salivary glands, manifesting as dry mouth and eyes other than its extraglandular manifestations.¹ There is no gold standard for diagnosing SS, and its diagnosis requires a combination of tests. SS is diagnosed based on ACR-EULAR criteria accounting for the involvement of salivary (four points – lymphocytic infiltrate (3), saliva flow rate (1)) and lacrimal gland (two points – Schirmer (1) and ocular surface staining scores (1)) other than positive auto-antibodies (three points).¹ A total score of >4 is required for the SS diagnosis. For salivary gland involvement in SS, a minor salivary gland biopsy is a gold standard for identifying the inflammatory process.¹ Unfortunately, lacrimal gland biopsy is technically challenging and is not performed to avoid damage to the remaining lacrimal gland tissue as there is only one gland in each eye, contrary to the numerous minor salivary glands in the oral cavity. As a disease, SS is heterogeneous in the extent of the involvement of the glandular tissues, and ocular involvement is measured using tear film tests.² The potential lacunae of ACR-EULAR criteria is that Schirmer or ocular surface staining has high variability, and ocular involvement is usually picked up late as patients present to an ophthalmologist when it has already reached severe damage.³ Imaging techniques like high-frequency ultrasound are valuable tools in diagnosing SS.^4–13 Also, being non-invasive, this imaging can assess the disease progression or response to treatment. Ultrasonography (USG) of the parotid gland is commonly performed as a non-invasive means to detect SS.⁶ However, lacrimal gland imaging has been explored in a few studies using USG or magnetic resonance imaging (MRI) for diagnosing SS.^4–20 Lacrimal gland imaging in SS has been performed for enlarged glands secondary to lymphoma, where a biopsy is performed for histopathological diagnosis.^21–24 The relevance of the lacrimal gland imaging in SS without clinically enlarged glands is unclear. The current meta-analysis critically appraises the diagnostic value of lacrimal gland imaging, be it USG or MRI, in differentiating gland involvement in SS patients.

Methods

The systematic and meta-analysis protocol was registered on PROSPERO (CRD42024497233). The study followed the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Inclusion criteria

1. Population: Patients with Sjogren’s syndrome belonging to any age group. Diagnosis should be made as per ACR-EULAR criteria or the standard SS criteria available for the year of publication.

2. Intervention: Studies that performed USG or MRI of the lacrimal gland.

3. Comparison: Studies where at least one control group, either healthy or non-SS dry eyes, was present.

4. Outcomes: Studies describing imaging features – at least one of the glandular features, like size, volume, or internal echotexture.

Exclusion criteria

Excluded studies were isolated case reports, case reports on lymphoma or non-Sjogren’s syndrome glandular enlargement, animal studies, conference abstracts, and review papers.

Search strategy

Electronic databases PubMed, Scopus, and COCHRANE, were searched for relevant studies till January 10 2024 (Figure 1). The following search queries were run: (Sjogren’s syndrome OR Dry eye disease OR Dry eyes OR dry eye) AND (Ultrasound OR Ultrasonography OR MRI OR Magnetic resonance imaging OR Radiology OR diagnostic imaging OR Radiological imaging OR magnetic resonance) AND (Lacrimal gland OR Lacrimal glands OR Lachrymal gland). Supplementary Figure 1 depicts the PICO strategy terms. The language was not limited to English, and all search items were included for screening.

Figure 1. PRISMA chart showing the details of reviewed and included articles.

Screening and risk of bias

The above-mentioned inclusion and exclusion criteria were used independently by two authors (SS, RV) to screen abstracts and titles. Rayyan website was used for screening the abstracts. Full texts of eligible studies were retrieved and reviewed by two authors. The eligible studies were critically reviewed for the risk of bias using the JBI (Joanna Briggs Institute) tool (Supplementary file 2).

Data extraction and statistics

The reviewers extracted data into an MS Excel sheet. Extracted data parameters included:

1. Study details (country, author, year of study, and study design);

2. Study participants details (numbers, mean age, SD, sex, race and ethnicity, duration of SS, diagnostic criteria of SS, and mean Schirmer values);

3. Imaging details (glands visualized on imaging, each parameter detail wherever reported like size, gland heterogeneity, intraglandular fat deposition, hypoechoic or hyperechoic internal intensity, and elastography index).

Also, data on the investigator (radiologist or rheumatologist) who imaged glands, USG frequency or MRI Tesla, and sequence were recorded. Review Manager (Version 5.4.1) was used for meta-analysis and Forest plot construction. Outcomes were calculated as odds ratios for imaging parameters – glandular heterogeneity and hyperechogenicity. The rest of the imaging parameters were not uniformly described across studies and could not be analyzed statistically.

Assessment of heterogeneity

The I² test was used to measure heterogeneity and calculated using RevMan software. The funnel plot could not be designed as there were less than 10 studies.

Results

Characteristics of included studies

Of the 438 screened records, 29 were sought for full-text (Figure 1). The full text was retrieved for nine articles only. Six studies used USG as an imaging technique, and three utilized MRI for lacrimal gland imaging.

Ultrasonography

Six studies on USG had a total of 179 patients diagnosed with SS based on ACR-EULAR criteria in four and 1985 criteria in one study (Table 1). Ethnicities were Italian (n = 2), Korean (n = 1), Turkish (n = 2), and Polish (n = 1). All these studies were case-control observational studies. The mean age of participants with SS was 54.6 ± 5.5 years, and they had been diagnosed with SS for 66.2 ± 51.8 months. The majority were females, 92.8% (245/264) in SS and control groups (90.8%, 297/327). The number of participants in the control group was 327 (mean age, 51.7 ± 8.3 years). Most studies did not report the exact USG probe frequency; instead, a range varying from 4 to 18 MHz was provided. Not all SS patients have visible glands on USG. Of 359 imaged glands of SS patients, 92.7% (333/359) of glands could be visualized on USG, whereas all glands were visible in healthy controls (99.3%, 355/358). In one study, the control group had non-SS DED patients where glands could be observed in 55.7% of eyes (63/113). The reported USG parameters were reduction in gland size (in two studies), heterogeneity within the gland (in five studies), hypo or hyperechogenicity (in four studies), and shear-wave elastography (SWE) index in three studies. Information on gland heterogeneity and hyperechogenicity was used for meta-analysis, where parameters were compared with healthy controls (Figures 2 and 3). Gland heterogeneity was associated with an increased possibility of SS as a diagnosis (RR 6.18, 95% CI, 3.31–11.55). Hyperechoic areas within the lacrimal gland did not predict SS diagnosis (RR 3.79, 95% CI, 0.08–171.3) due to large confidence intervals and lack of interobserver comparison of one huge weighted study. The lacrimal gland USG parameters were no different between pSS patients with positive serology or ocular dryness (symptoms or Schirmer values) versus SS patients with negative serology or clinical parameters.^4,11 However, in only one study, the visible glands had significantly worse ocular dryness and positive serology than SS patients with invisible glands.⁶ SWE, as a form of USG analysis, assesses the mechanical properties of the tissue. For the lacrimal gland, the mean SWE index was reported as 16.3 (healthy group – 6.4 kPa⁹) in one study and 8.9 (healthy – 3.7 kPa) in another study (Table 1). A SWE cut-off value of 7.2 kPa was 88.9% sensitive and 88% specific. However, another study reported a 4.6 kPa cut-off to be 94% sensitive and 87% specific. Both studies used different USG transducers and numbers of subjects. The number of SS patients with reduced Schirmer was 34% in one study and 56% in another, which could be the reason for differences in SWE cut-offs. A recent study reported SWE to be 16.3 kPa in SS compared to 7.3 kPa in controls.¹⁹ The cut-off value of 10.4 kPa was 70.6% sensitive and 97.6% specific. This study reported the mean Schirmer value to be 6.4 mm without describing patient numbers with reduced Schirmer values.

Table 1. Description of included studies on ultrasonography of the lacrimal glands in Sjogren’s syndrome.

Study	Age, mean (SD)	Ethnicity	Imaging personnel	USG probe frequency	Total no. of glands visible in Sjogren’s syndrome	Total no. of glands visible in control group	USG features in study	USG features in control	No. of glands with reduced Schirmer value in study group	Additional information
Giovagnorio et al.6	65 (12)	Italian	Radiologist	10–13 MHz	12/30	30/30	Hypoechoic – na Hyperechoic – 6 Heterogeneity – 6 Fibrous band – na	Hypoechoic – na Hyperechoic – na Heterogeneity – na Fibrous band – na	12	Color Doppler showed high resistance index in study than control’s lacrimal artery
De Lucia et al.11	51.6 (15)	Italian	Two rheumatologists	4–15 MHz	33/34	63/113	Hypoechoic – 8 Hyperechoic – 1 Heterogeneity – 13 Fibrous band – 3	Hypoechoic – 6 Hyperechoic – 5 Heterogeneity – 9 Fibrous band – 0	14	Glandular inhomogeneity and fibrous gland appearance significant difference b/w two groups
Kim et al.4	56.2 (18)	Korean	Rheumatologist	5–12 MHz	112/112	63/80a	Hypoechoic – na Hyperechoic – na Heterogeneity – 81 Fibrous band – na	Hypoechoic – na Hyperechoic – na Heterogeneity – 37 Fibrous band – na	40	Intraglandular lacrimal artery visible in 79/112 vs. 34/80 glands in study, control group, respectively.
Karadeniz et al.12	53.4 (12.9)	Turkish	Radiologist	9 MHz, SWE	43/46	23/23	Hypoechoic – na Hyperechoic – 4 Heterogeneity – 21 Fibrous band – na SWE index 8.9	Hypoechoic – na Hyperechoic – 2 Heterogeneity – 1 Fibrous band – na SWE index 3.7	15	A cut-off value of 4.6 kPa of SWE - 94% sensitive and 87% specific for Sjogren’s syndrome involvement.
Swiecka et al.9	50 (IQR 39–62)	Polish	Two radiologists	5–18 MHz, SWE	45/45	108	Hypoechoic – na Hyperechoic – na Heterogeneity – na Fibrous band – na SWE 16.3	Hypoechoic – na Hyperechoic – na Heterogeneity – na Fibrous band – na SWE 6.4	15	A cutoff point of 7.2 kPa of SWE - 88.9% sensitive and 88% specific for Sjogren’s syndrome involvement.
Ozer et al.19	51 (11)	Turkish	Two radiologists	9 MHz	85/95	84	Hypoechoic – 26 Hyperechoic – 45 Heterogeneity – 71 Fibrous band – na SWE 12.5	Hypoechoic – na Hyperechoic – na Heterogeneity – 36 Fibrous band – na SWE 7.3	na	All USG and SWE parameters significantly different b/w two groups

^aThe control group included non-SS dry eye patients.

Figure 2. Funnel plot of glandular heterogeneity calculated from three studies on lacrimal gland USG.

Figure 3. Funnel plot of glandular hyperechogenicity calculated from three studies on lacrimal gland USG.

Magnetic resonance imaging

Of three studies on MRI, two reported the MRI imaging features in terms of size and internal signal intensity, whereas one reported radiomics-based analysis without any other descriptions (Table 2). Ethnicities were Japanese (n = 2) and Romanian (n = 1). 1.5 T MRI with fat suppression T1 images is analyzed to interpret MRI findings. Of 58 total glands of SS patients imaged on MRI, there were 30 normal-sized glands, 10 enlarged, and 18 small-sized glands compared to 150 normal glands in the healthy control group. Two studies reported glandular heterogeneity in 48.3% (28/58) and 100% (11/11) of glands. Using a surface coil in one study provided better resolution, and 100% of glands were reported to have heterogeneity patches. The apparent diffusion coefficient (ADC) calculated on diffusion-weighted MR images was significantly less for SS glands than for healthy subjects. The tear volume test (Schirmer’s test) was low in atrophic glands; normal-sized glands had heterogeneous Schirmer values, whereas hypertrophic glands had moderately impaired Schirmer values. Figure 4 shows examples of lacrimal gland morphology on USG and MRI from the author’s practice.

Table 2. Description of included studies on the lacrimal glands MRI in Sjogren’s syndrome.

Study	Age,mean (SD)	Ethnicity	MRI protocol and image used	No. of glands in Sjogren’s syndrome	No. of glands in control group	MRI features in study	MRI features in control	Correlation with Schirmer value in study group
Izumi et al.18	65 (12)	Japanese	1.5 T MRI, fat suppressed, 3 mm section thickness	58	150	Reduced size – 18 Normal size – 30 Enlarged – 10 Heterogeneity – 28	Hypointense structure	5.2 ± 2.8 normal; 1.8 ± 1.2 mm atrophic; 4.7 ± 3.2 mm hypertrophic
Kawai et al.15	51.6 (15)	Japanese	1.5 T MRI, post-contrast T1 weighted, fat suppressed with 47 mm surface coil	11	31	Heterogeneity – 11 Reduced ADC – 11 (733 ± 35)	ADC 887 ± 103	NA
Muntean et al.17	56.2 (18)	Romania	1.5 T MRI, T1 weighted image	23	23	Radiomics based parameters	NA	NA

ADC: apparent diffusion coefficient; na: not available.

Figure 4. Post-gadolinium fat-suppressed coronal (A), and axial (B) 3 T MRI images showing the normal homogenously lacrimal glands in a control subject.

On high resolution ultrasonography (C), the gland is well marginated and has a homogenous internal echotexture. Post-gadolinium fat-suppressed coronal (D), and axial (E) 3 T MRI images in a patient with sjogren’s syndrome showing small sized lacrimal glands, with heterogeneous enhancement. On high resolution ultrasonography (F), the gland is ill defined and shows a heterogeneous internal architecture.

Quality of evidence

The inter-personnel variation was reported in two studies where two investigators imaged the glands, and inter-observer variation or reliability was reported. For a diagnostic imaging test, it is crucial to have two independent observers perform or analyze the images. The JBI tool revealed concern about confounding factors that were not identified in all studies, and cases and controls were not matched in the two studies.^6,12

Discussion

The current systematic review and meta-analysis identifies glandular heterogeneity on USG or MRI as an imaging feature identifying the lacrimal gland involvement in SS patients. The gland size, presence of the fibrous band, or hyperechogenicity lacks the strength to differentiate the glandular involvement in SS. The data on the MRI are insufficient to draw any conclusion. The specific situations where imaging would benefit are early SS with no clinical ocular involvement, suspected SS with inconclusive Schirmer scores or eyes without ocular staining, and lymphomatous lacrimal gland involvement due to SS. Future studies should include all types of SS patients, especially ones with normal or less reduced Schirmer values (>5 mm), rather than patients with very low Schirmer values (<5 mm), and early and late glandular involvement. A study correlating MRI and USG will support the USG findings as the former has better resolution.

The normal lacrimal gland appears hypoechoic with a homogenous internal echo pattern on USG. Different gland shapes, such as oval, circular, diamond with blunt angles, and irregular, have been reported in the studies. There is no specific reported association of any shape with gland pathology. Most studies have measured the gland size along the major and minor axis of the most prominent visible gland section on USG. Rather than size, the internal architecture of the gland is given more importance when describing SS patients’ USG features. The internal echo pattern becomes heterogeneous in most SS patients, irrespective of the USG probe used. The first USG study of the lacrimal gland in an SS patient was conducted in 2000 by Giovagnorio et al.⁶ The gland was reported to be enlarged in that study and could be visualized in 40% (6/15) of patients. Though SS causes acinar atrophy and reduction in the size of the lacrimal gland, the exact reason for gland enlargement was unexplained, other than lymphoma in two patients. Kim et al. even devised an LGUSG system based on USG features like size, heterogeneity, hypo or hyperechoic areas, fibrous bands, and the ability to see lacrimal arteries.⁴ Gland area (0.32 vs. 0.28), inhomogeneity (72.3% vs. 46.3%), presence of the intraglandular branch of the lacrimal artery (70% vs. 42%), and hyperechoic bands (56.2% vs. 37.5%) were significantly more in SS (n = 112) than non-SS dry eye (n = 80). They did not compare the data with unaffected normal lacrimal glands. Also, no interobserver reliability data were reported by Kim et al.⁴ De Lucia et al. reported the reliability of four different observers.¹¹ The inter-rater agreement was good for gland size and heterogeneity and excellent for hypo- or hyperechoic areas. The intra-rater reliability ranged from 92 to 96% for different USG parameters. Only gland heterogeneity (39.4% vs. 14.3%) and fibrous band (9.1% vs. 0%) appearance were significantly more in SS glands (n = 33) than in normal lacrimal glands (n = 100). High-intensity internal spots were also observed on MRI that were confirmed to be fat after studying fat-suppressed sequences.^15,18 Hence, heterogeneity within the gland, either on USG or MRI, is characteristic of SS involvement. Fat deposition within the glands is presumed to be the reason for heterogeneity, though it needs to be validated histologically. As gland parenchyma undergoes atrophy and is replaced by fat in the SS, mechanical properties of the gland get altered as measured using SWE. Only three studies have looked at SWE and provided different cut-offs of 7.2 kPa, 10.4 kPa, and 4.6 kPa.^9,14,19 A higher cut-off of 10.4 kPa was more specific, but lesser cut-offs were more sensitive. SWE needs to be explored further in large cohorts of SS patients. Again, SWE parameters were no different in SS patients with reduced versus normal Schirmer values in one study, whereas it was significantly higher in patients with ocular dryness in another study.^9,14 The Lacrimal artery has also been studied using color Doppler in two studies. A reduction in the artery’s diastolic flow and an increase in the resistive index occur in SS patients compared to healthy controls.^4,6 Though the lacrimal gland could not be visualized in all SS patients, the lacrimal artery and its flow velocity were detectable in all patients.

Radiology parameters do not show a good correlation with ocular symptoms and signs in SS patients. Only all small-sized glands on MRI had low Schirmer values, whereas normal and hypertrophic glands had normal to moderately low Schirmer values.¹⁸ Across USG studies, no USG parameter significantly differed between SS patients with positive versus negative ocular signs or serology. However, the correlation between the salivary gland and lacrimal gland USG score in SS patients is good.¹²

Diagnosis of SS is based on the 2016 classification criteria, where labial biopsy is advised in the absence of specific autoantibodies, such as anti-Ro/SS-A Ab.¹ The autoimmune process directly affects the lacrimal gland in the SS. However, examination techniques for the lacrimal gland focus on the conjunctival cul-de-sac tear volume and ocular surface changes. Conjunctival cul-de-sac volume is affected by numerous factors, like the instillation of any drops into the eye, temperature, and humidity; there is no established technique for examining the lacrimal gland with high sensitivity. Ocular surface staining has high specificity but is positive in eyes with advanced gland damage. Another technique for lacrimal gland examination is direct assessment. Direct assessment of the palpebral lobe of the lacrimal gland on slit-lamp shows a reduction in its size, increased vascularity, and reduced number of ductules in SS patients.²⁵ However, this technique cannot assess the entire lacrimal gland. The radiological imaging of the lacrimal gland has been explored in prospective clinical research studies with a control arm of healthy individuals. However, a comparison with individuals suspected of SS is missing. Its potential as a diagnostic test has not been compared with existing diagnostic criteria. Though technically it is challenging to examine the lacrimal gland on USG, it will be interesting to have a handy in-clinic imaging for identifying early involvement of SS.

The clinical implication also lies in treating SS other than diagnosis. If the gland has atrophied, then anti-inflammatory therapy has no role in improving the gland function. Sonography is also used for guiding lacrimal gland targeted therapies.²⁶

Gland visualization is a significant limiting factor in the potential of USG being a diagnostic device for SS. With a 10–13 MHz USG probe, only 12 glands could be seen out of 30 lacrimal glands of 15 pSS patients, whereas all glands could be visualized in 15 healthy controls.⁶ Could the reason for non-visualization be significant atrophy of the lacrimal gland in SS patients? Of nine patients with invisible lacrimal glands on USG, only two had abnormal Schirmer values. On the contrary, other studies have been able to visualize the glands in most SS patients.^4,7 Another limiting factor is adjacent fatty tissue, which affects the lacrimal gland delineation, and fat deposition within the gland with disease evolution would impact its visibility. MRI supersedes USG in this aspect, as one can obtain fat-suppressed sequences in MRI.

Radiological imaging of the lacrimal gland has a huge potential for being a non-invasive way of assessing lacrimal gland involvement in SS. Ophthalmologists need to be taught the imaging technique as most of them have USG in the eye hospitals. Collaboration between a sonologist, ophthalmologist, and rheumatologist is necessary to conduct a study that analyses the lacrimal gland USG in SS patients along with an appropriately matched control group. Also, serial USG of the lacrimal gland in different stages of the disease will help understand the sequence of gland enlargement versus atrophy in SS. The imaging can provide structural and volumetric information on the lacrimal gland that can also be useful in clinics.