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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

To determine the usefulness and prognostic value of a simplified salivary gland ultrasonography (SGUS) scoring system in primary Sjögren's syndrome (SS).

Methods

Patients with primary SS (n = 105) and controls (n = 57) were evaluated using a simplified SGUS scoring system. Parenchymal homogeneity in salivary glands was graded from 0 to 3, with grades 0 (normal) and 1 (mild inhomogeneity) being interpreted as normal or unspecific, and grades 2 (several rounded) and 3 (numerous or confluent hypoechoic lesions) as primary SS typical. Associations between SGUS and clinical, histologic, and laboratory disease characteristics were analyzed.

Results

The characteristic hypoechoic lesions (score 2 or 3) were found in 52% of primary SS patients and in 1 (1.8%) of controls (P < 0.001). Specificity and positive predictive value of abnormal SGUS for primary SS were both 98%, sensitivity and negative predictive values were 52% and 53%, respectively. Age or disease duration did not influence the SGUS result. Dryness did not differ between normal or abnormal SGUS. However, patients with pathologic SGUS had significantly more often signs and symptoms of systemic complications, higher disease activity, and more frequently markers of lymphoma development, such as salivary gland swelling, skin vasculitis, germinal center–like structures in salivary gland biopsy findings, and CD4+ T cell lymphopenia.

Conclusion

SGUS using a simplified score for assessment of parenchyma dyshomogeneity is highly specific for primary SS and offers the advantage of identifying patients with severe disease or at risk of lymphoma. However, early disease may be missed. SGUS is easy and rapidly performed and may be considered as an item in future modified classification criteria.


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 chronic autoimmune disease with dryness of mucosal epithelia due to inflammatory infiltrates in the exocrine glands. Systemic disease with involvement of various organ systems emerges in 30–50% of patients and the development of non-Hodgkin's lymphoma is the most serious complication, expected in 5–10% of patients within the first 10–15 years of followup.

Diagnosis of primary SS relies on a combination of clinical signs and symptoms, autoantibody testing, and salivary gland biopsy. The experienced and skilled clinician recognizes the syndrome, while others may take advantage of the existing classification criteria, which include various combinations of tests. The relatively unspecific salivary scintigraphy and the highly specific but invasive sialography are still part of the American–European Consensus Group (AECG) criteria set, but are now frequently considered inappropriate ([1, 2]). The recently presented provisional American College of Rheumatology (ACR) criteria ([3]) have been criticized for not offering an advantage over the widely used AECG criteria, due to not incorporating newer insights into pathogenic processes ([2, 4]).

Both criteria sets include salivary gland biopsy and anti-SSA/SSB autoantibodies as essential parts of the decision making. However, some patients refuse to undergo biopsy or present with negative findings, and in these cases alternative specific measures for diagnosis are needed. Moreover, a diagnostic tool that would facilitate stratification of patients into those with more severe systemic disease course or serious complications in contrast to those with pure exocrine disease would be of value for tailoring followup and treatment decisions.

We have recently proposed to evaluate the presence of germinal center (GC)–like structures in salivary gland biopsy findings in order to make a predictive categorization of primary SS patients into high or low risk with regard to lymphoma development ([5]). However, repeated biopsies are not feasible during the clinical followup process.

Ultrasonography is a nonradiating imaging method with outpatient clinic availability, which in experienced hands is performed easily and quickly without any harmful or invasive components. An increasing number of rheumatologists have access to and training in ultrasonography of joint structures. Patients tolerate ultrasound well and repeated investigations can be performed practically an unlimited number of times. Therefore, salivary gland ultrasonography (SGUS) may not only be useful as a diagnostic tool, but could also be suitable as an outcome variable in therapeutic trials ([6]) or to detect upcoming signs of disease progression and conversion into lymphoma over the years of followup.

A number of publications have presented convincing data on the usefulness of SGUS for diagnosis of primary SS ([7-11]). Various scoring systems evaluating size of the glands, parenchymal echogenicity and inhomogeneity, clearness of the borders, and vascularity were proposed ([7-9]).

The aim of the present study was to determine the usefulness and prognostic value of a simplified SGUS score in primary SS.

Box 1. Significance & Innovations

  • Ultrasonography of salivary glands in primary Sjögren's syndrome (SS) is a promising diagnostic method.
  • A simplified scoring system facilitates broad office-based use.
  • A primary SS–typical pattern can be identified, making the method suitable as part of future classification criteria due to high specificity.
  • Ultrasonography of salivary glands allows office-based immediate identification of patients at high risk of systemic disease course and lymphoma development, but may miss patients with early mild disease.

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 and controls

All patients fulfilled the AECG criteria ([1]) and were examined during regular outpatient visits. Sicca controls were patients seen for evaluation of primary SS without fulfilling the AECG criteria set. All participants were informed in detail about the nature of the examination and gave their informed consent. The study was approved by the Ethics Committee at Lund University.

Ultrasonographic examination

All patients were examined in supine position with the neck slightly extended and turned away from the side under study, using a real-time ultrasound machine (Flex Focus 400) with a linear 6–18 MHz transducer. Whenever possible, all 4 major salivary glands (both parotid and submandibular) were examined. Parenchymal echogenicity was compared to adjacent masseter muscle, and, when in doubt, to the appearance of a normal thyroid gland. Normal glands usually have higher echogenicity than muscle and similar echogenicity to thyroid; however, echogenicity can vary due to physiologic changes such as fat involution. Parenchymal homogeneity was scored as 0 if completely homogeneous, as 1 if mildly inhomogeneous, and as 2 if several rounded hypoechoic lesions were present. Finally, if the rounded hypoechoic lesions were either numerous or confluent, a score of 3 was given. A score of 0 was judged as normal. A score of 1 represented unspecific mild changes, which may be seen in early or mild primary SS. A score of 2 and 3 was interpreted as abnormal and as typical for SS (Figure 1). This scoring system evaluated the parenchymal homogeneity in accordance with the proposal by Hocevar et al ([8]). Aiming at a basic and simple scoring system, no further assessments were included. The final score was the highest score in any of the 4 salivary glands. An interobserver validity study was performed independently with 40 representative ultrasound pictures and 2 observers (ET and TM). The interobserver validity was excellent with a kappa value of 0.83 for the 4 scores and 0.89 for classification into primary SS typical or not ([12]).

image

Figure 1. Parotid ultrasonography. Examples of normal (score 0) or unspecific (score 1) and abnormal Sjögren's syndrome–typical (scores 2 and 3) parenchymal appearance.

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Clinical and laboratory examinations

Patients with primary SS are seen regularly every 6 to 12 months at the outpatient clinic. The diagnostic process usually includes lower lip salivary gland biopsies for assessment of focal sialadenitis and the presence of GC-like structures. Blood samples are drawn for cell counts including B and T lymphocyte subtypes. Laboratory samples included analysis of autoantibody status, immunoglobulin levels, complement levels, cryoglobulins, liver enzymes, and renal function tests. Systemic involvement was registered cumulatively. Disease activity was assessed using the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ([13]). The majority of ESSDAI assessments were performed by an independent assessor (TM) blinded for the result of the SGUS. The patients' and controls' subjective dryness was measured using the first question from the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) ([14]) on a 0–10 scale, with 10 representing the most severe dryness. Not surprisingly, primary SS patients experienced significantly more dryness than controls, with a mean ± SD value of 6.8 ± 2.1 on the ESSPRI dryness scale, compared to 4.52 ± 3.4 among the controls (P < 0.001). With the exception of newly referred patients with early disease, the SGUS investigator (ET) was not blinded for the patient's diagnosis.

Statistical analysis

All statistical tests were performed using SPSS, version 20.0 for Macintosh. Descriptive statistics are presented as mean ± SD or as percentages of available observations. Patients and controls, as well as patients with normal and abnormal SGUS, were compared by Pearson's chi-square test or Fisher's exact test, as appropriate, or by t-test for independent samples.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgments
  9. REFERENCES

A total of 162 SGUS investigations were performed. A total of 105 patients had primary SS according to the 2002 AECG criteria ([1]). The control group consisted of 19 sicca patients not fulfilling the AECG criteria, 18 patients with chronic inflammatory arthritis (rheumatoid arthritis and psoriatic arthritis; 2 patients with secondary SS and 1 with hepatitis B), 8 patients with various connective tissue diseases (systemic lupus erythematosus, primary biliary cirrhosis, systemic sclerosis [SSc; scleroderma], antiphospholipid syndrome, with 3 of these having secondary SS), 5 with systemic vasculitides, 1 with Crohn's disease and secondary SS, 1 with crystal arthritis, 1 with arthralgia, 1 with hyper-IgG4 syndrome, and 3 with hepatitis B or C and sicca syndrome.

Concordance in the scores for parotid and submandibular glands was high, only differing in 2 primary SS patients, where parotid glands appeared pathologic while the submandibular glands were normal.

The mean ± SD age at the time of the SGUS examination was 57 ± 15.0 years (range 25–91 years) among controls and 61 ± 14.9 years (range 20–91 years) among primary SS patients (P = 0.16). Ninety-one percent and 84%, respectively, were women among primary SS and controls (P = 0.16). Table 1 presents baseline characteristics of the primary SS patients included in the study.

Table 1. Baseline characteristics of primary SS patients*
CharacteristicNMean ± SD or %
  1. SS = Sjögren's syndrome; SGUS = salivary gland ultrasonography; ANA = antinuclear antibody; RF = rheumatoid factor; GC = germinal center–like structures.

Disease duration, years10512.3 ± 7.4
Age at SGUS study, years10560.6 ± 14.8
Anti-SSA/SSB positivity10571/55
ANA positivity10585
IgG, gm/liter10418.6 ± 7.96
RF positivity10159
Lower lip salivary gland biopsy sample with focal sialadenitis, focus score ≥18989
GC in salivary gland biopsy sample7427

Comparison between patients and controls: SGUS scoring of parenchymal changes

The characteristic hypoechoic lesions (score 2 or 3) (Figure 1) were found in 52% of the primary SS patients, but in only 1 of the controls (1.8%), i.e., a woman with SSc with SS overlap. The anticentromere-positive limited SSc developed years after the primary SS (i.e., evolving into secondary SS per definition in the AECG). The other 4 patients with secondary SS did not show abnormal scores. The difference in prevalence for a score of 2 or 3 for SGUS lesions between primary SS patients and controls was highly significant (P < 0.001). The primary SS patients presented SGUS findings evenly distributed among all 4 categories (27.6% for score 0, 21% for score 1, 23.8% for score 2, and 27.6% for score 3). In contrast, the controls showed normal glands, i.e., 70% for score 0, 28% for score 1, and only 1 patient with SSc and SS overlap presented with severely dyshomogeneic parenchyma in heavily enlarged parotid glands, as well as in the normal-sized submandibular glands. In summary, the specificity and the positive predictive value of abnormal SGUS for primary SS were both 98%, while sensitivity and negative predictive value were 52% and 53%, respectively.

Associations between primary SS disease characteristics and SGUS scores

Patients with abnormal SGUS scores did not differ significantly from those with normal findings with regard to disease duration, age at diagnosis, or age at SGUS examination. Therefore, abnormal SGUS findings were only slightly less prevalent among patients with early disease or those examined at diagnosis (Table 2). Focal salivary gland lymphocyte infiltrations were not associated with SGUS findings. Therefore, early salivary gland involvement is not detected with this simplified scoring method. Neither was subjective dryness associated with a more severe SGUS score. Instead, abnormal SGUS scores were predominantly found in patients with more severe disease prone to serious complications. Those with scores 2 and 3 had more often autoantibodies to SSA, SSB, antinuclear antibodies, rheumatoid factor, and significantly higher levels of IgG. Raynaud's phenomenon was more frequent and disease activity, as measured by the ESSDAI, was considerably and significantly higher in those with the primary SS typical hypoechoic lesions (score 2 or 3) (Table 2).

Table 2. Disease characteristics in primary SS patients with normal compared to abnormal SGUS*
 N, normal/ abnormal SGUSNormal SGUSAbnormal SGUSP
  1. Values are the mean ± SD or the percentage of available unless indicated otherwise. SS = Sjögren's syndrome; SGUS = salivary gland ultrasonography; ANA = antinuclear antibody; ESSDAI = EULAR Sjögren's Syndrome Disease Activity Index; ESSPRI = EULAR Sjögren's Syndrome Patient Reported Index.

Disease duration, years50/5511.6 ± 7.113.0 ± 7.70.28
Age at SGUS study, years50/5561.9 ± 14.859.4 ± 14.90.39
Age at diagnosis, years50/5550.0 ± 13.046.6 ± 14.20.21
Anti-SSA positive50/555090< 0.001
Anti-SSB positive50/553078< 0.001
ANA positive50/5572960.001
Focus score ≥1 in salivary gland biopsy findings45/4493931.0
IgG, gm/liter50/5414.5 ± 5.122.1 ± 7.8< 0.001
ESSDAI40/483.4 ± 4.38.1 ± 6.4< 0.001
ESSPRI dryness43/486.6 ± 1.87.0 ± 2.30.25
Systemic disease (cumulative/ever)47/5347770.001

Associations of SGUS scores with lymphoma risk markers

A number of predictors of lymphoma development have been proposed and summarized previously ([15]). In our cohort most of these are included in routine followup. SGUS scores of 2 or 3 were associated with clinical, serologic, histologic, and cytologic markers of lymphoma risk, namely GC-like structures in the original salivary gland biopsy findings, CD4+ T cell lymphopenia, and reduced number of memory B cells in the circulation, immunoglobulin oligo- or monoclonality in serum, the presence of salivary gland swelling, and purpura and skin vasculitis. Surprisingly, we could not detect an association with complement levels or cryoglobulins (Table 3). A total of 6 patients had lymphoma, of which 3 developed after the ultrasound examination (2 new, 1 relapse). The other 3 patients were in remission without treatment. Two of those in remission had a score of 0, while the other 4 patients had a score of 3 in their salivary gland ultrasound findings.

Table 3. Lymphoma risk markers in primary SS patients with normal compared to abnormal SGUS*
 N, normal/ abnormal SGUSNormal SGUSAbnormal SGUSP
  1. Values are the mean ± SD or the percentage of available unless indicated otherwise. SS = Sjögren's syndrome; SGUS = salivary gland ultrasonography; GC = germinal center.

  2. a

    CD4+ T cell lymphopenia is defined as CD4+ T cell count <30% of total lymphocytes or CD4+:CD8+ ratio ≤0.8.

GC-like changes in salivary gland biopsy41/3315420.007
Parotid enlargement ever/any grade45/533166< 0.001
Purpura/skin vasculitis45/5013340.019
Cryoglobulinemia36/401980.13
Mono- or oligoclonal bands in serum50/5110270.02
C3, gm/liter43/471.04 ± 0.291.01 ± 0.260.50
C4, gm/liter43/470.26 ± 0.160.21 ± 0.080.077
Blood CD4+ T cells38/4448.8 ± 10.639.0 ± 11.4< 0.001
CD4+ T cell lymphopeniaa38/4411320.020
CD4+/CD8+ T cell ratio38/442.47 ± 1.621.53 ± 0.990.002
Blood-memory B cells14/203.15 ± 1.521.74 ± 1.980.032
Blood-naive B cells14/208.38 ± 3.8710.84 ± 8.520.32

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgments
  9. REFERENCES

A number of unresolved questions remain in primary SS. How can an earlier diagnosis be achieved? What would the best classification criteria look like? How can lymphoma development be predicted and detected in time? Since the publication of the provisional ACR criteria in 2012 ([3]), a debate has emerged about the design of useful new criteria ([2, 4, 16]). Repeatedly, SGUS has been proposed as a new imaging modality useful for diagnosis and as a replacement for sialography, scintigraphy, and possibly biopsy ([9, 10]). However, different research groups have presented different scoring systems, including a varying number of characteristics such as size and volume, echogenicity and homogeneity, clearness of borders, and vascularity.

Here we present the results of a study using a very simple scoring system for parotid and submandibular glands, having the advantage of being easy to learn and rapid in performance. This technique would allow rheumatologists and patients to include the examination into a regular outpatient visit and would be suitable for repeated longitudinal analyses. Our score is restricted to the evaluation of parenchymal homogeneity, which is performed according to a previous study by Hocevar et al ([8]), and a primary SS–typical finding is defined. Interestingly, a recent study from France could not document significant associations with primary SS for other assessments such as gland size or vascularity; only parenchymal homogeneity was useful as diagnostic tool ([9]).

In consensus with other authors and different systems, our simplified score is highly specific for primary SS. Therefore, it would be useful as one of several items within a classification criteria set. Again, the easiness of office-based rapid performance, similar to Schirmer's test and sialometry, would confer an important advantage in this scenario. In fact, the presence of hypoechoic rounded multiple parenchymal lesions seems to be a pathognomonic feature of primary SS. Indeed, there was one patient with SSc and secondary SS with these lesions (score 3), but one might doubt the correctness of this classification. The patient had heavily swollen parotid glands, very severe dryness, classical biopsy findings, and only recently developed a mild limited SSc. The SGUS finding instead might tell us the correct diagnosis being either overlap of primary SS and limited SSc, or primary SS with some features of the latter disease.

Taken as an isolated investigation, the simplified score presented in this work is not useful for early diagnosis of primary SS. Sensitivity is low, and only less than half of the patients examined during the diagnostic process or during early disease have pathologic results, despite lymphocytic infiltrates in their lower lip salivary glands and a high symptom burden. Therefore, for early diagnosis requiring high sensitivity of a test, additional SGUS markers or other tests have to be identified and included. Given the availability of effective symptomatic therapies, such as pilocarpine or cevimeline ([17, 18]), or the possibility of stopping disease progress with early aggressive biologic therapy ([19]), our score should not be applied for selection of patients for early treatment approaches. There was, however, no relationship between age or disease duration and SGUS score, but the number of included very early primary SS patients was low.

On the other hand, our score seems very useful for identifying patients at risk for systemic primary SS and lymphomagenesis. Patients with GC-like structures in their salivary gland biopsy findings and those with cellular abnormalities in peripheral blood, such as CD4+ T cell lymphopenia, but also those with high systemic disease activity measured by ESSDAI, are overrepresented among those with pathologic scores. Therefore, SGUS-detected parenchymal dyshomogeneity would add immediate useful information with regard to followup strategies differentiating high- and low-risk patients.

In conclusion, SGUS using a simplified scoring system taking into account only dyshomogeneity of the parenchyma is suitable as an additional item within a future modified classification criteria due to the high specificity and positive predictive value for primary SS. It is also of high value for identification of patients prone to systemic disease complications, high disease activity, and lymphoma development. Its advantage is the easy technique and possibility of rapid performance by most rheumatologists with access to ultrasound equipment. For early detection of primary SS, however, and probably for followup monitoring within clinical trials and of lymphoma development, more advanced and elaborate scoring systems, including Doppler assessments of vascularity, will be necessary ([6]). SGUS may achieve broad acceptance for use in diagnosis, classification, and monitoring of primary SS, but the method and scoring may have to be adjusted to different clinical situations and needs.

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. Theander 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. Theander.

Acquisition of data. Theander, Mandl.

Analysis and interpretation of data. Theander, Mandl.

Acknowledgments

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgments
  9. REFERENCES

We thank Professor John Hamburger and Dr. John Rout for providing repeated training in the performance of SGUS at the Departments of Oral Medicine and Radiography, Birmingham Dental Hospital, Birmingham, UK. We also thank Malin V. Jonsson, Broegelmann Research Laboratory, Bergen, Norway, for frequent fruitful discussions of SGUS methods and findings and for contributions to the GC evaluation of available salivary gland biopsies. Furthermore, we thank Professor Gunnar Warfvinge at the Department of Oral Pathology, Dental School, Lund University, for evaluating salivary gland biopsies with regard to focal sialadenitis and GC-like structures. We also thank Miriam Welsh-Ingelström for language revision of the manuscript.

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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