The Role of Major Salivary Gland Ultrasound in the Diagnostic Workup of Sicca Syndrome: A Large Single-Centre Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have applied the OMERACT scoring system to 132 adult patients in a single centre undergoing Salivary gland US for suspected sjogren’s syndrome. They found that USS demonstrated moderate sensitivity and high specificity for the diagnosis of SS.

The OMERACT USS working group developed and published a consensus salivary gland US score in 2019 (1). Following the publication of these criteria a meta-analysis of 65 studies published in 2020 (2), which included 54 diagnostic accuracy studies and a total of 6087 patients, plus two more recent accuracy studies involving 269 and 243 patients (3, 4) all confirmed the utility of USS in the diagnosis of SS. Overall sensitivity in the meta-analysis was 80% with a specificity of 90%. The two additional studies were consistent with this, reporting a sensitivity of 69% and 72% and specificity of 98% and 94% respectively. This current study reports a reduced sensitivity of 32.4% but higher specificity of 96.84% compared to these studies.  The authors conclude that this is due to higher rates of minor salivary gland biopsy (100%) in this study compared to no more than 34% in previous studies and the short disease duration (<3 years in more than half the patients).

The authors conclude from their data that in patients who are negative on serology and on ultrasound proceeding to minor salivary gland biopsy is not required – confirming the published work of Al Tabaa et al (3)

Minor

Many authors have moved away from classifying Sjogrens as primary or secondary, calling it simply Sjogren’s. In this respect utilising the abbreviation SS for sicca symptoms may cause confusion. Particularly as in the British literature SS = Sjogren’s syndrome  Microsoft Word - LIST OF ACCEPTED ABBREVIATIONS.docx (oup.com).

 

 

1.          Sandrine J-J, Maria Antonietta D, Agostino, Celine N, Esperanza N, Sarah O, et al. Video clip assessment of a salivary gland ultrasound scoring system in Sjögren’s syndrome using consensual definitions: an OMERACT ultrasound working group reliability exercise. Annals of the Rheumatic Diseases. 2019;78(7):967.

2.          Ramsubeik K, Motilal S, Sanchez-Ramos L, Ramrattan LA, Kaeley GS, Singh JA. Diagnostic accuracy of salivary gland ultrasound in Sjögren's syndrome: A systematic review and meta-analysis. Therapeutic advances in musculoskeletal disease. 2020;12:1759720x20973560.

3.          Al Tabaa O, Gouze H, Hamroun S, Bergé E, Belkhir R, Pavy S, et al. Normal salivary gland ultrasonography could rule out the diagnosis of Sjögren's syndrome in anti-SSA-negative patients with sicca syndrome. RMD open. 2021;7(1).

4.          van Nimwegen JF, Mossel E, Delli K, van Ginkel MS, Stel AJ, Kroese FGM, et al. Incorporation of Salivary Gland Ultrasonography Into the American College of Rheumatology/European League Against Rheumatism Criteria for Primary Sjögren's Syndrome. Arthritis care & research. 2020;72(4):583-90.

 

Comments on the Quality of English Language

The authors have applied the OMERACT scoring system to 132 adult patients in a single centre undergoing Salivary gland US for suspected sjogren’s syndrome. They found that USS demonstrated moderate sensitivity and high specificity for the diagnosis of SS.

The OMERACT USS working group developed and published a consensus salivary gland US score in 2019 (1). Following the publication of these criteria a meta-analysis of 65 studies published in 2020 (2), which included 54 diagnostic accuracy studies and a total of 6087 patients, plus two more recent accuracy studies involving 269 and 243 patients (3, 4) all confirmed the utility of USS in the diagnosis of SS. Overall sensitivity in the meta-analysis was 80% with a specificity of 90%. The two additional studies were consistent with this, reporting a sensitivity of 69% and 72% and specificity of 98% and 94% respectively. This current study reports a reduced sensitivity of 32.4% but higher specificity of 96.84% compared to these studies.  The authors conclude that this is due to higher rates of minor salivary gland biopsy (100%) in this study compared to no more than 34% in previous studies and the short disease duration (<3 years in more than half the patients).

The authors conclude from their data that in patients who are negative on serology and on ultrasound proceeding to minor salivary gland biopsy is not required – confirming the published work of Al Tabaa et al (3)

Minor

Many authors have moved away from classifying Sjogrens as primary or secondary, calling it simply Sjogren’s. In this respect utilising the abbreviation SS for sicca symptoms may cause confusion. Particularly as in the British literature SS = Sjogren’s syndrome  Microsoft Word - LIST OF ACCEPTED ABBREVIATIONS.docx (oup.com).

 

 

1.          Sandrine J-J, Maria Antonietta D, Agostino, Celine N, Esperanza N, Sarah O, et al. Video clip assessment of a salivary gland ultrasound scoring system in Sjögren’s syndrome using consensual definitions: an OMERACT ultrasound working group reliability exercise. Annals of the Rheumatic Diseases. 2019;78(7):967.

2.          Ramsubeik K, Motilal S, Sanchez-Ramos L, Ramrattan LA, Kaeley GS, Singh JA. Diagnostic accuracy of salivary gland ultrasound in Sjögren's syndrome: A systematic review and meta-analysis. Therapeutic advances in musculoskeletal disease. 2020;12:1759720x20973560.

3.          Al Tabaa O, Gouze H, Hamroun S, Bergé E, Belkhir R, Pavy S, et al. Normal salivary gland ultrasonography could rule out the diagnosis of Sjögren's syndrome in anti-SSA-negative patients with sicca syndrome. RMD open. 2021;7(1).

4.          van Nimwegen JF, Mossel E, Delli K, van Ginkel MS, Stel AJ, Kroese FGM, et al. Incorporation of Salivary Gland Ultrasonography Into the American College of Rheumatology/European League Against Rheumatism Criteria for Primary Sjögren's Syndrome. Arthritis care & research. 2020;72(4):583-90.

 

Author Response

Thank You for the suggestion. We have added the work of Al Tabaa in the References, as it reinforces our conclusions (see lines 363-364 and references).

In our work we omitted to include patients with secondary Sjogren syndromes, as we have not diagnosed strong overlap with other connective tissue diseases. A patient with peripheral synovitis (the one reported in figure 5) had not sufficient criteria nor serology for rheumatoid arthritis or SLE.

Moreover, recent US works failed to show significant US differences between primary and secondary Sjogren, in terms of SGUS appearance [see. Martel A et al Joint Bone Spine 86 (2019) 211–217, added to the references].

We have modified the abbreviations along all the text, with SS for primary Sjogren Syndrome, while syndrome sicca has been written in extenso.

Moreover, we have added brief paragraphs in Results and Discussion to specify that we have no patients with secondary SS (lines 164 and 384-388).

 

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript retrospectively addresses the reliability of SGUS for the diagnosis of Sjogren's syndrome in patients with sicca symptoms.  There are several issues requiring authors' attention:

- Please report the acquisition parameters for SGUS (gain, TGC, etc..) and the technical features of the equipment (e.g. maximum depth and axial resolution).

- Why was a sum of the SGUS scores employed? Was a cut-off set for the total score of the glands?

- Why a functional test of salivary glands, such as unstimulated salivary flow rate, was not employed?

- Please provide a reference for the method of assessment of the FS and describe the criteria and cut-offs employed.

- Other previous studies assessed the correlation between ultrasonography and histology. Please reformulate the first paragraph of the Discussion as in the light of the present literature (10.1111/jop.13162; 10.55563/clinexprheumatol/rdbm3h) the statement appears too bold. 

Comments on the Quality of English Language

Minor issues

Author Response

- Please report the acquisition parameters for SGUS (gain, TGC, etc..) and the technical features of the equipment (e.g. maximum depth and axial resolution).

We add some acquisition parameters in the text (lines 113-115). The axial resolution varies on the basis of frequency (and length of wave). The smallest distance measurable was 0.1 mm for the 8-24 MHz probe. However, for the analysis of the gland sono-structure, the global image appearance gives a substantial idea of the possible inflammatory infiltration, without necessity of measurement of the smallest hypoechoic foci.

- Why was a sum of the SGUS scores employed? Was a cut-off set for the total score of the glands?

As reported in Discussion (lines 295-296), the optimal cut-off for a single gland is 2, substantially equal to previous works. Nevertheless, we routinely explore all the glands, because of a possible difference in SGUS appearance, especially in the very early phases of the disease. So, we have proposed the global sum (of 4 glands) other than the single side sum (parotid+ submandibular of the same side). This approach has been proposed also by other Authors (Zhang 2021].

- Why a functional test of salivary glands, such as unstimulated salivary flow rate, was not employed?

In our hospital the functional test for salivary flow is not available.

- Please provide a reference for the method of assessment of the FS and describe the criteria and cut-offs employed.

Conticini E, Bardelli M, Vitale A, De Stefano R, Falsetti P, Selvi E, Bacarelli MR, D'Alessandro R, Cantarini L, Frediani B, Gentileschi S. Diagnostic role of minor salivary glands biopsy in Sjögren's syndrome: correlations between histology and autoimmunity in a large, monocentric cohort. Reumatologia. 2023;61(2):109-115. doi: 10.5114/reum/163213. Epub 2023 May 10. PMID: 37223369; PMCID: PMC10201380.

we have added this article to the bibliography.

- Other previous studies assessed the correlation between ultrasonography and histology. Please reformulate the first paragraph of the Discussion as in the light of the present literature (10.1111/jop.13162; 10.55563/clinexprheumatol/rdbm3h) the statement appears too bold. 

We have modified the sentence (lines 279-282) as You suggested.

Reviewer 3 Report

Comments and Suggestions for Authors

Major concerns

ž   The first sentence of the main document is distorting: in Ref.1, the authors stated only up to 30 % of people aged over 65 years suffered dry eye and dry mouth symptoms, whereas did not define ‘Sicca syndrome’. The definition of ‘Sicca syndrome’ in this study is not clear. Is there any definition of ‘Sicca syndrome’ globally accepted?

ž   The authors studied ultrasonographic images of major salivary glands, the sites of saliva production affected by Sjögren’s syndrome. Why did not the authors perform salivary secretion tests such as non-stimulate whole saliva evaluation, which is a basic diagnosis and functional item in Sjögren’s syndrome. Without comparing results of saliva secretion tests and MGUS, the findings of the study cannot be specific to  Sjögren’s syndrome.

ž   The abbreviation of ‘SS’ in this manuscript is confusing because Sjögren’s syndrome is commonly abbreviated to SS.

ž   The patients in this study were classified into primary Sjögren’s syndrome or not. How about secondary Sjögren’s syndrome based on 2002 AECG classification criteria for Sjögren’s syndrome?

ž    

Minor concerns

ž   It is not clear what ‘FR’ in line 348 and Figure 5 means.

ž   It is not clear what ‘SSj’ in Table 2 means.

Author Response

ž   The first sentence of the main document is distorting: in Ref.1, the authors stated only up to 30 % of people aged over 65 years suffered dry eye and dry mouth symptoms, whereas did not define ‘Sicca syndrome’. The definition of ‘Sicca syndrome’ in this study is not clear. Is there any definition of ‘Sicca syndrome’ globally accepted?

The sicca syndrome definition was derived from the propaedeutic works of 2002 AECG  criteria  (i.e. Workshop on Diagnostic Criteria for Sjögren’s syndrome. I. Questionnaires for dry eye and dry mouth. II. Manual of methods and procedures. Clin Exp Rheumatol 1989;7:212–19 and “sicca questionnaire” of 2002 AECG classification criteria.) we have included this article in the bibliography.

ž   The authors studied ultrasonographic images of major salivary glands, the sites of saliva production affected by Sjögren’s syndrome. Why did not the authors perform salivary secretion tests such as non-stimulate whole saliva evaluation, which is a basic diagnosis and functional item in Sjögren’s syndrome. Without comparing results of saliva secretion tests and MGUS, the findings of the study cannot be specific to  Sjögren’s syndrome.

In our hospital the functional test for salivary flow is not available.

ž   The abbreviation of ‘SS’ in this manuscript is confusing because Sjögren’s syndrome is commonly abbreviated to SS.

We have modified the abbreviations along all the text, with SS for primary Sjogren Syndrome, while syndrome sicca has been written in extenso.

 

ž   The patients in this study were classified into primary Sjögren’s syndrome or not. How about secondary Sjögren’s syndrome based on 2002 AECG classification criteria for Sjögren’s syndrome?

In our work we omitted to include patients with secondary Sjogren syndromes, as we have not diagnosed strong overlap with other connective tissue diseases. Some patients with peripheral synovitis (as the one reported in figure 5) did not have sufficient criteria nor serology for rheumatoid arthritis or SLE.

Moreover, recent US works failed to show significant US differences between primary and secondary Sjogren, in terms of SGUS appearance [see. Martel A et al Joint Bone Spine 86 (2019) 211–217].

Moreover, we have added brief paragraphs in Results and Discussion to specify that we have no patients with secondary SS (lines 164 and 384-388).

minor:

FR means rheumatoid factor. We have corrected in line 348 and figure 5.We have written Sjogren syndrome in extenso in the figure 5

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

There are no further comments

Reviewer 3 Report

Comments and Suggestions for Authors

(No further comments)