Diagnostic Approach to Secondary Sjögrens Syndrome: Case Report

Sjögren’s syndrome (SS) is a chronic, multisystem inflammatory disorder of probable autoimmune etiology and progressive nature, characterized by hypofunction of the exocrine glands, mainly affecting the epithelium of the salivary and lacrimal glands and causing clinical pictures of keratoconjunctivitis sicca (xerophthalmia) and xerostomia. This case report will describe the diagnostic methods and therapeutic approach used in a patient with a condition compatible with Secondary Sjögren’s Syndrome (SSS). The patient underwent diagnostic tests, schimmer tests, parotid gland ultrasonography, and minor salivary gland biopsy to confirm the diagnosis and interviews.

Introduction

Sjögren’s syndrome (SS) is a chronic, multisystem inflammatory disorder of probable autoimmune etiology, with a progressive character, characterized mainly by hypofunction of the exocrine glands and progressive lymphocytic infiltration of various exocrine and non-exocrine organs, affecting mainly the epithelium of the salivary and lacrimal glands with a characteristic clinical presentation of xerostomia and xerophthalmia [1], [2]. Two forms of Sjögren’s Syndrome are recognized in the literature: Primary Sjögren’s Syndrome (pSS) and Secondary Sjögren’s Syndrome (SSS), the latter manifesting the sicca syndrome in association with other autoimmune disorders [3].

There is no consensus in the literature on the most effective method for diagnosing Sjögren’s Syndrome, the most widely used being the SICCA [4], [5]. Other more widely accepted classification criteria are: San Diego criteria for the diagnosis of SS-1986; San Francisco criteria for the diagnosis of primary SS and secondary SS-1994; European criteria modified by the American-European Consensus Group-2002; Classification for SS proposed by the American College of Rheumatology (ACR)-2012. Diagnosis involves checking for ocular and oral symptoms, mainly through eye tests, minor salivary gland biopsy, sialometry and the presence of circulating antibodies in the serum [1], [6], [7].

The treatment of SS will depend on the symptoms and their degree of severity. It is purely symptomatic and aims to modify the course of the disease, avoiding or minimizing sequelae [1], [8], [9].

The aim of this article is to report the diagnostic approach to the case of a patient with a condition compatible with Secondary Sjögren’s Syndrome, using the most widely accepted criteria.

Case Report

A 36-year-old female patient, leucoderma, married, teacher, non-smoker, non-alcoholic, came to the Surgery clinic of a University Center in August 2019, complaining of intense dry mouth, dysphagia, pain when breathing for two months, when teaching in the classroom, in addition to dry eyes for at least eight months.

In the anamnesis, the patient reported using Reuquinol, Nifedipna and ophthalmic lubricant eye drops after being diagnosed with Scleroderma and Hashimoto’s thyroiditis, two autoimmune diseases (AIDs), around 2016.

As the symptoms of xerophthalmia and xerostomia presented were closely correlated with SS, the rheumatologist raised the diagnostic hypothesis of SS, requiring the opinion of the dental surgeon and requesting a biopsy procedure to aid in the diagnosis.

The extraoral physical examination showed no increase in volume in the salivary gland regions, only dryness of the face, eye irritation and popping in the Temporomandibular Joint, followed by pain (Fig. 1). Intraoral physical examination revealed dryness and irritation. The intraoral physical examination showed only minor lip cracks, but the palate, floor of the mouth, gums and tongue were clinically normal with no lesions in the salivary gland regions, with only xerophthalmia, xerostomia and burning (pain when breathing and swallowing) (Fig. 2).

Fig. 1. Extra-oral clinical aspects, dryness and irritation compatible with SS (August 2019).

Fig. 2. Intraoral clinical aspect. Dry lips and mucosa with preserved dental condition (August 2019).

As the clinical findings of this first stage were not enough to obtain a definitive diagnosis, complementary tests such as incisional biopsy of the minor salivary gland from the lower lip mucosa, ultrasound of the salivary glands, tests for specific antibodies (anti-RO/SS-A, anti-LA/SS-B, anti-nuclear factor-ANF, rheumatoid factor-RF), Schirmer’s test and sialometry tests were ordered in accordance with the most widely accepted and internationally validated diagnostic criteria.

After the clinical examinations, a surgical procedure was carried out for an incisional biopsy of the minor salivary glands of the lower lip (Fig. 3). The histopathological section obtained from the minor salivary gland biopsy revealed more than one “foci/4 mm²”-a significant presence (50 cells)-of inflammatory infiltrate (Fig. 4a), showing areas of acinar degeneration (Fig. 4b), revealing a characteristic aspect of SS, the presence of a chronic lymphocytic sialoadenitis process.

Fig. 3. Lower lip mucosa after minor salivary gland biopsy (August 2019).

Fig. 4. Histopathological section of the biopsy with significant presence of lymphocytic infiltrate (August 2019): a) Photomicrograph showing smaller glandular parenchyma with foci of inflammatory infiltrate (star), characterizing chronic sialoadenitis, HE (100×); b) Higher magnification photomicrograph showing in detail the inflammatory infiltrate with more than 50 lymphocytes permeating the acini, HE (400×).

To check for symptoms of keratoconjunctivitis sicca, the Schirmer type I eye test (without the use of anesthetic), also known as the quantitative tear study test, was selected as the method to assess whether tear production is sufficient to keep the eye lubricated, thus measuring basal and reflex tear secretion.

A sterile standardized filter paper (Whatman No 41, Tear touch-Schirmer Tear Test Strips) was 5 mm wide and 35 mm long was used for the test (Fig. 5).

Fig. 5. Schirmer strips used in tear flow tests (August 2020).

The patient was positioned in a sitting position with her head straight, then a fold was made 5 mm from the edge before opening the package and after opening the filter it was placed in the lateral third of the palpebral edge of the patient’s lower ocular conjunctival sac for 5 minutes. After the 5 minutes, the length of the filter paper that remained damp was measured. The left eye was measured at 22 mm and the right eye was measured at 25 mm after 5 minutes. The photo of the left eye shows a wet extension in the image measuring 28 mm, as the photo was taken at 6 minutes. shows the filter completely wet 4 minutes after it was removed from the ocular conjunctiva (Fig. 6).

Fig. 6. Schirmer test type I showing wet extension after 5 minutes (August 2020): a) Lacrimal flow obtained in the left eye; b) Wet Schirmer strips after removal of the ocular conjunctiva; c) Lacrimal flow obtained in the right eye.

The most widely accepted diagnostic criteria consider that there is evidence of ocular involvement characteristic of the diagnosis of keratoconjunctivitis sicca when the Schirmer test tear production measurement is less than or equal to 5 mm in 5 minutes.

According to the Schirmer tape tear secretion classification scale (Table I) used, there was no objective evidence of ocular impairment or hypolacrimation. The patient’s tear production was considered normal, with no dryness, characterizing it as negative for dry eye syndrome. The patient reported having used artificial tears two hours before the procedure, which may or may not have influenced this result. As the symptom still persists, whether or not the region has ocular involvement can be verified by repeating the test or performing alternative tests suggested by the diagnostic criteria mentioned above.

Table I. Lacrimal Production Classification Scale

Amount of wet tears (mm)	Classification of tear production	Degree of dryness	Dry eye syndrome
25–30 mm	Normal production	Sem secura	–
10–15 mm	Possible insufficien production (initial or subclinical keratoconjunctivitis sicca with hyposecretion)	Olho seco	–
06–09 mm	Insufficient production	Secura leve	–
02–05 mm	Insufficient production	Secura moderada	+
00–01 mm	Insufficient production	Secura severa	+

Serum autoantibodies for rheumatoid factor (RF), antinuclear antibodies (ANA) and specific antibodies against the SSA/RO and SSB/LA antigens were requested as evidence of the presence of systemic autoimmune disease. The RF had been positive years before during the approach carried out by the rheumatologist for the diagnosis of scleroderma (DAI) and was not requested again.

The FAN test was positive, with a reactive nucleus and a dotted nuclear pattern with a titer of more than 1/640. The test report did not specify the type of pattern, which could be suggestive of either Scleroderma (the most common specific pattern is the centromeric punctate nuclear pattern) or Sjögren’s Syndrome, SLE or Lupus (fine punctate nuclear pattern), so it was necessary to correlate with more specific tests. In this case, the FAN was considered suggestive of Sjögren’s, given that the results obtained for specific autoantibodies confirmed a serological pattern that was reactive for anti-SS-A/Ro (91.0 U/mL), which is the most common positive pattern related to Sjögren’s syndrome, and non-reactive for anti-SSB/La (less than 7.0 U/mL).

Although no increase in volume was observed in the gland region, nor any limitation in mouth opening, an ultrasound of the cervical region was requested to check the level of involvement of possible alterations in the salivary gland regions. The examination was carried out in two-dimensional mode with a multifrequency linear transducer and the images showed that the parotid, submandibular and sublingual glands had a diffusely heterogeneous texture, predominantly hypoechoic bilaterally, with intraparotid lymph nodes and echogenic beams in between (possibly fibrosis beams).

The evaluation of these findings is compatible with the underlying condition suggestive of Sjögren’s disease but indicates that there is a structural alteration of the gland, characteristic of a chronic inflammatory process that is probably causing fibrosis of the gland but does not allow us to infer that there has been an alteration in the function of the glands.

In order to assess the dry mouth symptom reported by the patient and check for objective evidence of impaired and reduced salivary flow, non-stimulated sialometry was proposed as an assessment method, but it was not possible to carry out the procedure as the necessary equipment (beaker or millimeter tube) did not arrive in time to be compatible with the patient’s schedule.

Throughout the study, the patient presented positive result patterns for ocular and oral symptoms (subjective evidence), histopathological findings, specific and non-specific serum autoantibodies and the presence of previous IAD (objective evidence), a negative result pattern for ocular involvement (Schimer’s test) and a non-specific result for salivary gland involvement, as shown in (Table II).

Table II. Results of the Tests Carried Out in the Case’s Diagnostic Approach

Criteria	Results	Evidence for SS
Eye symptoms	Eye dryness for more than 8 months, use of lubricating eye drops and irritation	+
Oral symptoms	Xerostomia, difficulty swallowing, burning sensation	+
Ocular signs	Schirmer test	–
Note: patient still reports symptoms despite the	OE: 22 mm and OD: 25 mm
use of eye drops. Test carried out two hours after application. It may be necessary to repeat or perform another test based on the criteria.	Normal tear production
Histopathological finding	Focal lymphocytic sialadenitisGreater than 1 focus/4 mm2	+
Salivary gland involvement	Ultrasound with findings compatible with the underlying condition of Sjögren’s disease	Non-specific
Note: USG is not yet a validated method for the criteria used.	Note: Sialometry was not performed	*More specific test required
Evidence of serum autoantibodies	Positive serological pattern for SSA/RO (91.0 U/mL, FAN (1:640, dotted nuclear pattern) and RF. Non-reactive pattern for SSB/LA (<7.0 U/mL)	+
Autoimmune disease prior to SS symptoms	Scleroderma and Hashimoto’s Thyroiditis (Diagnosed about 4 years ago)	+

According to the results obtained from the multidisciplinary tests requested, despite the impossibility of carrying out the alternative objective test, and applying them to the diagnostic criteria for SS, it was possible to infer that:

1) The diagnosis according to the San Diego Criteria is inconclusive, not classifying the clinical picture as possible SS [10].

2) When the other criteria were considered, it was possible to secure more conclusive diagnoses such as SSs by the San Francisco Criteria, probable SSs by the AECG Criteria, “definite” SS by the ACR Classification and SSp by the ACR-EULAR Criteria [11]–[14].

3) In order to classify the clinical picture among the most validated criteria and with the current clinical findings, it was necessary to extrapolate the exclusive SSp criteria to SSS.

There is agreement that the patient’s clinical picture according to Table III is compatible with Sjogren’s Syndrome in most of the diagnostic criteria, despite the absence of objective evidence of salivary and lacrimal gland involvement. Considering the literature, the clinical picture is more specifically compatible with SS, as she had IAD prior to the diagnosis of SS.

Table III. Classification of the Patient’s Condition According to the Most Widely Accepted Criteria

Diagnostic criteria	Items	Diagnostic classification
[10]-San Diego Criteria	a) eNr	<3 items, the criterion does not even
NOTE: Considers 4 items, evaluates only objective evidence	b) eNr	classify as possible SS, evidence of dry
and classifies only as “definite” SS or possible SS	c) +	keratoconjunctivitis and decreased
	d) +	salivary flow is required.
[11]-San Francisco Criteria	SSp a) +
NOTE: Includes objective evidence and differentiates the	b) −	Secondary Sjögren’s Syndrome
syndrome into SSp and SSs	SSs a) +
	b) +
[12]-AECG Criteria	1) +	Probable Secondary SS
OBS: Considers symptoms (subjective evidence), signs and	2) +	Note: In item 5 on salivary gland
findings (objective evidence), allowing the syndrome to be	3) −	involvement in this study, ultrasound was
classified as probable SSp, SSp, probable SSs and SSs.	4) +	used, a method not included in the
	5) eNr	criteria, but there were findings
	6) +	characteristic of SS. If considered, the classification would be changed to SSs.
[13]-ACR classification	1) +
NOTE: classifies only the presence of the disease throughobjective evidence without distinguishing between SSp andSSs, considering the division obsolete.	2) +3) eNr	Sjögren’s Syndrome
[14]-ACR-EULAR Criteria	1) + (3)
NOTE: The criterion considers 5 items of objective evidence	2) + (3)
classifying only SSp. Classification applies to any individual	3) eNr (0)	Primary Sjögren’s Syndrome
who meets the inclusion criteria, who does not have any	4) – (0)	Score = 6
condition listed as an exclusion criterion, and who has a score ≥4 when adding up the weights of the following items	5) eNr (0)
Inclusion criteria	+
Exclusion criteria	–

When the diagnosis was made without evidence of functional impairment of the salivary and lacrimal glands according to the criteria, in addition to the persistence of symptoms of xerostomia and xerophthalmia, the patient was advised to undergo a sialometry test and at least one ocular staining test in order to institute the treatment appropriate to the degree of symptomatology.

Discussion

Sjögren’s syndrome (SS) mainly affects females, with a higher diagnostic prevalence in women in the 4^th and 5^th decades of life [15]–[18]. The patient’s age at onset of symptoms and diagnosis in this case was lower than the average presented in the literature.

Disregarding the symptoms, both on the part of the patient and the doctor has been suggested as a factor which may explain the fact that in some cases the diagnosis is made at a later age [19]. This was not the case with the patient, who had previously been diagnosed with two autoimmune diseases, had been regularly followed up by a rheumatologist, and when she reported the primary symptoms characteristic of sicca syndrome (dry mouth, dry eye, burning and oropharyngeal irritation), a multidisciplinary investigation was duly initiated, and she was referred to a dental surgeon and an ophthalmologist for tests to check for involvement of the salivary and lacrimal glands.

Several sets of diagnostic criteria have been proposed for the classification of Sjögren’s syndrome (SS) over the years, among the most widely accepted are the 1994 San Francisco Criteria, the 1986 San Diego Criteria, the 2002 AECG Criteria, the 2012 ACR Criteria and the 2016 ACR/EULAR Criteria [10]–[14]. According to these criteria, the most common tests listed among them that were considered accessible, specific and less invasive used in the diagnostic classification were minor salivary gland biopsy of the lip, microscopic histological examination, complementary laboratory tests for serum autoantibodies to anti-RO/SS-A, anti-LA/SS-B, antinuclear factor (ANF), rheumatoid factor (RF), the unstimulated sialometry test and the Schirmer I test.

Ultrasound (USG) images of the salivary glands can show typical findings of SS, such as sialoadenitis, and USG is a conservative alternative that can avoid more invasive interventions such as biopsies and more toxic ones such as sialography [20]. USG of the salivary glands is very important in controlling the progression of the disease and its eventual conversion into lymphoma [21]. Because it is not yet a validated method according to current criteria and the findings in the cases are compatible and suggestive only of structural alterations, salivary gland USG was not considered as an alternative test for the category of objective evidence of salivary gland involvement during the diagnostic classification carried out. However, it is now known that there is an increased risk of developing lymphoma in patients with more than one associated IAD, and given that the patient now has a confirmed diagnosis of Scleroderma, Hashimoto’s Thyroiditis and Sjogren’s Syndrome, the test was significant.

Most patients with SS (84%) have a previous diagnosis of some other autoimmune disease, mainly because it is related to other immunological alterations [22]. The distinction between the primary and secondary forms of SS is based on an initial definition of the disease and may now be obsolete, and it is of little use to confuse distinguishing in a given patient one autoimmune disease as secondary to another [13]. Considering the scarcity of studies in patients associated with other autoimmune diseases, these proposed criteria and treatment recommendations can be extrapolated to secondary Sjögren’s syndrome [23]. Thus, despite the divergences in the classification of the patient’s condition between the primary and secondary forms, there was agreement that the clinical picture is compatible with Sjogren’s Syndrome in 4 of the 5 diagnostic criteria evaluated.

Most of the diagnostic criteria do not have sufficiently high sensitivity and specificity for a reliable diagnosis of SS. The 2002 American-European Consensus (AECG) classification criteria are considered the gold standard [24]. The current classification ACR/EULAR Criteria has been shown to have high sensitivity (96%) and specificity (95%) when compared to previous classifications, as it is based only on objective tests and does not allow substitution of exams, making it a well-accepted method for the assertive diagnosis of SSp [14]. In the study, the diagnosis of the patient’s clinical condition for these criteria was probable SSs and SSp, respectively. By comparing the criteria and even with the lack of objective evidence required to consider the involvement of the salivary and lacrimal glands positive, it was possible to confirm the diagnosis of SS in these criteria, and it is worth highlighting the importance that the positive patterns in the histopathological findings of the biopsy, the serology of specific serum autoantibodies and proof of keratoconjunctivitis sicca, guarantee the classification of the most recent criteria. The divergences between the criteria in the classification of the diagnosis, in this case, may have been mainly due to the following:

1. The impossibility of carrying out some of the objective tests proposed in the methodology of this work (sialometry).
2. The limitation of using only one of the objective evidence methods proposed by the criteria that establish the involvement of the lacrimal glands (Schirmer test) and salivary glands (sialometry), these being chosen because they are easier to carry out, more accessible and less invasive in each category.
3. Some criteria lack specificity between SSp and SSs, classifying only the presence of SS disease or being used for the early diagnosis of SSp.
4. A need for referral for more specific ophthalmic tests which should be carried out by a trained professional and which seem to carry greater weight in the classification.
5. The use of methods of objective evidence of salivary impairment is not yet validated by the criteria and consensus used, such as salivary gland ultrasound.

Despite being able to establish a diagnosis using the criteria, the absence of objective evidence of salivary and lacrimal gland involvement meant that it was not possible to clarify the degree of gland involvement in the main areas of dry complaints reported by the patient, made it difficult to obtain a prognosis and made it impossible to direct the patient to an appropriate treatment until more specific tests were carried out.

Conclusion

Among the limitations of this case, this study found that it is possible to diagnose SS through less invasive, more accessible and specific tests and that the positivity of the biopsy, serology and eye test criteria together increases the specificity for Sjögren’s Syndrome in the classification of the most recent diagnostic criteria, that more objective methods better clarify the degree of involvement of the target organs of dry complaints, providing an appropriate syndromic picture, and that the multidisciplinary involvement of rheumatologists, dental surgeons and ophthalmologists is essential in obtaining a more assertive and earlier diagnosis.