Sjögren’s syndrome: history and challenges in diagnosis

INTRODUCTION

Sjögren’s syndrome is an autoimmune disorder characterised by attacks on mucous membranes, tear ducts, and salivary glands. Additionally, it can lead to dysfunction of other organs, including the kidneys, stomach, lungs, and liver [1]. This condition affects 1% of the general population, making it the most common connective tissue disease. The majority of affected individuals are women aged 30-50 years. Approximately half of the cases represent the primary form of the disease. The cause of the syndrome, similar to other autoimmune diseases, remains unknown [2]. Suspected factors include genetic and environmental factors, such as viruses, including HCV and HIV. The current hypothesis suggests that the coexistence of these factors may contribute to the development of the disease. There are 2 types of the syndrome: primary and secondary, which develop in the course of various diseases. Secondary syndrome typically accompanies rheumatoid arthritis [3].
The symptoms of the disease are often nonspecific, and available markers are not present in many patients. Symptoms can be divided into 2 groups: those resulting from impaired secretory function of exocrine glands and those resulting from impaired function of other organs [4]. Standard symptoms include those resulting from changes in lacrimal and salivary glands. Patients often experience discomfort due to bilateral dryness of the cornea and conjunctiva, perceived as a sensation of sand under the eyelids, itching, and burning. Additionally, they report dryness in the oral cavity, during chewing, swallowing food, and loss of taste. Accelerated tooth decay is also common [1]. In addition to glandular symptoms, patients report joint and muscle pain, lymph node enlargement, as well as symptoms of Raynaud’s syndrome, lung changes, which are usually scantily symptomatic, as well as in the kidneys and pancreas. Cardiovascular symptoms such as heart block, pericarditis, and pulmonary hypertension are also possible [5]. Patients often complain of sleep disturbances and worsening mood [3].
There is no cure for the disease. Currently, treatment is divided into categories depending on the form of the disease. In the case of secondary forms, the main treatment focuses on therapy for the underlying disease, while in primary forms, symptomatic treatment is employed. Therapy can be local or systemic. In dry eye syndrome, primary local treatment consists of artificial tears, gels, or eye ointments. In cases of dry mouth, the treatment method depends on the function of the salivary glands; in severe cases, saliva substitution is used. Systemic symptoms, most commonly musculoskeletal pain, are often treated with full doses of paracetamol or NSAIDs, but not for longer than 7-10 days [6].
The primary objective of this research is to meticulously summarise and analyse the current knowledge on the vast spectrum of diagnostic methodologies employed in addressing Sjögren’s syndrome. Moreover, by examining the historical context, this research endeavours to shed light on the advancements as well as challenges inherent in diagnosing dry eye syndrome.

REVIEW METHODS

This article was based on scientific publications retrieved from databases including PubMed, Google Scholar, Wiley Library, Web of Science, and the NCBI database. Due to the broad thematic scope, the selected articles encompass both older and contemporary works. The majority of the articles are in English, with only a few in Polish language. Following preliminary evaluation and meta-analyses of articles pertaining to the history and diagnosis of Sjögren’s syndrome, appropriate articles were selected. The publications were analysed using a non-systematic review method, aiming to provide a concise synthesis of available information.

BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE

HISTORY OF THE DISEASE

The first case of a 42-year-old patient with bilateral and painless enlargement of the lacrimal and salivary glands was first described in 1888 by Jan Mikulicz-Radecki [7]. In 1927, Alexander Schaffer compared this case with other diseases leading to enlargement of the salivary glands, such as sarcoidosis and lymphomas [8]. In 1933, Henryk Sjögren described 19 cases of dry eye syndrome, which led to the disease being named after him [7]. Twenty years later, Morgan and Castleman compared Mikulicz’s disease and Sjögren’s syndrome, noting many similarities. For a long time, Mikulicz’s disease was considered a subtype of Sjögren’s syndrome [9]. However, in later years, 2 separate diseases were distinguished. Currently, dry eye syndrome is recognised as a distinct systemic connective tissue disease [3].

DEVELOPMENT OF DIAGNOSIS AND DIAGNOSTIC CRITERIA

Diagnosing the disease is a comprehensive and challenging process. Patients often receive a diagnosis late. This process is multi-staged and relies on multiple diagnostic criteria. The first diagnostic criteria were published as early as 1965 [10]. Between 1989 and 1996, the American-European Consensus Group conducted a multicentre study aimed at achieving 4 main objectives: selecting confirming questions that could help determine the symptoms of Sjögren’s syndrome, selecting the most sensitive and specific diagnostic tests for the disease, developing a set of criteria, and approving the final criteria. In 2002, the American-European Consensus Group published criteria that included 6 main points [11].
In 2012, The American College of Rheumatology (ACR) proposed diagnostic criteria for Sjögren’s syndrome. The diagnosis of this condition can be made after meeting inclusion criteria and not meeting exclusion criteria, while simultaneously fulfilling at least 2 of the 3 main diagnostic criteria. Inclusion criteria include the presence of at least one symptom of dry eyes or mouth, which are assessed based on 5 questions. Exclusion criteria concern the prior diagnosis of one of 7 diseases, such as a history of head and neck radiotherapy, active hepatitis C virus infection, AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, and IgG4-related disease. The 3 main diagnostic criteria are positive Ro (SSA) or La (SSB) antibodies, lip biopsy showing the presence of lymphocytic foci, and dry form of corneal and conjunctival inflammation with observed eye discoloration [12].
In 2016, both the ACR and the European League Against Rheumatism (EULAR) developed common diagnostic criteria (Table 1) [3, 13].
As of 2024, our diagnostic procedures still rely on the criteria established in 2016 [3]. It is noteworthy that the latest guidelines from EULAR have not altered the diagnostic criteria; rather, they have primarily focused on refining management protocols and approaches [13].

DIAGNOSTICS – ANCILLARY TESTS

Sjögren’s syndrome poses a substantial diagnostic hurdle due to its multifaceted nature. To overcome this challenge, medical professionals frequently employ a variety of supplementary tests to gain comprehensive insights into the condition’s underlying causes and severity. These tests help refine treatment approaches and improve patient outcomes by tailoring interventions to individual needs.

LABORATORY TESTS

In blood tests, hypergammaglobulinaemia is observed in 80% of patients, ANA antibodies at a concentration above 1 : 80 occur in over 90% of patients, while anti-Ro antibodies are present in 55% and anti-La antibodies in 40% of patients. Additionally, rheumatoid factor is detected at high titres in over 60% of patients, and anaemia as well as leukopaenia are also often present [3]. Based on the above tests, it is not possible to definitively diagnose the condition. Therefore, further tests are necessary to confirm the diagnosis. In the diagnosis of Sjögren’s syndrome, antibodies play a significant role, enabling early detection of the disease even in its latent stage, thereby contributing to faster diagnosis. There are assumptions about the relationship between the presence of antibodies and clinical symptoms; however, this mechanism has not been fully elucidated. In the latest guidelines, due to low specificity, the presence of antinuclear antibodies and rheumatoid factor is not taken into account [14]. The most important role in diagnosis is played by anti-Ro 60 and anti-Ro 52 antibodies, which are subunits of SS-A, targeting low-molecular-weight ribonucleoproteins. It is suggested that SS-A/Ro antibodies are synthesised in the salivary glands. Diagnostic significance is only attributed to the simultaneous presence of both these antibodies, because individually they may also be present in other autoimmune diseases such as systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, primary biliary cirrhosis, or rheumatoid arthritis [3]. Moreover, numerous studies have observed significant associations of anti-Ro (SS-A) antibodies with extraglandular diseases, including vasculitis and haematological changes. Consequently, patients with these antibodies often exhibit systemic symptoms such as vasculitis, serological hyperactivity, or haematological abnormalities [15]. Based on the 2016 guidelines, patients with Sjögren’s syndrome and a positive antibody result do not require confirmation of diagnosis through histopathological examination [3].

UTILISATION OF ULTRASOUND EXAMINATION

Ultrasonography, utilising ultrasound waves, is a cost-effective and easy-to-perform examination commonly used in the diagnosis of dry eye syndrome. It allows for the assessment of the size and structure of the salivary glands and can detect cysts or enlarged lymph nodes. The image of salivary glands in a patient suspected of having Sjögren’s syndrome in ultrasound examination is characterised by heterogeneity with reduced echogenicity, resembling a honeycomb pattern. Among small hypoechoic areas, hyperechoic bands are visible. These changes are typically bilateral. Acoustic shadows are often observed, caused by hyperechoic bands and point reflections of high echogenicity [16]. Another feature is the presence of anechoic fluid-filled areas, which are segmentally dilated salivary ducts. The boundaries of the salivary glands in the ultrasound image are often difficult to determine, and assessing the posterior edge is practically impossible due to the blurring of structure boundaries. The volume of the salivary glands may undergo changes, both increases and decreases. Increased vascular flow and numerous calcifications are also observed in the examination. The sensitivity of the examination ranges from 60% to 90%, with specificity exceeding 90% [17].
Although performing USG is not included in current guidelines, increasing evidence suggests it may be a good alternative to salivary gland biopsy. Results of sialography and salivary scintigraphy often correlate with USG findings [18]. It is worth noting that in the initial stages of the disease, the submandibular and sublingual glands are affected, and over time, the parotid glands are also involved. There is a difference between them: the first 2 glands constantly secrete saliva, while the parotid gland responds to various stimuli. Currently, USG is considered a promising diagnostic method in Sjögren’s syndrome, but it still requires standardisation of parameters to be assessed during the examination. There is currently no “gold standard” diagnostic test for diagnosing Sjögren’s syndrome [13].

THE SIGNIFICANCE OF SIALOGRAPHY IN DIAGNOSING SJÖGREN’S SYNDROME

Sialography is based on X-rays and contrast medium, the result of this study being a so-called sialogram, which provides a detailed and clear visualisation of the salivary duct system. There are 2 main types of sialography: conventional and tomographic. The entire procedure consists of 3 phases and it takes approximately 20 minutes to complete. The first phase involves filling the ducts, and the second phase involves filling the salivary acini. The duct-filling phase of the examination can provide valuable information, especially in the presence of salivary gland swelling, such as in cases of inflammation. The last phase involves the removal of the contrast agent from the tissues. This is an important phase of the examination because it can indicate the presence of various pathologies, such as inflammation, obstruction, or tissue destruction [19]. The entire examination does not require special preparation or specific post-examination instructions. The advantages of this examination include its speed of execution and the possibility of obtaining immediate results [20]. Sialography is used in the diagnosis of various conditions, such as Sjögren’s syndrome, sialosis, salivary gland stones, tuberculosis, syphilis, and various inflammatory conditions. There are contraindications to performing the examination, such as pregnancy, allergy to the contrast agent, purulent salivary gland inflammation, salivary gland tumours, or planned or recent thyroid radioisotope scanning. Complications after the examination are rare and may include mild exacerbation of inflammation or an allergic reaction to the contrast agent. In cases of extravascular administration of the contrast agent, pain related to excessive pressure at the injection site may occur [19]. Sialograms conducted in patients with Sjögren’s syndrome often present a characteristic image resembling a cherry blossom, resulting from observations of irregular dilations and constrictions of the glandular ducts. This unique pattern can serve as a valuable indicator aiding in the recognition of Sjögren’s syndrome and monitoring its progression [20]. However, findings from certain studies unequivocally indicate that the diagnostic value of sialography in assessing Sjögren’s syndrome significantly depends on the skills of the observer. This implies that interpreting sialographic images requires specialised knowledge and experience. This fact may limit the universality of sialography as a diagnostic tool in routine clinical practice. Despite these limitations, sialography remains a crucial tool in evaluating the oral component of Sjögren’s syndrome. Its potentially high sensitivity and specificity in diagnosing Sjögren’s syndrome, coupled with the ability to assess disease severity, make it a valuable tool in the comprehensive evaluation of patients suspected of having Sjögren’s syndrome [20].

INSIGHTS FROM SCINTIGRAPHY

The main purpose of salivary gland scintigraphy is the visualisation and quantitative assessment of active parenchyma and secretory function of the salivary glands. Scintigraphy is a non-invasive diagnostic procedure widely used in rheumatology, endocrinology, and gastroenterology. It is employed for diagnosing thyroid nodules, hyperthyroidism, dementia syndromes, and various other conditions. The procedure is relatively safe, utilising ionising radiation. It typically lasts from 15 to 60 minutes and does not require specific patient preparation. Following the examination, patients are advised to consume a large amount of water and empty their bladder frequently [21]. It should be noted that patients emit a small amount of ionising radiation post-examination, which poses no risk to others. Scintigraphy can be repeated multiple times, with no age restrictions, within a one-day procedure. During the examination, the patient lies under a gamma camera and receives the radioisotope 99mTc intravenously, facilitating salivary gland imaging [22]. Complications associated with this procedure are rare or virtually absent. However, contraindications to the examination include pregnancy or suspicion of pregnancy, lactation period, severe thyroid ophthalmopathy, and allergic reaction to iodine [23]. In dry eye syndrome, delayed uptake, reduced accumulation, and delayed excretion of the tracer after stimulation are observed.

THE SCHIRMER TEST

The Schirmer test is a procedure aimed at measuring the quantity of tears secreted. To perform the test, a strip of blotting paper measuring 5 × 35 mm is used. The end of the strip, measuring 5 mm in length, is placed under the lower eyelid in the conjunctival sac. In the case of normal tear secretion, approximately 10 mm of the strip should be moistened within 5 minutes, measured from the edge of the eyelid [24]. There are 2 types of the Schirmer test: type I and type II. Furthermore, type I can be further divided into tests conducted with anaesthesia and those conducted without anaesthesia. Type I without anaesthesia, which determines the total amount of tears secreted, type I with anaesthesia, and type II. Type I with anaesthesia allows for the assessment of basal tear secretion, while type II enables the examination of reflex tear secretion after irritation of the oral mucosa. During the test, the patient should avoid blinking and keep their eyes wide open [25].

APPLICATION OF DYE TESTS

Dye tests, such as the van Bijsterveld Scale, are used to assess changes in the cornea and conjunctiva. The procedure involves instilling dye into the eye, such as rose Bengal stain. A result equal to or greater than 4 points on the van Bijsterveld Scale is one of the diagnostic criteria for Sjögren’s syndrome, according to the American-European Consensus Group [26]. The Whitcher method, also based on dyes, may be helpful in diagnosing dry eye syndrome. To assess the quantity of saliva secretion, the Saxon or Navazesh and Kumar methods are used, whereby a normal amount is considered to be more than 0.1 ml/min [27].

HISTOPATHOLOGICAL EXAMINATION

Historically, minor salivary gland biopsy has been a crucial diagnostic tool in the evaluation of Sjögren’s syndrome. Currently, the histopathological examination of the labial salivary gland and analysis of inflammatory infiltrates play a pivotal role [28]. This is a minimally invasive procedure, usually performed under local anaesthesia. An analysis of 1700 results was conducted, resulting in the demonstration of a strong correlation between lymphocytic infiltration and the findings of other tests such as anti-Ro. During the procedure, 4-6 minor salivary gland biopsies are taken, which is equivalent to an area of approximately 4 mm2.
In the twentieth century, Daniels et al. established that the presence of inflammatory foci in the biopsy material, with a focus score equal to or greater than 1, is sufficient to confirm the diagnosis of Sjögren’s syndrome [29]. Focal lymphocytic sialadenitis is characterised by one or more dense aggregates containing 50 or more lymphocytes, typically observed in perivascular or periductal areas. However, this hallmark cannot be attributed if dominated by features of nonspecific chronic sialadenitis or chronic sclerosing sialadenitis [28].
The ACR and the European League Against Rheumatism classification criteria for labial salivary gland biopsy in Sjögren’s syndrome are shown in Table 2 [30].

CONCLUSIONS

Autoimmune diseases present a challenge and pose numerous diagnostic problems in today’s medical practice. Diagnosing Sjögren’s syndrome requires ruling out a range of other conditions, such as rheumatoid arthritis, amyloidosis, AIDS, or sarcoidosis. The entire diagnostic process is based on the main criteria as well as inclusion and exclusion criteria. Many physicians rely on additional tests such as ultrasonography, salivary gland scintigraphy, sialography, as well as the Schirmer test. Currently, patients are being diagnosed more quickly due to the expansion of diagnostic methods and increased awareness of autoimmune diseases, including dry eye syndrome. Minor symptoms can be indicative of more serious issues, including the risk of developing cancer.

Disclosures

This research received no external funding.
Institutional review board statement: Not applicable.
The authors declare no conflict of interest.

References