Introduction
Sjögren’s syndrome (SS) is a chronic systemic autoimmune inflammatory disease characterised by dense lymphocytic infiltration of the exocrine glands, as well as other tissues and organs (1). Depending on whether it is a case of an isolated entity or an entity within another systemic inflammatory disease, it is divided into primary (pSS) and secondary Sjögren’s syndrome (sSS) (1). Sjögren’s syndrome is a disease with extremely heterogeneous clinical features and a variable course and prognosis. There is no single clinical, pathological or radiological marker that would serve as a “gold standard” for the diagnosis or classification of the disease. Involvement of the salivary and lacrimal glands, and the consequent dryness of the eyes and lack of saliva are among the most common clinical manifestations of the disease. The course and long-term prognosis of the disease as well as the clinical features depend on the distribution of inflammatory activity. Symptoms of dryness, pain and fatigue are benign manifestations of the disease that are present in the majority of patients and significantly affect the quality of life, while severe systemic manifestations occur in 20 to 40% of patients, and some patients will also present with lymphoma (2,3). SS is a relatively common autoimmune disease, the second most common after rheumatoid arthritis (1,4). In over 95% of cases, patients with primary SS are women(5), and the ratio of female to male patients varies depending on different studies, from 20:1 to 9:1 in favour of the female gender. It most often occurs in patients who are in their 40s or 50s (1). The prevalence of secondary SS depends on the diseases with which it occurs. Thus, the prevalence of sSS in systemic lupus erythematosus varies from 6.5 to 19%, in rheumatoid arthritis from 4 to 31%, and in systemic sclerosis from 14 to 20.5%. In patients with rheumatoid arthritis, it usually occurs as a late manifestation of the disease, while in patients with systemic lupus erythematosus, SS precedes the diagnosis of lupus by about two years. It is not uncommon that sSS also occurs as part of autoimmune events specific to a particular organ, such as primary biliary cirrhosis and Graves’ disease. (1).
Although the drugs used can relieve the symptoms and prevent the development of complications in this disease, they often do not lead to a satisfactory remission or cure. However, the development of new therapeutic options for the treatment of various autoimmune diseases, including SS, and numerous clinical trials have highlighted the need for a better definition and earlier recognition of this disease.
History of Sjögren’s syndrome
Anecdotal records of the condition we know today as Sjögren’s syndrome date back to the second half of the 19th century. In 1882, in his lecture “On the origin of retinal detachment”, Thomas Leber described three patients with dry inflammation of the cornea and conjunctiva with the formation of filaments, and he called this condition filamentary keratitis (6). Although he did not associate it with ocular surface dryness, his observations played an important role in the later definition of SS. In the late 1880s, Hutchinson and Hadden independently published reports of patients with severe dry mouth and consequent oral complications. Hutchinson is the author of the term “xerostomia” (6–8). Polish surgeon Johann Mikulicz-Radecki was born in 1892. described the case of a patient with painless symmetrical enlargement of the lacrimal and salivary glands, and the histopathological record of the salivary gland samples today fits the clinical features of MALT lymphoma (mucosa-associated lymphoid tissue) infiltration. In the mid-20s of the 20th century, the dermatologist Gougerot described the cases of three patients with progressive and chronic dryness of the mouth due to atrophy of the salivary glands and associated dryness of the eyes, nose, larynx and vagina. At the end of the 1920s, Houwer described cases of patients with chronic and bilateral filamentary keratitis, and half of these patients also suffered from associated arthritis. (7,8).
Although numerous authors “paved the way” for Henrik Sjögren, he was the only one who concluded that it is a systemic disease and not just an ocular disorder in his 1933 doctoral dissertation “Zur Kenntnis der Keratoconjunctivitis Sicca Keratitis filiformis bei hypofunction der Tranendriisen”. He came to the above conclusions based on the follow-up of 19 patients with keratoconjunctivitis, 13 of whom also had associated arthritis. (8).
The opinion that it is an autoimmune disease first appeared in the 1950s, and this position was supported by Alspaugh’s discovery of anti-SSA (anti-Ro) and anti-SSB (anti-La) antibodies. Through the efforts of a working group led by Haralampos Moutsopoulos in the 1970s and 1980s, it was discovered that SS is a chronic autoimmune disease characterized by infiltration of exocrine glands with B and T-lymphocytes, that the risk of developing lymphoma is up to 44 times higher than in the general population, and that certain characteristics could point to a case of primary and secondary SS depending on the presence or absence of associated systemic collagenosis (8).
ESTABLISHING diagnosis of Sjögren’s syndrome
The diversity and complexity of the clinical features of SS complicates the process of diagnosis and therapy. The diagnosis of SS is often delayed, and the disease is often misdiagnosed as another autoimmune disease, most often systemic lupus erythematosus or rheumatoid arthritis. Certain subtypes of the disease (especially those without sicca symptoms) are more challenging to establish an accurate diagnosis, and due to a lack of understanding of the entire spectrum, the disease may remain undiagnosed. The diagnosis of SS should be suspected in individuals with persistent symptoms of dry eyes or oral cavity, enlargement of the parotid glands, and pathological findings of serological tests (e.g. anti-SS-A, anti-SS-B, rheumatism factor, hyperglobulinemia)(9). Dryness of the mouth often leads to a significant worsening of cavities, especially in the area of chewing surfaces or tooth cervix, hyperlobulated tongue (Figure 1), chronic erythematous oral candidiasis.
Making a diagnosis only on the basis of positive SS-A and SS-B antibodies is not advisable, considering that the said antibodies can be detected in other autoimmune diseases, but also in healthy individuals (10). Although medicine advances every day with the development of new diagnostic methods and tools, there is still no single diagnostic test that would confirm or exclude the diagnosis of SS, but it is established based on a combination of clinical and laboratory indicators.
The diagnosis of SS is established with objective indicators of dry eyes and/or mouth or damage to the glandular parenchyma (after excluding other possible causes) with the presence of serological or histological evidence of autoimmunity. In certain age groups, the standard clinical features of SS varies, so the presence of recurrent parotitis is much more common in children, while objective indicators of dry eyes and mouth are not always present (11). A recent multicentre trial conducted on a large number of patients showed that young patients (up to 35 years of age) had a higher frequency of salivary gland enlargement, lymphadenopathy, leukopenia, hypocomplementemia, and hypergammaglobulinemia and lymphoma compared to a control population of middle-aged patients with Sjögren’s syndrome. Older patients (over the age of 65) had more frequent sicca symptoms and interstitial lung pathology, as well as a higher incidence of lymphoma (12). It is known that about 20% of patients will not develop sicca-symptoms, but will present themselves with a colourful palette of systemic manifestations. (2,4,5). Most systemic manifestations are included in the Sjögren’s syndrome disease activity index (ESSDAI, EULAR Sjögren’s syndrome disease activity index). New research shows that more than a quarter of patients with pSS may have manifestations that are not covered by the mentioned index, the most common of which is Raynaud’s syndrome, which was present in 15% of patients according to a recently conducted research (5). Furthermore, numerous works show that systemic manifestations can occur well before sicca symptoms, which often significantly delays the establishment of an accurate diagnosis (13). However, due to the non-specificity of systemic manifestations, the diagnosis can be made in the case of a positive finding of anti-SSA antibodies and other laboratory indicators characteristic of the disease.
Typical sicca symptoms will often be present in pSS at the time of diagnosis, and the percentage of patients varies between 86–95% in published studies (5,12). Other clinical manifestations that occur in more than 10% of patients with pSS are joint manifestations (41%), pulmonary manifestations (12%), lymphadenopathy (11%), general symptoms, fatigue and in 10% of cases skin manifestations such as palpable purpura of the lower legs (5,14). Involvement of the peripheral nervous system (peripheral neuropathy) occurs in 10% of patients, kidney involvement in about 5%, while chronic gastritis and dysphagia occur in about 2–3% of patients. According to the available studies, estimates of involvement of the central nervous system vary significantly, as there are no clearly established criteria for diagnosis (15).
Symptoms of dry eye as part of sicca syndrome should be suspected when patients report daily eye problems lasting more than 3 months, have a continuous feeling of sand or a foreign body in the eyes, and if they need to use artificial tears more than 3 times a day. Xerostomia and symptoms of sialoadenitis are suspected if patients report a feeling of dry mouth lasting more than 3 months, waking up at night to drink water, consuming liquids to be able to eat dry food, and episodic or constant swelling in the salivary gland area (16). For the purpose of examining sicca symptoms, a validated questionnaire (16) was created, which is shown in the Table 1.
Of course, these complaints are subjective in nature and it is necessary to objectivize them in order to establish a diagnosis. The three most common tests for the objectivization of dry eye: Schirmer’s test, tear break-up time test (TBUT) and ocular staining test (OSS) (9). OSS and Schirmer’s test are two criteria in the 2016 joint criteria of EULAR and ACR. (17). Xerostomia and salivary gland changes are objectivized by sialometry, imaging methods and biopsy (18). Sialometry is used to quantify or measure the amount of saliva produced. If 0.1 mL of saliva or less is secreted in one minute without stimulation, the criteria for xerostomia are met. The sensitivity of sialometry is 56%, and the specificity is 81%. (9). It should be kept in mind that sialometry is not valid if the patient is chronically taking drugs with anticholinergic effects such as some antihistamines, benzodiazepines, antidepressants. Technetium Tc-99m pertechnetate salivary scintigraphy and contrast sialography are no longer frequently used. The imaging methods that are preferred today are magnetic resonance imaging and easily available ultrasound, and they are supported by the specificity for SS greater than 90%, i.e. 93% and 92% respectively in the case of an ultrasound (19). The advantage of ultrasound is that it can be used in diagnosis, but also in disease follow-up. Moreover, salivary gland ultrasound has been shown to be a diagnostic tool comparable to salivary gland biopsy. Biopsy, i.e. histopathological analysis of small salivary glands (sensitivity 80%, specificity 82%) is still the gold standard in the diagnosis of SS, and in the 2016 classification criteria it has the highest number of points (17). Sialometry and biopsy are the only methods listed in the latest classification criteria for assessing salivary gland function (17). Laboratory, serological, radiological and histopathological findings characteristic for the diagnosis of Sjögren’s syndrome are presented in Table 2.
To establish a diagnosis, after the objectivization of sicca-symptoms or in the case of systemic manifestations of the disease, it is necessary to perform an immunoserological test. It should be emphasized that testing for the presence of autoantibodies should be used to confirm a working diagnosis, and not be used as a screening test, considering that a healthy part of the population may have a positive finding of autoantibodies. Therefore, in the context of objectivized sicca-symptoms and a negative finding of antinuclear antibodies (ANA), it is unlikely that this is a patient with SS. In addition to autoantibodies (ANA positive in over 85% of cases, anti-SSA in 50 to 70%, rheumatoid factor (RF) in 50 to 60%, anti-SSB in 33 to 50%), there are other laboratory indicators indicative of SS such as which are accelerated erythrocyte sedimentation rate in 80 to 90% of cases, hypergammaglobulinemia in 80%, anaemia of chronic disease in a quarter of cases and leukopenia in 10% of cases. Thrombocytopenia is rarely present. A rare serological finding is anticentromeric antibodies that can be detected in up to 5% of cases, without or only with some clinical characteristics for systemic sclerosis, and anti-CCP without other elements for rheumatoid arthritis (20). New research shows the importance of new antibodies in predicting certain disease manifestations and long-term complications, which could have great clinical significance in the future (21).
Part of the patients will be diagnosed in the stage of developed lymphoproliferative disease, considering that compared to other systemic inflammatory diseases, SS has the highest risk for the development of lymphoma, according to the standardized incidence of 9 to 44 or 5 to 15, depending on whether these were published before the year 2000 or in the later period. The most common histological subtype of lymphoma are MALT lymphomas (2). Certain clinical and laboratory characteristics are associated with an increased risk of developing lymphoma. Due to the large clinical spectrum of this disease, the differential diagnosis of Sjögren’s syndrome is very broad and includes other systemic autoimmune diseases (primarily systemic lupus erythematosus and rheumatoid arthritis), infections (hepatitis C virus (HCV), human immunodeficiency virus (HIV), cytomegalovirus (CMV), various non-autoimmune causes of dry mouth or eyes (age, medications), IgG4-related disease, sarcoidosis, amyloidosis, lymphoma, Graft vs. Host Disease (GVHD) and other diseases.
Classification criteria of Sjögren’s syndrome
Classification criteria that were originally developed and validated for the purpose of standardizing cohorts of patients for inclusion in clinical trials and studies, often serve as an aid in clinical practice when establishing a diagnosis. Given the extremely heterogeneous clinical features of SS, it is understandable why more than eleven different classification criteria for SS have been proposed over the years since 1960. Figure 2 shows the development of individual classification criteria for Sjögren’s syndrome throughout history.
The classification criteria that were developed until 1993 were mostly based on the clinical experience of leading experts or on the data of individual centres, and therefore none of them were accepted by the wider scientific community (22,23). When it comes to the older criteria for the diagnosis of SS, the most used were: the San Francisco criteria (proposed in 1975 and subsequently revised in 1984), the Copenhagen criteria (proposed in 1976) and the Japanese criteria (published in 1978), as well as the Greek and the Californian criteria proposed in 1986. (22–27). The Japanese criteria have been updated several times, the last time being in 1999.
In the San Francisco criteria that were proposed in 1965, the introduction of a new diagnostic criterion was recommended – the presence of focal sialoadenitis in the biopsy samples of the minor salivary glands to determine the presence of the oral component of Sjögren’s syndrome instead of the subjective assessment of xerostomia based on the presented research conducted on 100 patients (22). The criteria were revised in 1984, when it was confirmed in 362 patients that focal sialoadenitis in an adequate sample is an objective criterion specific for SS (23). The Copenhagen criteria required at least two pathological objective tests for the assessment of dry eye and mouth for classification (24). The first Japanese criteria were published in 1978 and were used in Japan for over 20 years. For classification, it was necessary to have a subjective feeling of dry mouth or eyes and at least one of the following: a) two pathological eye tests, b) focal sialoadenitis or c) abnormal sialography/scintigraphy (25). In the last revised Japanese criteria from 1999, which were formed as a result of the work of the Japanese working group for SS, it was not necessary to have subjective symptoms of dryness for classification, and serological findings and stimulated sialometry were introduced as criteria for assessing saliva secretion. These classification criteria contained four major components: histology, oral tests (sialography/scintigraphy/stimulated sialometry), ocular tests (Schirmer’s test + Rose Bengal staining test/fluorescein) and serology (SS-A or SS-B). For classification, it was necessary to have at least two of the four criteria (28). According to the data recorded on 900 patients, it was estimated that the criteria have a sensitivity of 96%, a specificity of 90.5% and an accuracy for the diagnosis of SS of 94.5%. (28). These latest Japanese criteria were quite similar to the preliminary European classification criteria published 6 years earlier. The Greek criteria published in 1986 were based on a study of 52 patients with sicca symptoms. According to them, for classification it was necessary to have focal sialoadenitis (≥2 focus/4 mm2) with one of the following criteria: a) subjective dryness of the eye plus a pathological finding of the Schirmer’s test plus a pathological finding of the Rose Bengal staining test, b) anamnestic or current enlargement of the parotid glands and c) sensation of dry mouth and pathological finding of stimulated sialometry (26). The Californian criteria, also called the San Diego criteria, also published in 1986, are criteria of a more restrictive nature. According to these criteria, for the diagnosis it was necessary to have focal sialoadenitis (≥2 foci/4 mm2), a feeling of dry mouth with a pathological finding of stimulated and non-stimulated sialometry, a pathological finding of the Schirmer’s test and one of the dye tests (Rose Bengal staining or fluorescein test) and a positive finding of one of the serological tests (IgM-RF [titer ≥ 160] or ANA [titer ≥ 160] or SS-A or SSB antibodies) (27). Exclusion criteria (lymphoma, chronic Graft vs. Host Disease – GVHD), acquired immunodeficiency syndrome, sarcoidosis are also listed in them for the first time. The differences and similarities of individual criteria up to 1993 are presented in Table 3.
In 1993, preliminary European classification criteria for SS were proposed (7). They were widely used for the next ten years, both in clinical practice and in observational and interventional studies. During the development of the classification criteria in 1993, a questionnaire on dry eyes and mouth was designed and validated, which is used in a minimally modified form in the current classification criteria. Three questions for dry eye and three questions for dry mouth were chosen, which had high sensitivity and low specificity and so well discriminated patients from controls and served as screening (Table 1) (7). For the classification of primary SS, the patient had to have four out of six criteria present. In addition to symptoms of dry eyes and mouth, the criteria included an objective finding of dry eye (Schirmer’s test ≤ 5 mm/5 min, Rose Bengal score ≥ 4), then histological evidence of salivary gland involvement, one of the objective tests of salivary gland involvement (salivary gland scintigraphy, parotid sialography and unstimulated saliva secretion (≤ 1.5 ml/15 min) and serological proof of autoimmunity (presence of SSA or SSB antibodies, ANA or RF). Table 4 shows the differences and similarities of the classification criteria published from 1993 until today. Although the above classification criteria were widely accepted, they had several problems. A combination of ocular and oral symptoms and dry eye tests and salivary gland involvement tests could also be found in patients with sicca symptoms who did not necessarily have SS. Patients with true primary SS, but without subjective sicca-symptoms, could just as easily be omitted from the classification.
These criteria were subsequently revised by the American-European Consensus Group (AECG) and published new revised criteria in 2002 (8). In order to correct the problems with the earlier criteria, the patient had to have one of the following two findings characteristic of the disease for classification: a) positive antibodies characteristic of the disease (SSA or SSB) or b) a positive biopsy of minor salivary glands. These classification criteria, unlike the previous ones, introduced the classification of sSS in patients with another autoimmune disease with the presence of sicca symptoms and with two additional criteria from the group (III, IV or V). In 2012, the new, somewhat modified classification criteria of the ACR were published, which did not bring major news or diagnostic advances (30). For classification, it was necessary to have at least two of the three criteria: 1. serological criterion (positive anti SSA and/or anti SSB antibodies or positive rheumatism factor and ANA in a titer greater than 1:320), 2. ophthalmological criterion (ocular staining score, OSS ≥ 3), 3. presence of lymphocytic sialedenitis in the biopsy of minor salivary glands. In a study that compared the classification criteria AECG and ACR, matching results of these two sets of criteria were shown, and no clear evidence was presented for the increased value of the new ACR criteria compared to the old AECG criteria from a clinical perspective (31).
The joint criteria of ACR and EULARA from 2016 are currently used to classify the disease. They can be used in patients with at least one symptom of dry eyes or mouth according to the AECG questionnaire or in suspected systemic disease. The new parameter in the current criteria is that each criterion does not have the same weight, that is, it does not signify the same number of points. The classification is based on the weighted sum of five criteria: positive SSA antibodies and focal lymphocytic sialoadenitis with focus sum ≥1 focus/4 mm2, consisting of three points each, then Schirmer’s test and OSS ≥5 for the objectivization of dry eyes and unstimulated salivation ≤0, 1 mL/min consisting of one point each. The patient must have 4 or more points in order for the classification to be successful. Positive SSB antibodies in the absence of SSA antibodies are no longer a criterion, and ANA and RF have also been dropped from the criteria. The reason for this decision was that a very small number of patients who met the ACR criteria had negative SSA and SSB antibodies, and positive ANA and RF (21).
A comparison of the AECG classification criteria from 2002 and the latest ACR/EULAR classification criteria showed excellent agreement between them (κ = 0.92). (32). However, the ACR/EULAR classification criteria were still more sensitive and additionally classified patients without sicca symptoms, who had systemic manifestations as pSS, which once again confirms the importance of including systemic manifestations in the classification criteria. This study showed that the sensitivity of the new ACR/EULAR criteria is 87.4%, and the specificity is 95.4% when the physician’s diagnosis is taken as the standard. (32). It has also been shown that the inclusion of salivary gland ultrasound in the ACR/EULAR criteria can further increase their sensitivity (32). Summary of main features of classification criteria from 1993 to 2016 are presented in table 4.
Conclusion
Over the years, significant progress has been made in the understanding of Sjögren’s syndrome as a systemic disease. This is especially outlined in the latest ACR/EULAR classification criteria from 2016, where the classification includes patients with systemic manifestations of the disease without sicca symptoms. However, the complexity of the clinical features of this disease still makes timely diagnosis and early recognition difficult. Therefore changes are not expected in a future in this field.
Financial support: The authors confirm that there has been no significant financial support for the research, authorship or publication of this article.
Conflict of interest statement: The authors declare no conflict of interest.
REFERENCES / Literatura
31. Rasmussen A, Ice JA, Li H, Grundahl K, Kelly JA, Radfar L et al. Comparison of the American-European Consensus Group Sjögren’s syndrome classification criteria to newly proposed American College of Rheumatology criteria in a large, carefully characterised sicca cohort. Ann Rheum Dis. 2014;73(1):31–8.
32. Le Goff M, Cornec D, Jousse-Joulin S, Guellec D, Costa S, Marhadour T et al. Comparison of 2002 AECG and 2016 ACR/EULAR classification criteria and added value of salivary gland ultrasonography in a patient cohort with suspected primary Sjögren’s syndrome. Arthritis Res Ther. 2017;19(1):269.
Figure 1 Dry mouth and hyperlobulated tongue in patient with primary Sjögren’s syndrome (author’s personal arhive)
Slika 1. Suhoća usta i hiperlobulirani jezik u bolesnice s primarnim Sjögrenovim sindromom (vlastita arhiva autora)
Table 1 Questionnaire on dry mouth and eyes with suspected Sjögren’s syndrome. (adapted according to reference No 16)
Tablica 1. Upitnik o suhoći usta i očiju kod sumnje na Sjögrenov sindrom (prilagođeno prema referenciji br. 16)
Table 2 Laboratory, serological, radiological and histopathological findings characteristic of the diagnosis of Sjögren’s syndrome.
Tablica 2. Laboratorijski, serološki, radiološki i patohistološki nalazi karakteristični za dijagnozu Sjögrenovog sindroma
Legend / Legenda: ESR / SE – erythrocyte sedimentation rate / brzina sedimentacije eritrocita; CRP – C reactive protein / C-reaktivni protein; CBC / KKS – complete blood count / kompletna krvna slika; C3, C4 – complement / komplement; ANA – antinuclear antibodies / antinuklearna antitijela; RF – rheumatoid factor / reumatoidni faktor; TBUT – tear break-up time; OSS – ocular staining score / ocjena bojenja površine oka; MR – magnetic resonance imaging / magnetska rezonancija; US / UZV – ultrasound / ultrazvuk
Figure 2 Development of classification criteria for Sjögren syndrome throughout history
Slika 2. Razvoj klasifikacijskih kriterija za Sjögrenov sindrom kroz povijest
Table 3 Differences and similarities of classification criteria proposed up to 1993 (adapted according to reference No 27)
Tablica 3. Razlike i sličnosti klasifikacijskih kriterija predloženih do 1993. godine (prilagođeno prema referenciji br. 27).
Legend / Legenda: ANA – antinuclear antibodies / antinuklearna antitijela; IgM-RF – rheumatoid factor – imunoglobulin M / reumatoidni faktor imunoglobulin M; pSS – primary Sjögren’s syndrome / primarni Sjögrenov sindrom; sSS – secondary Sjögren’s syndrome / sekundarni Sjögrenov sidrom
Table 4 Differences and similarities of classification criteria published between 1993 and 2016.
Tablica 4. Razlike i sličnosti klasifikacijskih kriterija objavljenih 1993. – 2016. godine
Legend / Legenda: ANA – antinuclear antibodies / antinuklearna antitijela; RF – rheumatoid factor / reumatoidni faktor; TBUT – tear break-up time; OSS – ocular staining score / ocjena bojenja površine oka; AIDS –aquired immunodeficiency syndrome / sindrom stečene imunodeficijencije; GVHD – graft versus host disease / kronična bolest presatka protiv primatelja; HCV – hepatitis C virus / virus hepatitisa C; IgG4 – immunoglobulin G4 / imunoglobulin G4.