Sjogren’s syndrome (SS) is an autoimmune disease that mainly affects the exocrine glands leading to ocular and oral dryness alongside with other systemic manifestations, which are reported to occur in a quarter of patients. The histological hallmark of SS is the lymphoplasmacytic infiltration of lacrimal and salivary glands. Though the origin of this is unknown, it is believed that an intrinsic activation of glandular epithelial cells leads to an increased rate of apoptosis of these cells and migration of the Ro-60 antigen on the cell surface. This in turn activates the T and B cells and causes them to accumulate in glandular tissues and secret multiple cytokines that include interferon gamma, interleukin 17 and B-cell activating factors (BAFF). BAFF, which is expressed on monocytes, dendritic cells and activated T cells, together with T and B cell-attracting chemokines, create a microenvironment that supports B cell aggregation, differentiation and local production of the anti-Ro and anti-La antibodies. The histological features of the involved exocrine glands resemble that of germinal centers in the lymph nodes during chronic infection. SS may occur with (secondary SS) or without (primary SS) an underlying rheumatological or autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis.
2 Classification criteria for primary Sjogren’s syndrome
The diagnosis of primary SS relies on a combination of clinical features, serological tests, exocrine functional tests and tissue biopsies. Before 2016, there were two most widely-used classification criteria for primary SS, namely the American-European Consensus Group criteria (AECG criteria, 2002) and the Sjogren’s International Collaborative Clinical Alliance criteria (SICCA criteria, 2012). As the SICCA criteria were provisionally approved by the American College of Rheumatology (ACR), it was sometimes quoted as the ACR criteria for primary SS by various investigators.
The AECG criteria consist of six items including ocular symptoms, oral symptoms, ocular signs, salivary gland involvement, histopathology of the minor salivary glands and autoantibodies.⍰Table 1summarizes the AECG criteria for SS. An individual is classified as having primary SS if: (1) the presence of any four of the six items, as long as item IV (histology) or VI (serology) is positive, or (2) presence of any 3 of the 4 objective items (III – VI). The AECG criteria have a sensitivity of 97.2% and specificity of 90.2%.
AECG criteria for Sjogren’s syndrome.
|Ocular symptoms (at least one)|
|Symptom of dry eyes for at least 3 months|
|A foreign body sensation in the eyes|
|Use of artificial tears 3 or more times per day|
|Oral symptoms (at least one)|
|Symptoms of dry mouth for at least 3 months|
|Recurrence of persistent swollen salivary glands|
|Need for liquids to swallow dry food|
|Ocular signs (at least one)|
|Abnormal Schirmer’s test|
|Positive vital dye staining of eye surface|
|Minor salivary gland biopsy showing focal lymphocytic sialadenitis|
|Oral signs (at least one)|
|Unstimulatory whole salivary flow|
|Abnormal parotid sialography|
|Abnormal salivary scintigraphy|
|Anti-Ro, anti-La or both antibodies positive|
A group of diseases should be excluded before a diagnosis of primary SS is made. These include previous head and neck radiation treatment, hepatitis C infection, acquired immunodeficiency disease, pre-existing lymphoma, sarcoidosis, graft-versus-host disease and use of anti-cholinergic drugs.
The SICCA criteria can be applied to individuals who present with signs or symptoms suggestive of SS. The classification of primary SS relies on at least 2 out of the following 3 objective features: (1) positive serum anti-Ro and/ or anti-La (or positive rheumatoid factor and ANA titer > 1:320), (2) labial salivary gland biopsy features and (3) ocular staining score > 3. The exclusion criteria are similar to that of AECG criteria, with the addition of IgG4-related disease and amyloidosis, and the removal of anticholinergic drugs and lymphoma. This set of criteria has a sensitivity of 92.5% and specificity of 95.4%.
In 2016, American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) published a new set of classification criteria for primary SS. It employs a set of inclusion criteria, which are collections of ocular and oral symptoms that very much resemble items I and II of the AECG criteria. Yet one of the questions, “Have you had recurrently or persistently swollen salivary gland as an adult?” is not adopted. The exclusion criteria are almost the same as SICCA criteria, but the presence of hepatitis C must be confirmed with polymerase chain reaction. The 2016 ACR/ EULAR criteria are shown in Table 2.
2016 ACR/ EULAR classification criteria
Inclusion criteria: any individual with the presence of positive answer to at least one of the following questions:
- Have you had daily, persistent, troublesome dry eyes for more than 3 months?
- Do you have a recurrent sensation of sand and gravel in the eyes?
- Do you use tear substitutes more than 3 times a day?
- Have you had a daily feeling of dry mouth for more than 3 months?
- Do you frequently drink liquids to aid in swallowing dry food?
Or in whom there is suspicion of SS from the ESSDAI questionnaire.
|Labial salivary gland with focal lymphocytic sialadenitis and focus score of > 1 foci/4 mm2||3|
|Ocular staining score > 5 in at least one eye||1|
|Schirmer’s test < 5 mm/ 5 minutes in at least one eye||1|
|Unstimulated whole saliva flow rate < 0.1 ml/ minutes||1|
An individual with a score of > 4 is classified as having primary SS
One of the new changes in 2016 ACR/ EULAR criteria is the weighting on certain objective items. Labial salivary gland biopsy and anti-Ro positivity each carries 3 points, whereas ocular stain score, Schirmer’s test and unstimulated whole saliva flow each carries 1 point only. An individual with a score of > 4 is classified as having primary SS. This set of criteria has a sensitivity of 96% and specificity of 95%.
Another special point in the ACR/EULAR criteria is that the presence of anti-La is no longer considered as a classification item. This is based on the results of a large observational study involving 3297 subjects published in 2015. In this study, 1236 subjects had positive anti-Ro or anti-La antibodies. The authors found that the presence of anti-La antibody, but without anti-Ro antibody, had no significant association with the phenotypic features of primary SS. The significance of the sole presence of an anti-La antibody is the same as patients without any antibodies. Therefore, the anti-La antibody was eliminated in the classification criteria.
A recent report from Japan attempted to validate the performance of the 2016 ACR/ EULAR criteria for primary SS. The authors compared this new set of criteria with older criteria including AECG and SICCA criteria in their own cohort of patients. This study involved 499 patients from 10 hospitals. Clinical diagnosis by physician in-charge was set as the “gold standard”. It was reported that that this new ACR/EULAR criteria had a significantly higher sensitivity but lower specificity when compared with the older classification criteria for primary SS.
In view of the lack of a “gold standard” for the diagnosis of SS, ways of further improving the sensitivity and specificity of the current classification criteria are being explored. One aspect would be the use of improved serological assays for the autoantibodies. Anti-Ro (52kd) and anti-Ro (60kd) had been investigated on their use in other autoimmune diseases such as systemic lupus erythematosus and inflammatory myositis. An isolated elevation of anti-Ro (52kd) was associated with primary Sjogren syndrome, inflammatory myositis, systemic sclerosis and primary biliary cirrhosis. Ultrasonography of the salivary glands had also been explored since early 2000s for its use in the diagnosis and monitoring of patients with SS. In the early stage of primary SS, the gland can be normal or becomes enlarged and hyperechoic, whereas in the late stage it may shows a multicystic or reticular pattern with an atrophic gland. The incorporation of novel antibodies and ultrasonographical features in the classification criteria are being considered as possible ways to further refine it.
3 Conventional and novel therapies of primary Sjogren’s syndrome
3.1 Non-pharmacological and topical treatment for sicca symptoms
Therapies of primary SS can be classified as pharmacological and non-pharmacological. A systematic review in 2015 summarized the non-pharmacological treatment options in primary SS. In this paper, 17 articles were screened but 12 were excluded. Of the 5 papers included in this review, only one study was considered to have low degree of bias. In most of these earlier works, the diagnostic criteria of the primary SS were either not stated or were heterogeneous; the sample size was small and there were no details regarding the baseline data of the participants. Overall, the punctum plugs appeared to be effective for keratoconjunctivitis sicca but they were not regarded as a disease-specific treatment modality. Other treatment options, including oral lubrication devices, psychodynamic therapy and acupuncture are not proven to be useful in primary SS.
A study looking at the efficacy of acupuncture in primary SS is afoot in mainland China. This is a single-center double-blinded controlled trial using the AECG criteria to recruit subjects with primary SS. The control group of subjects will receive sham acupuncture, in which the needle will not puncture the skin at all. The result of the above study is yet to be reported.
Despite the lack of good quality controlled trials, non-pharmacological therapies’ treatments are often prescribed for relief of sicca symptoms. Artificial tears (e.g., hypromellose) remain the first-line treatment for xerophthalmia. Eye lubricants (e.g., solcoseryl eye gel) are also useful. Cyclosporine A and steroid eye drops are used by ophthalmologists as the second line treatment of serious or refractory sicca symptoms of the eyes.
Artificial saliva is the first-line treatment for xerostomia. Muscarinic agents such as pilocarpine and cevimeline have been shown to be effective in randomized control trials conducted in the late 1990s’ in terms of improvement of salivary flow upon a period of 12 weeks. [10-11] However, these agents are mostly poorly tolerated due to prominent side effects of sweating, flushing, nausea, diarrhea and chills.
3.2 Immunosuppressive therapies for primary SS
Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) such as methotrexate (MTX) and hydroxychloroquine (HCQ) are often used to treat joint symptoms, myalgia, cutaneous manifestations (e.g., purpura, annular erythema and pernio-like lesions) and elevated inflammatory markers in primary SS. However, the efficacy of these csDMARDs is only reported in open-label studies but not supported by evidence from large randomized controlled trials.
Recently, a placebo-controlled double-blinded randomized controlled trial from Korea was attempted to investigate the efficacy of HCQ in primary SS as classified by the AECG criteria. Twenty-six patients were recruited and it was found that over a period of 16 weeks, there were no statistical differences in the change of eye symptoms, ocular staining, Schirmer’s test results, ocular surface disease index, tear film break-up time and other inflammatory markers including erythrocyte sedimentation rate, IL6, B-cell activating factors and Th17 cells between the HCQ and placebo arms of patients. It was concluded that HCQ did not have apparent benefits in the treatment of dry eyes or systemic inflammation in primary SS. The result was different from a previous retrospective open-label study in which HCQ was shown to improve local symptoms, arthralgia, myalgia and erythrocyte sedimentation rate after a mean observation of 3 years. However, it is noteworthy that the Korean study mainly focused on ophthalmological and serum inflammatory parameters but not arthralgia, myalgia or salivary gland function. Moreover, the duration of follow-up of this study was much shorter.
Cyclosporine A, on the other hand, is promising for the treatment of primary SS. A recent phase II investigator-initiated open-label pilot study of the use of low-dose cyclosporine A (at 2mg/ kg/ day) in articular manifestation of primary SS showed that the drug was effective in reducing the number of tender and swollen joints after 16 weeks. In this study, 70% of subjects had reduction of two or more tender and swollen joints. The reported side effects were consistent with the known toxicity profile of cyclosporine A.
Systemic involvement of primary SS is heterogeneous; with virtually any organ system may be involved. Cardiopulmonary, renal and neurological manifestations are usually treated with high-dose glucocorticoids with or without combination with other non-glucocorticoid immunosuppressive agents. Renal manifestations such as distal renal tubular acidosis have well been described in primary SS. The reported prevalence of renal involvement in primary SS ranges from 1–30% in various studies.  Renal biopsy is often required to guide treatment strategy. Membranoproliferative glomerulonephritis is the commonest form of glomerulonephritis in primary SS. Renal tubulo-interstitial disease is also common in primary SS, which is present in approximately two-thirds of patients with kidney dysfunction who have undergone a renal biopsy.
3.3 Novel biological therapies for primary Sjogren’s syndrome
As the B cells are central to the pathogenesis of SS, B cell-targeted therapies have been mostly studied in primary SS in the past few years. Rituximab has shown promising results in the earlier trials [17-18] but its efficacy cannot be reproduced in subsequent larger multi-center randomized controlled trials including the French TEARS trial  and the British TRACTISS trial .
A meta-analysis regarding the efficacy rituximab in primary SS was recently published. Four randomized controlled trials were included in this meta-analysis and they were all placebo-controlled. Among the included studies, only one evaluated lacrimal function, which was measured by lissamine stain test, and ocular symptoms that were reported by a visual analogue scale. Both parameters showed significant improvement after 24 weeks of treatment with rituximab. Salivary flow rate was evaluated in three other studies, but only one of them showed improvement after rituximab treatment. The pooled results, nonetheless, demonstrated efficacy in favor of rituximab. Other treatment outcomes such as Schirmer’s test, oral dryness score, fatigue score and disease activity score showed no statistically significant improvement with rituximab. The authors concluded that there was moderately good quality evidence to suggest that treatment with a single course of rituximab may improve lacrimal gland function but low quality evidence of this drug for improving the salivary flow. As systemic manifestations were not evaluated in these studies and the follow-up period was relatively short, poor prognostic factors of primary SS could not be studied.
On the other hand, multiple case reports have shown efficacy of rituximab in the treatment of other systemic manifestations of primary SS. One case of mesangial glomerulonephritis even achieved remission after 3 treatment cycles of rituximab as monotherapy .
Another systemic manifestation of SS is interstitial lung disease (ILD). A retrospective study from Taiwan  involving 10 patients with moderate-to-severe ILD showed that rituximab improved the diffusion capacity of lungs (KCO) and patient global assessment score 6 months after a course of rituximab infusion. The activity score as assessed by high-resolution computer tomography of the lungs also showed improvement with rituximab but this did not reach statistical significance.
Belimumab, a monoclonal antibody targeting B-cell activating factor (BAFF) has been studied in primary SS. In a phase II open-label trial of belimumab (BELISS trial), the drug was shown to improve patient report index and disease activity index after treatment for 12 months . However, other outcomes such as salivary flow, Schirmer’s test and salivary gland biopsy score did not show significant improvement with belimumab.
Epratuzumab, a humanized IgG1 and anti-CD22, has been studied in both phases I and II studies. The preliminary results were promising, with improvement in salivary flow, Schirmer’s test, fatigue score and inflammatory surface reactants demonstrated after treatment.
T-cell targeted therapy is being studied as well in primary SS. Abatacept, a soluble fusion protein with domain of CTLA4 linked to the modified Fc portion of human IgG1 had been studied in the rheumatoid arthritis-associated SS by a Japanese group. In this open-labeled, prospective observation multi-center study, abatacept was shown effective to improve salivary flow and Schirmer’s test results over a period of 1 year. A phase III trial regarding the use of abatacept involving 88 subjects in primary SS is underway.
Efalizumab, a humanized monoclonal antibody targeting CD11a, has also been investigated in primary SS. However, the study was halted due to the potential of this biological agent to cause progressive multifocal leukoencephalopathy . Anti-TNF alpha agents including infliximab  and etanercept  both failed to demonstrate efficacy in primary SS. Interferon-targeted therapy has been studied in primary SS as well. In one large double-blinded, placebo-controlled randomized controlled trial, interferon alpha was given via oromucosal route. Unfortunately, the drug failed to show benefit in reducing oral dryness and stimulated salivary flow .
Baminercept, a lymphotoxin beta receptor Ig1 fusion protein, is being investigated for its potential effect to disrupt the dendritic cell networks and germinal center reactions in primary SS. A phase II trial nonetheless concluded that it was no more effective than a placebo for improving salivary flow and ocular dryness .
Another phase III trial regarding the use of tocilizumab in primary SS is in progress (NCT01782235). Other biological agents being studied in primary SS include anti-CD40, anti-ICOS-L, anti-BAFF-R and Pi3Kinase inhibitors. An interesting phase II trial looking into co-administration of rituximab and belimumab is also in progress . Table 3 summarizes the upcoming trials regarding biological therapies for primary SS.
Recent and ongoing clinical trials of the novel biological agents in primary SS.
|Drug name||Target of action|
|CFZ 533||Anti-CD 40 monoclonal antibody|
|AMG 557/ MEDI587||Anti-ICOS-L monoclonal antibody|
|VAY 736||Anti-BAFF-R monoclonal antibody|
|Belimumab + Rituximab||Anti-BAFF and anti-CD 20|
In summary, despite still being considered a disease without a cure, a refinement of classification, as well as innovative approaches are being investigated and developed over the past few years for primary SS. Further studies for diagnosis, evaluation and treatment for this disease are in progress. With the new 2016 ACR/ EULAR classification criteria and recent advances in treatment modalities, it is hoped that the management of primary SS can be improved in the near future.
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Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61: 554-8.)| false 10.1136/ard.61.6.554
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Shiboski SC, Shiboski CH, Criswell LA, Baer AN, Challacombe S, Lanfranchi H, et al. American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjogren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64: 475-87.)| false 10.1002/acr.21591
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