Primary Sjögren’s syndrome and the eye

Open AccessPublished:October 18, 2019DOI:https://doi.org/10.1016/j.survophthal.2019.10.004

      Abstract

      Primary Sjögren syndrome is an autoimmune disease that mainly affects exocrine glands such as the salivary and lacrimal glands. In addition, systemic involvement is common. Primary Sjögren syndrome is of particular interest to ophthalmologists as it constitutes an important differential diagnosis in conditions with dry eye disease. In addition, ocular tests for more precisely diagnosing and monitoring primary Sjögren syndrome have become increasingly important, and new therapeutics for local and systemic treatment evolve as a result of increased understanding of immunological mechanisms and molecular pathways in the pathogenesis of primary Sjögren syndrome. We provide an update of interest to ophthalmologists regarding pathogenesis, diagnosis, investigative procedures, and treatment options.

      Keywords

      1. Introduction

      The Swedish ophthalmologist Henrik Sjögren (1899–1986) published his thesis “Zur kenntnis der Keratoconjunctivitis Sicca” in 1933, describing a series of patients with musculoskeletal pain, dry eyes, and dry mouth.
      • Sjögren H.
      Zur Kenntnis der Keratoconjunctivitis sicca.
      Sjögren syndrome is a chronic inflammatory autoimmune disease histopathologically characterized by lymphocytic infiltration of exocrine glands leading to a clinical picture of dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca).
      • Jonsson R.
      • Brokstad K.A.
      • Jonsson M.V.
      • Delaleu N.
      • Skarstein K.
      Current concepts on Sjögren's syndrome - classification criteria and biomarkers.
      ,
      • Jonsson R.
      • Vogelsang P.
      • Volchenkov R.
      • Espinosa A.
      • Wahren-Herlenius M.
      • Appel S.
      The complexity of Sjogren's syndrome: novel aspects on pathogenesis.
      Sjögren syndrome may occur alone—primary Sjögren syndrome (pSS)—or as part of other chronic inflammatory diseases—secondary Sjögren syndrome. It is disputed whether secondary Sjögren syndrome is identical to pSS or represents a general tendency of all autoimmune diseases to affect exocrine glands. Dryness is the main symptom, but a majority of the pSS patients also experience systemic manifestations such as fatigue and migrating muscular and joint pain.
      • Goransson L.G.
      • Herigstad A.
      • Tjensvoll A.B.
      • Harboe E.
      • Mellgren S.I.
      • Omdal R.
      Peripheral neuropathy in primary sjogren syndrome: a population-based study.
      ,
      • Harboe E.
      • Tjensvoll A.B.
      • Maroni S.
      • et al.
      Neuropsychiatric syndromes in patients with systemic lupus erythematosus and primary Sjogren syndrome: a comparative population-based study.
      ,
      • Jonsson R.
      • Jonsson M.V.
      Histopathology and Glandular Biopsies in Sjögren's Syndrome.
      Based on a meta-analysis, the prevalence of pSS worldwide is estimated to 0.06%, with 90% of the patients being female.
      • Qin B.
      • Wang J.
      • Yang Z.
      • et al.
      Epidemiology of primary Sjogren's syndrome: a systematic review and meta-analysis.
      The disease onset is frequently insidious with vague symptoms over many years, and delayed diagnosis is common.
      • Goransson L.G.
      • Haldorsen K.
      • Brun J.G.
      • et al.
      The point prevalence of clinically relevant primary Sjogren's syndrome in two Norwegian counties.
      Here we present a comprehensive update of the eye involvement in pSS.

      2. Diagnosis

      The challenges of understanding and defining the pSS disease concept are reflected in more than 10 different classification or diagnostic criteria published since 1965. The American-European Consensus Group classification criteria have been widely used since 2002
      • Vitali C.
      • Bombardieri S.
      • Jonsson R.
      • et al.
      Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group.
      (Table 1). A new set of classification criteria based on only objective findings was presented by the American College of Rheumatology in 2012,
      • Shiboski S.C.
      • Shiboski C.H.
      • Criswell L.
      • et al.
      American College of Rheumatology classification criteria for Sjogren's syndrome: a data-driven, expert consensus approach in the Sjogren's International Collaborative Clinical Alliance cohort.
      swiftly followed by another set of criteria that represents a joint effort to establish an agreement between the American-European Consensus Group classification criteria and American College of Rheumatology criteria
      • Shiboski C.H.
      • Shiboski S.C.
      • Seror R.
      • et al.
      2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjogren's syndrome: A consensus and data-driven methodology involving three international patient cohorts.
      (Table 2). Both sets of criteria include the serological markers anti-Ro (SSA) and/or anti-La (SSB) and a focus score ≥1, defined as a number of lymphocytic foci (contain ≥50 lymphocytes) per 4 mm2 of glandular tissue. Shiboski and coworkers
      • Shiboski C.H.
      • Shiboski S.C.
      • Seror R.
      • et al.
      2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjogren's syndrome: A consensus and data-driven methodology involving three international patient cohorts.
      advocate the use of only objective findings to establish the pSS diagnosis, although dryness reported by patients is still mandatory for fulfillment of diagnosis. Presently, a diagnosis of pSS relies on a combination of clinical, histological, and immunological findings, in combination with relevant subjective symptoms (dry eyes and/or mouth).
      Table 1American-European Consensus Group criteria for Sjögren's syndrome
      • Vitali C.
      • Bombardieri S.
      • Jonsson R.
      • et al.
      Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group.
      Objective criteria:
      • I. Ocular signs: unanesthetized Schirmer test ≤5 mm in 5 minutes. Rose bengal score ≥4 according to van Bijsterveld's scoring system, or other ocular dye scores.
        Other types of ocular dye scores and their cutoff values were not further specified, but a suggestion was made to the use of fluorescein stain for corneal surface and lissamine green for the conjunctival surface.
      • II. Involvement of salivary gland by functional testing: Unstimulated whole salivary flow (≤1.5 ml in 15 minutes), parotid sialography showing the presence of diffuse sialectasis (punctate, cavitary, or destructive pattern), without evidence of obstruction in the major ducts or salivary scintigraphy showing delayed uptake, reduced concentration, and/or delayed excretion of tracer.
      • III. Presence of auto-antibodies: anti-Ro (SSA) or anti-La (SSB), or both.
      • IV. Histopathology: In minor salivary glands, obtained through normal-appearing mucosa:
        • Focal lymphocytic sialadenitis, evaluated by an expert histopathologist, with a focus score ≥1, defined as a number of lymphocytic foci (contain ≥50 lymphocytes) per 4 mm2 of glandular tissue.
      Subjective criteria:
      • V. Oral symptoms.
      • VI. Ocular symptoms.
      Classification of pSS requires 3 of 4 objective criteria.

      Alternatively 4 of 6 criteria (objective and subjective), of which at least III and/or IV of the objective criteria must be present.
      pSS, primary Sjögren syndrome.
      Other types of ocular dye scores and their cutoff values were not further specified, but a suggestion was made to the use of fluorescein stain for corneal surface and lissamine green for the conjunctival surface.
      Table 2American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome 2016
      • Shiboski C.H.
      • Shiboski S.C.
      • Seror R.
      • et al.
      2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjogren's syndrome: A consensus and data-driven methodology involving three international patient cohorts.
      ItemWeight/score
      Labial salivary gland with focal lymphocytic sialadenitis and focus score of ≥1 foci/4 mm2.3
      Presence of auto-antibodies: anti-Ro or anti-La.3
      Ocular staining score
      • van Bijsterveld O.P.
      Diagnostic tests in the Sicca syndrome.
      ≥5 or van Bijsterveld score
      • van Bijsterveld O.P.
      Diagnostic tests in the Sicca syndrome.
      ≥4 in at least one eye.
      1
      Schirmer's test ≤5 mm/5 min in at least one eye
      Patients who are normally taking anticholinergic drugs should be evaluated for objective signs of salivary hypofunction and ocular dryness after a sufficient interval without these medications in order for these components to be a valid measure of oral and ocular dryness.
      .
      1
      Unstimulated whole saliva flow rate ≤0.1 mL/min.1
      The classification of primary Sjögren's syndrome applies to any individual who meets the inclusion criteria
      Inclusion criteria are applicable to any patient with at least one symptom of ocular or oral dryness, defined as a positive response to at least one of the following questions: (1) Have you had daily, persistent, troublesome dry eyes for more than 3 months? (2) Do you have a recurrent sensation of sand or gravel in the eyes? (3) Do you use tear substitutes more than three times a day? (4) Have you had a daily feeling of dry mouth for more than 3 months? (5) Do you frequently drink liquids to aid in swallowing dry food? or in whom there is suspicion of Sjögren's syndrome from the European League Against Rheumatism SS Disease Activity Index questionnaire (at least one domain with a positive item).
      , does not have any of the conditions listed as exclusion criteria
      Exclusion criteria include prior diagnosis of any of the following conditions, which would exclude diagnosis of SS and participation in SS studies or therapeutic trials because of overlapping clinical features or interference with criteria tests: (1) history of head and neck radiation treatment, (2) active hepatitis C infection (with confirmation by PCR), (3) AIDS, (4) sarcoidosis, (5) amyloidosis, (6) graft-versus-host disease, and (7) IgG4-related disease.
      , and has a score of ≥4 when the weights from the five criteria items below are summed.
      Patients who are normally taking anticholinergic drugs should be evaluated for objective signs of salivary hypofunction and ocular dryness after a sufficient interval without these medications in order for these components to be a valid measure of oral and ocular dryness.
      Inclusion criteria are applicable to any patient with at least one symptom of ocular or oral dryness, defined as a positive response to at least one of the following questions: (1) Have you had daily, persistent, troublesome dry eyes for more than 3 months? (2) Do you have a recurrent sensation of sand or gravel in the eyes? (3) Do you use tear substitutes more than three times a day? (4) Have you had a daily feeling of dry mouth for more than 3 months? (5) Do you frequently drink liquids to aid in swallowing dry food? or in whom there is suspicion of Sjögren's syndrome from the European League Against Rheumatism SS Disease Activity Index questionnaire (at least one domain with a positive item).
      Exclusion criteria include prior diagnosis of any of the following conditions, which would exclude diagnosis of SS and participation in SS studies or therapeutic trials because of overlapping clinical features or interference with criteria tests: (1) history of head and neck radiation treatment, (2) active hepatitis C infection (with confirmation by PCR), (3) AIDS, (4) sarcoidosis, (5) amyloidosis, (6) graft-versus-host disease, and (7) IgG4-related disease.

      3. Genetic aspects

      Dysregulation of immune homeostasis and inflammation is fundamental in all systemic autoimmune conditions, and disease is considered to arise from an interplay between environmental factors and genetic susceptibility. There are known associations between autoimmune diseases and genetic variants in the human leukocyte antigen region, and an additional number of genes outside the human leukocyte antigen region have been associated with pSS. Examples of such non–human leukocyte antigen genes are IRF5-TNPO3, STAT4, and IL12A. Variants of these genes may cause dysregulation in both adaptive and innate immunity that is important for development of pSS.
      • Lessard C.J.
      • Li H.
      • Adrianto I.
      • et al.
      Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren's syndrome.
      ,
      • Li Y.
      • Zhang K.
      • Chen H.
      • et al.
      A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjogren's syndrome at 7q11.23.
      ,
      • Reksten T.R.
      • Lessard C.J.
      • Sivils K.L.
      Genetics in Sjogren Syndrome.
      Epigenetic mechanisms are powerful regulatory functions of gene expression and influence the phenotype of individuals. Silencing mRNA, DNA methylation, and histone modification are examples of epigenetic regulation. Epigenetic findings in monocytes and B cells indicate that active histone markers are associated with pSS risk variants,
      • Konsta O.D.
      • Le Dantec C.
      • Charras A.
      • et al.
      An in silico Approach Reveals Associations between Genetic and Epigenetic Factors within Regulatory Elements in B Cells from Primary Sjogren's Syndrome Patients.
      and another study revealed strong indications of an epigenetic modulation of interferon (IFN)-regulated genes in pSS.
      • Imgenberg-Kreuz J.
      • Sandling J.K.
      • Almlof J.C.
      • et al.
      Genome-wide DNA methylation analysis in multiple tissues in primary Sjogren's syndrome reveals regulatory effects at interferon-induced genes.
      Upcoming technologies provide the possibility to map both the entire genome and the transcriptome at affordable costs, and it is expected that such analyses will reveal more of the genetic complexity of heterogeneous disorders like pSS. Variants of genes expressed in lacrimal glands and on ocular surface may be assessed and could increase the understanding of etiology and pathogenesis with increasing possibilities for new treatment options.

      4. Immune response

      4.1 Immunological markers

      Activation of B cells is one of the immunological characteristics of pSS and leads to hypergammaglobulinemia and production of various autoantibodies of which anti-Ro (-SSA) and/or anti-La (-SSB) are considered immunological hallmarks of the disease. These autoantibodies are found in 50% to 70 % of patients and are associated with more severe disease.
      • Fayyaz A.
      • Kurien B.T.
      • Scofield R.H.
      Autoantibodies in Sjogren's Syndrome.
      Anti-Ro-52 antibody is presently the most important immunological marker in pSS
      • Oke V.
      • Wahren-Herlenius M.
      The immunobiology of Ro52 (TRIM21) in autoimmunity: a critical review.
      ; however, other antibodies are sometimes used, namely the Sjő battery of markers.
      • Shen L.
      • Suresh L.
      • Lindemann M.
      • et al.
      Novel autoantibodies in Sjogren`s syndrome.
      Anti-Ro and anti-La antibodies can be detected years previous to the clinical onset of pSS,
      • Jonsson R.
      • Theander E.
      • Sjostrom B.
      • Brokstad K.
      • Henriksson G.
      Autoantibodies present before symptom onset in primary Sjogren syndrome.
      indicating that autoimmunity, and even pathological injury, can start long before clinical disease is evident.

      4.2 Interferons

      In addition to a genetic predisposition, it is hypothesized that specific external “triggers” are necessary for autoimmune disease to develop. Viral infections have been proposed as candidates in pSS. Increased antiviral response is reflected by increased production of different types of IFNs and upregulation of IFN-regulated genes—“the interferon signature.”
      • Ronnblom L.
      The type I interferon system in the etiopathogenesis of autoimmune diseases.
      An increased IFN type I production by plasmacytoid dendritic cells occurs in pSS and seems to be “out of control,” just as in a poorly controlled viral infection. This could lead to activation of the innate and adaptive immune systems and cause self-reactive activity against tissues of the body.
      • Ronnblom L.
      The type I interferon system in the etiopathogenesis of autoimmune diseases.
      Whether the increased IFN production is due to a genetic defect of IFN control or reflects an imperfect handling of viruses is uncertain.

      5. Histopathological findings in salivary and lacrimal glands

      B- and T-lymphocytes and other immune cells infiltrate exocrine glands in pSS
      • Jonsson M.V.
      • Skarstein K.
      Follicular dendritic cells confirm lymphoid organization in the minor salivary glands of primary Sjogren's syndrome.
      . Lacrimal and salivary glands are both affected. Lacrimal gland biopsy is usually obtained from the palpebral part of the gland under local anesthesia. The procedure is technically more challenging than biopsy of the minor salivary glands (MSGs). Bleeding perioperatively may occur, and there is a risk of injury to the secretory ducts. Histological examinations of tissue specimens from the MSG are therefore standard for diagnosis.
      • Daniels T.E.
      Labial salivary gland biopsy in Sjogren's syndrome. Assessment as a diagnostic criterion in 362 suspected cases.
      ,
      • Jonsson R.
      • Jonsson M.V.
      Histopathology and Glandular Biopsies in Sjögren's Syndrome.
      ,
      • Risselada A.P.
      • Kruize A.A.
      • Goldschmeding R.
      • Lafeber F.P.
      • Bijlsma J.W.
      • van Roon J.A.
      The prognostic value of routinely performed minor salivary gland assessments in primary Sjogren's syndrome.
      MSG biopsy is performed under local anesthesia through a small incision on the inside of the lower lip, and at least 4–5 minor salivary glands are removed. Complications rarely occur, but sometimes a mucocele, reduced sensitivity in the biopsy area, or local infection may follow.
      • Varela Centelles P.
      • Sanchez-Sanchez M.
      • Costa-Bouzas J.
      • Seoane-Romero J.M.
      • Seoane J.
      • Takkouche B.
      Neurological adverse events related to lip biopsy in patients suspicious for Sjogren's syndrome: a systematic review and prevalence meta-analysis.

      5.1 Focus score

      “Focus score” is a semiquantitative assessment of the lymphocytic infiltration of the gland and is defined as the number of separate clusters (foci) of ≥50 mononuclear cells per 4 mm2 in a section of tissue from a salivary gland biopsy (Fig. 1). One or more foci of mononuclear cells per 4 mm2 (focus score ≥1) count as one of the objective criteria for classification of pSS (Tables 1 and 2).
      Figure thumbnail gr1
      Fig. 1When assessing the focus score, a grid can be used to determine the total area of minor salivary gland tissue. For the grid in this figure and using the 2.5x magnification, five squares equal to 2 mm, that is, 5 x 5 squares represents 4 mm2. The number of foci containing 50 or more mononuclear cells is then determined, divided by the total area, and focus score presented as the number of foci per 4 mm2. In cases where two or more inflammatory cell foci are close together and merge or even seem confluent, the foci are counted separately.
      Photo: Kathrine Skarstein. With permission from Springer Nature.

      5.2 Ectopic germinal centers

      In conditions with intense immunological stimulation, ectopic (“tertiary”) germinal center–like aggregates sometimes develop outside secondary lymphoid organs (lymph nodes)
      • Bombardieri M.
      • Lewis M.
      • Pitzalis C.
      Ectopic lymphoid neogenesis in rheumatic autoimmune diseases.
      ,
      • Pipi E.
      • Nayar S.
      • Gardner D.H.
      • Colafrancesco S.
      • Smith C.
      • Barone F.
      Tertiary Lymphoid Structures: Autoimmunity Goes Local.
      (Fig. 2). Germinal center–like structures occur in MSG in approximately 25% of the pSS patients and is related to a more severe and systemic disease
      • Jonsson M.V.
      • Skarstein K.
      • Jonsson R.
      • Brun J.G.
      Serological implications of germinal center-like structures in primary Sjögren's syndrome.
      and possibly associated with increased risk for B cell malignancies,
      • Theander E.
      • Vasaitis L.
      • Baecklund E.
      • et al.
      Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjogren's syndrome.
      although the latter is still disputed.
      Figure thumbnail gr2
      Fig. 2Histopathological view of the chronic inflammation in minor salivary glands obtained from the inside of the lower lip in a patient with Sjögren's syndrome. A and B: Low- and high-power view of salivary glands stained by hematoxylin and eosin (H&E) with focal periductal infiltrates of mononuclear inflammatory cells. C and D: Low- and high-power view of organized lymphoid tissue infiltrates, also termed ectopic germinal centers or germinal center-like lesions.
      Photo: Malin V. Jonsson. With permission from BestPractice Reumatologi/Onkologi.

      6. Eye involvement in primary Sjögren syndrome

      6.1 Lacrimal glands

      Histopathological studies of lacrimal glands in pSS patients (Fig. 3) are rare owing to technical challenges and risk of complications. We found 12 relevant studies published after 1970, Table 3. Most of these studies are old, include few patients, and some involve subjects with dry eye conditions other than pSS. Four articles describe findings in both lacrimal and salivary glands. Most authors adapt existing grading systems for MSG biopsies when describing lacrimal gland histology.
      • Hernández-Molina G.
      • Kimura-Hayama E.
      • Ávila-Casado M.C.
      • Sanchez-Guerrero J.
      Diagnostic Procedures (II): Parotid scintigraphy, Parotid Ultrasound, Magnetic Resonance, Salivary Gland Biopsy.
      Only the Japanese criteria for pSS allow for the use of lacrimal gland biopsies for diagnosis.
      • Fujibayashi T.
      • Sugai S.
      • Miyasaka N.
      • Hayashi Y.
      • Tsubota K.
      Revised Japanese criteria for Sjogren's syndrome (1999): availability and validity.
      Figure thumbnail gr3
      Fig. 3Biopsy of a lacrimal gland with focal infiltrations of mononuclear cells in obviously normal glandular parenchyma (blue staining). The red staining represents surrounding mainly loose connective tissue.
      Photo: Emilius Janssen. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
      Table 3Relevant articles regarding pSS and lacrimal gland (LG) biopsies published since 1970
      ConditionMethodsMain findingsReference
      SS, sicca syndrome, and “possible” SS.Histology, hematoxylin-eosin (H-E).No specific features distinguished the LG of SS from those of the sicca syndrome.
      • Williamson J.
      • Gibson A.A.
      • Wilson T.
      • Forrester J.V.
      • Whaley K.
      • Dick W.C.
      Histology of the lacrimal gland in keratoconjunctivitis sicca.
      SS.“Routine histologic analysis.”

      Immunocytochemical.

      Southern blot.
      The destruction of the tubuloacinar architecture of LG tissue in SS appears secondary to lymphoproliferation of B cells and T helper cells. Infection of LG tissue with EBV may play a role in the pathogenesis of the SS in selected cases.
      • Pepose J.S.
      • Akata R.F.
      • Pflugfelder S.C.
      • Voigt W.
      Mononuclear cell phenotypes and immunoglobulin gene rearrangements in lacrimal gland biopsies from patients with Sjogren's syndrome.
      pSS.Immunohistochemistry.

      PCR.

      Southern hybridization.
      Amplification of EBV DNA in LG of pSS patients are at a greater frequency than in normal controls.
      • Pflugfelder S.C.
      • Crouse C.
      • Pereira I.
      • Atherton S.
      Amplification of Epstein-Barr virus genomic sequences in blood cells, lacrimal glands, and tears from primary Sjogren's syndrome patients.
      SS.Immunohistochemistry.

      PCR.

      In situ hybridization.
      These studies suggest that EBV may play a role in the pathology in the LG. B lymphoproliferation and epithelial pathologic changes were observed in SS.
      • Pflugfelder S.C.
      • Crouse C.A.
      • Monroy D.
      • Yen M.
      • Rowe M.
      • Atherton S.S.
      Epstein-Barr virus and the lacrimal gland pathology of Sjogren's syndrome.
      SS.Histology, (H-E).

      PCR.
      The amount of genome (EBV) in the LG was more than 10 times that in the SG, not only in the SS patients but also in the controls.
      • Tsubota K.
      • Fujishima H.
      • Toda I.
      • Katagiri S.
      • Kawashima Y.
      • Saito I.
      Increased levels of Epstein-Barr virus DNA in lacrimal glands of Sjogren's syndrome patients.
      Five articles have done a direct comparison between biopsies of lacrimal gland and SG.
      SS and RA.PCR.

      Southern hybridization.
      These results showed that the infiltrating T cells in LG of SS patients are polyclonal, and LG and SG do not share the same dominant T-cell clonotypes.
      • Mizushima N.
      • Kohsaka H.
      • Tsubota K.
      • Saito I.
      • Miyasaka N.
      Diverse T cell receptor beta gene usage by infiltrating T cells in the lacrimal glands of Sjogren's syndrome.
      Five articles have done a direct comparison between biopsies of lacrimal gland and SG.
      Suspected SS.Histology (H-E).LG has a more evident histopathology than labial SG biopsy specimens. The authors recommend that both SG and LG biopsies should be performed in patients with suspected SS to reduce false-negative results and improve diagnostic accuracy.
      • Xuan J.
      • Shen L.
      • Malyavantham K.
      • Pankewycz O.
      • Ambrus Jr., J.L.
      • Suresh L.
      Temporal histological changes in lacrimal and major salivary glands in mouse models of Sjogren's syndrome.
      Five articles have done a direct comparison between biopsies of lacrimal gland and SG.
      SS.Histology (H-E).

      Immunohistochemistry.

      PCR.

      Southern blot.

      Single-strand conformation polymorphism.
      These findings suggest that some autoreactive T cells infiltrating into the lips and eyes recognized restricted epitopes of a common autoantigen in patients with SS.
      • Matsumoto I.
      • Tsubota K.
      • Satake Y.
      • et al.
      Common T cell receptor clonotype in lacrimal glands and labial salivary glands from patients with Sjogren's syndrome.
      Five articles have done a direct comparison between biopsies of lacrimal gland and SG.
      Dry eye and SS.Histology (H-E).Patients with poor reflex tearing were more likely to have autoantibodies and lymphocytic infiltration of the exocrine glands in LG biopsy consistent with SS.
      • Tsubota K.
      • Xu K.P.
      • Fujihara T.
      • Katagiri S.
      • Takeuchi T.
      Decreased reflex tearing is associated with lymphocytic infiltration in lacrimal glands.
      SS and non-SS.Histology (H-E).

      Immunohistochemistry.
      Alpha E beta 7 integrin, by interacting with E-cadherin, mediates the adhesion between CD81 T lymphocytes and acinar epithelial cells in SS and participates in inducing epithelial cell apoptosis, leading to secretory dysfunction of exocrine glands.
      • Fujihara T.
      • Fujita H.
      • Tsubota K.
      • et al.
      Preferential localization of CD8+ alpha E beta 7+ T cells around acinar epithelial cells with apoptosis in patients with Sjogren's syndrome.
      Five articles have done a direct comparison between biopsies of lacrimal gland and SG.
      pSS, sSS, and chronic graft-versus-host disease.Immunohistochemistry.

      Immunoblotting.
      Altered distribution of beta-fodrin in glandular epithelial cells may induce impaired secretory function and perpetuate an autoimmune response to beta-fodrin, leading to autoantibody production and glandular destruction in SS.
      • Kuwana M.
      • Okano T.
      • Ogawa Y.
      • Kaburaki J.
      • Kawakami Y.
      Autoantibodies to the amino-terminal fragment of beta-fodrin expressed in glandular epithelial cells in patients with Sjogren's syndrome.
      pSS and non-SS with dry eye.Histology (H-E).

      Electron microscopy.

      Immunohistochemistry.

      Quantitative fluorescence in situ hybridization of telomeres.
      The results of this study indicate that telo-FISH is a viable method of assessing telomere length in LG and that telomere length in SS is shorter and associated with lower levels of expression of p63 and nucleostemin than in non-SS.
      • Kawashima M.
      • Kawakita T.
      • Maida Y.
      • et al.
      Comparison of telomere length and association with progenitor cell markers in lacrimal gland between Sjogren syndrome and non-Sjogren syndrome dry eye patients.
      pSS, primary Sjögren syndrome.
      Five articles have done a direct comparison between biopsies of lacrimal gland and SG.
      Table 4Some tests used to diagnose and to investigate different aspects of ocular damage related to pSS
      TestDescriptionProsConsReference
      Schirmer's test.
      Already accepted as part of the diagnostic tests today.110,135
      Indication of the quantitative function of the lacrimal gland.Easy to perform.Moderate repeatability.

      Uncomfortable for patients.
      • Nichols K.K.
      • Mitchell G.L.
      • Zadnik K.
      The repeatability of clinical measurements of dry eye.
      ,
      • Versura P.
      • Frigato M.
      • Cellini M.
      • Mulè R.
      • Malavolta N.
      • Campos E.C.
      Diagnostic performance of tear function tests in Sjogren's syndrome patients.
      Ocular dye score.
      Already accepted as part of the diagnostic tests today.110,135
      Visualization of organ-specific damage.High reliability in grading among trained. Little discomfort for patients.Requires slit lamp and somewhat difficult to interpret without ophthalmological experience.
      • Rose-Nussbaumer J.
      • Lietman T.M.
      • Shiboski C.H.
      • et al.
      Inter-grader Agreement of the Ocular Staining Score in the Sjogren's International Clinical Collaborative Alliance (SICCA) Registry.
      Tear meniscus height.Optical coherence tomography (OCT) measures the lower (and or upper) tear meniscus.High degree of accuracy.

      Easy to quantify.
      Requires expensive equipment.

      Poorly validated against pSS.
      • Tung C.I.
      • Perin A.F.
      • Gumus K.
      • Pflugfelder S.C.
      Tear meniscus dimensions in tear dysfunction and their correlation with clinical parameters.
      Tear breakup time and tear film evaluation, both clinically and with optical-based methods.Assess the tear film stability and quality using different light sources and filters. Automated methods can also do topographic evaluation of the tear film and give a dynamic evaluation of the characteristic properties of the tear film.Provides a functional assessment of the tear film. Automated methods may detect subclinical changes in the tear film.Tear breakup time requires a slit lamp (and the use of fluorescein). Poor reproducibility, though more reliable results are found in DED than in a normal population. Topographical evaluation required expensive special equipment and is poorly validated against pSS.
      • Blackie C.A.
      • Solomon J.D.
      • Scaffidi R.C.
      • Greiner J.V.
      • Lemp M.A.
      • Korb D.R.
      The relationship between dry eye symptoms and lipid layer thickness.
      ,
      • Savini G.
      • Prabhawasat P.
      • Kojima T.
      • Grueterich M.
      • Espana E.
      • Goto E.
      The challenge of dry eye diagnosis.
      ,
      • Sweeney D.F.
      • Millar T.J.
      • Raju S.R.
      Tear film stability: a review.
      ,
      • Yu A.Y.
      • Lu T.
      • Pan A.P.
      • et al.
      Assessment of Tear Film Optical Quality Dynamics.
      Tear film osmolarity measurements.Measures the molecular concentration of osmotically active particles in the tear film.Considered the gold standard for diagnosing DED, and correlates with the severity of DED (objective and subjective). Easy to perform.Requires expensive equipment.
      • Chalmers R.L.
      • Begley C.G.
      • Caffery B.
      Validation of the 5-Item Dry Eye Questionnaire (DEQ-5): Discrimination across self-assessed severity and aqueous tear deficient dry eye diagnoses.
      ,
      • Utine C.A.
      • Bicakcigil M.
      • Yavuz S.
      • Ciftci F.
      Tear osmolarity measurements in dry eye related to primary Sjogren's syndrome.
      Tear proteomic, tear protein analysis, and conjunctival impression cytologic specimens.Tears or conjunctival impression cytologic specimens are collected to be analyzed with mass spectrometry other appropriate equipment.Can provide detailed information about cellular processes, for example, inflammation, immunity, and oxidative stress.It is not clear what the clinical application will be.
      • Aragona P.
      • Aguennouz M.
      • Rania L.
      • et al.
      Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease.
      ,
      • Li B.
      • Sheng M.
      • Li J.
      • et al.
      Tear proteomic analysis of Sjogren syndrome patients with dry eye syndrome by two-dimensional-nano-liquid chromatography coupled with tandem mass spectrometry.
      pSS = primary Sjögren syndrome.
      Already accepted as part of the diagnostic tests today.
      • Shiboski C.H.
      • Shiboski S.C.
      • Seror R.
      • et al.
      2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjogren's syndrome: A consensus and data-driven methodology involving three international patient cohorts.
      ,
      • Vitali C.
      • Bombardieri S.
      • Jonsson R.
      • et al.
      Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group.
      Mouse models have been widely used to understand the pathogenesis of pSS.
      • Delaleu N.
      • Nguyen C.Q.
      • Peck A.B.
      • Jonsson R.
      Sjogren's syndrome: studying the disease in mice.
      ,
      • Lee B.H.
      • Gauna A.E.
      • Pauley K.M.
      • Park Y.J.
      • Cha S.
      Animal models in autoimmune diseases: lessons learned from mouse models for Sjogren's syndrome.
      The lacrimal glands of nonobese diabetic mice, variant strain (NOD.B10.H2b), exhibit many of the same features as the lacrimal glands in pSS patients, including lymphocytic infiltrations and loss of secretory functions.
      • Meng Z.
      • Klinngam W.
      • Edman M.C.
      • Hamm-Alvarez S.F.
      Interferon-γ treatment in vitro elicits some of the changes in cathepsin S and antigen presentation characteristic of lacrimal glands and corneas from the NOD mouse model of Sjφgren's Syndrome.
      Nonobese diabetic mice demonstrate disturbances in the lacrimal gland morphology of secretory vesicles and in the distribution of key effectors of exocytosis, and the mouse models indicate that pSS starts as an organ-specific disease in the lacrimal and the submandibular glands.
      • Xuan J.
      • Shen L.
      • Malyavantham K.
      • Pankewycz O.
      • Ambrus Jr., J.L.
      • Suresh L.
      Temporal histological changes in lacrimal and major salivary glands in mouse models of Sjogren's syndrome.
      This is in agreement with a human study reporting that glandular inflammation first develops in the lacrimal glands.
      • Xu K.P.
      • Katagiri S.
      • Takeuchi T.
      • Tsubota K.
      Biopsy of labial salivary glands and lacrimal glands in the diagnosis of Sjogren's syndrome.
      Several animal models for pSS exists, among them the Aec and IL-12 transgenic mice both exhibiting glandular T-cell infiltration, TSP-1KO mice which have anti-SSA and anti-SSB serum autoantibodies and early changes in the ocular surface microbiota, and CD25KO mice exhibit disrupted immune tolerance that leads to accelerated lacrimal gland destruction and goblet cell loss.
      • de Paiva C.S.
      • Hwang C.S.
      • Pitcher III, J.D.
      • et al.
      Age-related T-cell cytokine profile parallels corneal disease severity in Sjogren's syndrome-like keratoconjunctivitis sicca in CD25KO mice.
      ,
      • Turpie B.
      • Yoshimura T.
      • Gulati A.
      • Rios J.D.
      • Dartt D.A.
      • Masli S.
      Sjogren's syndrome-like ocular surface disease in thrombospondin-1 deficient mice.
      ,
      • Vosters J.L.
      • Landek-Salgado M.A.
      • Yin H.
      • et al.
      Interleukin-12 induces salivary gland dysfunction in transgenic mice, providing a new model of Sjogren's syndrome.
      ,
      • You I.C.
      • Bian F.
      • Volpe E.S.
      • de Paiva C.S.
      • Pflugfelder S.C.
      Age-related conjunctival disease in the C57BL/6.NOD-Aec1Aec2 Mouse Model of Sjogren Syndrome develops independent of lacrimal dysfunction.

      6.2 Lacrimal functional unit/tear film

      The lacrimal gland and its efferent nerves in addition to the afferent nerves of the conjunctiva and cornea are a functional unit that produces the aqueous component of the tear film.
      • Rocha E.M.
      • Alves M.
      • Rios J.D.
      • Dartt D.A.
      The aging lacrimal gland: changes in structure and function.
      The tear reflex is dependent on intact nerve terminals in the cornea. Both the density of sensory nerve fibers and their function seem to be reduced in pSS compared to healthy subjects.
      • Bianciardi G.
      • Latronico M.E.
      • Traversi C.
      Entropy of corneal nerve fibers distribution observed by laser scanning confocal microscopy: A noninvasive quantitative method to characterize the corneal innervation in Sjogren's syndrome patients.
      ,
      • Villani E.
      • Magnani F.
      • Viola F.
      • et al.
      In vivo confocal evaluation of the ocular surface morpho-functional unit in dry eye.
      A functional impairment of corneal nerves can reduce eye symptoms from dry eye disease (DED) but simultaneously exterminates the desired tear reflex, thereby reducing tear production even more.
      • Meng I.D.
      • Kurose M.
      The role of corneal afferent neurons in regulating tears under normal and dry eye conditions.
      From the surface, the tear film consists of three layers—lipid, aqueous, and mucin—although it is debated whether there is a clear delineation between the middle aqueous and inner mucin layer.
      • Holland E.J.
      • Mannis M.J.
      • Lee W.B.
      The Tear Film: Anatomy, Structure and Function.
      The conjunctival goblet cells produce mucin that helps stabilize the tear film due to its hydrophilic character
      • Stevenson W.
      • Pugazhendhi S.
      • Wang M.
      Is the main lacrimal gland indispensable? Contributions of the corneal and conjunctival epithelia.
      in addition to secretion of immunoregulatory factors. Meibomian gland dysfunction is one of the most common causes of DED, characterized by chronic terminal duct obstructions and/or qualitative/quantitative changes in the glandular secretion. It is frequently, but not always, associated with pSS. In vivo confocal scanning microscopy and impression cytology studies show that the conjunctiva is frequently affected in pSS and has more squamous metaplasia, goblet cell loss, and mucous aggregates compared to healthy control subjects and patients with other causes of DED.
      • Menzies K.L.
      • Srinivasan S.
      • Prokopich C.L.
      • Jones L.
      Infrared imaging of meibomian glands and evaluation of the lipid layer in Sjogren's syndrome patients and nondry eye controls.
      ,
      • Sullivan D.A.
      • Dana R.
      • Sullivan R.M.
      • et al.
      Meibomian Gland Dysfunction in Primary and Secondary Sjögren Syndrome.
      ,
      • Tsubota K.
      • Xu K.P.
      • Fujihara T.
      • Katagiri S.
      • Takeuchi T.
      Decreased reflex tearing is associated with lymphocytic infiltration in lacrimal glands.
      PSS leads to reduced tear flow as a result of inflammatory destruction of acini and ducts, in addition to damage of secretomotor innervation. Keratinization of the conjunctival and corneal epithelia is seen in severe pSS.
      • Chen Y.T.
      • Nikulina K.
      • Lazarev S.
      • et al.
      Interleukin-1 as a phenotypic immunomodulator in keratinizing squamous metaplasia of the ocular surface in Sjogren's syndrome.
      Photophobia is common, and patients complain of functional vision loss from dryness and discomfort. In the early stages of disease, some patients may have increased tear flow due to changes in the composition of the tear fluid and lower viscosity. More vague symptoms are also associated with DED. Patients may complain of discomfort, itching eyes upon awakening, and low tolerance for harsh weather without explicit complaints of dry eye. Paradoxically, some patients with severe pSS-related DED do not complain of dry eyes despite objective signs, probably due to decreased ocular sensation due to advanced dry eye disease.
      An increase of proinflammatory cytokines is observed both on the ocular surface and in tears from patients with pSS when compared to DED patients and healthy subjects.
      • Lee S.Y.
      • Han S.J.
      • Nam S.M.
      • et al.
      Analysis of tear cytokines and clinical correlations in Sjogren syndrome dry eye patients and non-Sjogren syndrome dry eye patients.
      Tumor necrosis factor-α, interleukin(IL)-1α, IL-1β, IL-6, and IFN-γ are among the most frequently reported cytokines.
      • Caffery B.E.
      • Joyce E.
      • Heynen M.L.
      • Ritter 3rd, R.
      • Jones L.A.
      • Senchyna M.
      Quantification of conjunctival TNF-alpha in aqueous-deficient dry eye.
      ,
      • Li S.
      • Gallup M.
      • Chen Y.T.
      • McNamara N.A.
      Molecular mechanism of proinflammatory cytokine-mediated squamous metaplasia in human corneal epithelial cells.
      ,
      • Solomon A.
      • Dursun D.
      • Liu Z.
      • Xie Y.
      • Macri A.
      • Pflugfelder S.C.
      Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease.

      6.3 Other eye manifestations

      Vision-threatening diseases like uveitis, episcleritis/scleritis, optic neuropathy, retinal vasculitis, cicatrizing conjunctivitis, sterile corneal ulcer/infiltration, or corneal melt/perforation are more frequent in pSS.
      • Akpek E.K.
      • Mathews P.
      • Hahn S.
      • et al.
      Ocular and systemic morbidity in a longitudinal cohort of Sjogren's syndrome.
      It has been claimed that men with pSS are more vulnerable to ocular complications and extraglandular systemic manifestations compared with women,
      • Mathews P.M.
      • Hahn S.
      • Hessen M.
      • et al.
      Ocular complications of primary Sjogren syndrome in men.
      although this is debated.
      • Ramos-Casals M.
      • Solans R.
      • Rosas J.
      • et al.
      Primary Sjögren syndrome in Spain: clinical and immunologic expression in 1010 patients.
      Thus, collaboration between ophthalmologists and other physicians is needed to ensure an appropriate multidisciplinary approach to the pSS patient.

      7. Eye-diagnostic tools for investigation of pSS

      7.1 Symptoms

      Eye dryness, itching, and pain are often the first symptoms that lead to investigation of possible pSS. Validated questionnaires are available to assess DED; for example, the Oxford scheme, area–dens combination index, and the National Eye Institute–recommended system.
      • Grubbs Jr., J.R.
      • Tolleson-Rinehart S.
      • Huynh K.
      • Davis R.M.
      A review of quality of life measures in dry eye questionnaires.
      These grading scores all have excellent interobserver reliability.
      • Sook Chun Y.
      • Park I.K.
      Reliability of 4 clinical grading systems for corneal staining.
      The American-European Consensus Group classification criteria include three questions relevant to the eye (e.g., “Do you have a recurrent sensation of sand or gravel in the eyes?”).
      • Vitali C.
      • Bombardieri S.
      • Jonsson R.
      • et al.
      Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group.
      Patient-reported dryness is poorly correlated with the objective measures of glandular function in pSS.
      • Alunno A.
      • Bartoloni E.
      • Valentini V.
      • et al.
      Discrepancy between subjective symptoms, objective measures and disease activity indexes: the lesson of primary Sjögren's syndrome.
      The Ocular Surface Disease Index is a frequently used questionnaire that consists of 12 questions probing dry eye symptoms. This distinguishes between normal subjects and those having dry eye and can be used to measure the severity of the eye symptoms and their effect on visual function. Using Rasch analysis, Dougherty and coworkers, however, found that the response category structures are not ideal and suggested that the test should be optimized.
      • Dougherty B.E.1
      • Nichols J.J.
      • Nichols K.K.
      Rasch analysis of the Ocular Surface Disease Index (OSDI).
      Other questionnaires (https://eyewiki.aao.org) have been developed like the Symptom Assessment In Dry Eye (SANDE), which include two visual analog scales assessing the frequency and severity of dry eye syndrome
      • Schaumberg D.A.
      • Gulati A.
      • Mathers W.D.
      • et al.
      Development and validation of a short global dry eye symptom index.
      and Dry Eye Questionnaire which measures several symptoms using the four variables intensity in the morning, intensity late in the day, degree of irritation, and frequency.
      • Chalmers R.L.
      • Begley C.G.
      • Caffery B.
      Validation of the 5-Item Dry Eye Questionnaire (DEQ-5): Discrimination across self-assessed severity and aqueous tear deficient dry eye diagnoses.
      These tests are less frequently used compared to Ocular Surface Disease Index.

      7 .2 Lacrimal function/function of the tear film

      Schirmer test is a standard assessment for measures of aqueous tear production (Fig. 4, Table 4). Though it can be shortly troublesome for the patient, it is safe, easy to perform, and inexpensive (Fig. 3). The correlation between DED symptoms and Schirmer test is poor, and there is some controversy on its repeatability, especially for the higher scores.
      • Nichols K.K.
      • Mitchell G.L.
      • Zadnik K.
      The repeatability of clinical measurements of dry eye.
      ,
      • Sullivan B.D.
      • Crews L.A.
      • Messmer E.M.
      • et al.
      Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications.
      ,
      • Vitale S.
      • Goodman L.A.
      • Reed G.F.
      • Smith J.A.
      Comparison of the NEI-VFQ and OSDI questionnaires in patients with Sjogren's syndrome-related dry eye.
      Figure thumbnail gr4
      Fig. 4Schirmer I test: A small strip of filter paper is placed inside the lower eyelid. The eyes are closed, and after 5 minutes, the length (mm) of moistening of the filter paper is measured. More than 10 mm moisture is considered normal. This variant is recommended for use in pSS criteria. Schirmer II test: Sometimes a topical anesthetic is placed into the eye before the filter paper. This ensures that only basal tear secretion is being measured. pSS, primary Sjögren syndrome.
      Van Bijsterveld's ocular score uses rose bengal to stain abnormal areas on the cornea and conjunctiva, mainly due to uncoating of mucin.
      • Machado L.M.
      • Castro R.S.
      • Fontes B.M.
      Staining patterns in dry eye syndrome: rose bengal versus lissamine green.
      ,
      • van Bijsterveld O.P.
      Diagnostic tests in the Sicca syndrome.
      This is the only staining score explicitly mentioned in the American-European Consensus Group classification criteria. The rose bengal dye is nowadays often replaced by lissamine green for conjunctival staining and fluorescein for corneal staining, as these are better tolerated.
      • Whitcher J.P.
      • Shiboski C.H.
      • Shiboski S.C.
      • et al.
      A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjogren's Syndrome International Registry.
      High reliability in grading by the ocular staining score has been found among trained ophthalmologists.
      • Rose-Nussbaumer J.
      • Lietman T.M.
      • Shiboski C.H.
      • et al.
      Inter-grader Agreement of the Ocular Staining Score in the Sjogren's International Clinical Collaborative Alliance (SICCA) Registry.
      The latest classification criteria for pSS use only objective eye findings (in at least one eye): ocular staining score ≥5 or van Bijsterveld's test score ≥4 or Schirmer test ≤5 mm/5 min.
      • Shiboski C.H.
      • Shiboski S.C.
      • Seror R.
      • et al.
      2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjogren's syndrome: A consensus and data-driven methodology involving three international patient cohorts.
      Tear breakup time is an indicator of tear film stability, and commonly used in the assessment of DED. Five to ten μl of fluorescein is installed, the patient is asked to look straight ahead, and the tear film is observed under blue light. The time between the last blink and the first dry spot in the tear film is equal to the tear breakup time. Normal subjects show variability in tear breakup time. More than 10 seconds is considered normal, 5–10 seconds marginal, and less than 5 seconds abnormal.
      Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommitte of the International Dry Eye workshop (2007).
      ,
      • Nichols J.J.
      • Nichols K.K.
      • Puent B.
      • Saracino M.
      • Mitchell G.L.
      Evaluation of tear film interference patterns and measure of tear break-up time.
      It has been proposed that a combination of the Ocular Surface Disease Index, tear breakup time, and corneal fluorescein staining is the best approach to distinguish SS from other causes of DED.
      • Garcia D.M.
      • Reis de Oliveira F.
      • Módulo C.M.
      • et al.
      Is Sjögren's syndrome dry eye similar to dry eye caused by other etiologies? Discriminating different diseases by dry eye tests.
      More recently, in vivo confocal microscopy has been used to demonstrate the effect of dry eye at a cellular level,
      • Lee O.L.
      • Tepelus T.C.
      • Huang J.
      • et al.
      Evaluation of the corneal epithelium in non-Sjőgren's and Sjőgren's dry eyes: an in vivo conofocal microscopy study using HRT III RCM.
      including decreased conjunctival and corneal epithelial cell density, corneal nerve changes, and conjunctival squamous metaplasia.
      • Kojima T.
      • Matsumoto Y.
      • Dogru M.
      • Tsubota K.
      The application of in vivo laser scanning confocal microscopy as a tool of conjunctival in vivo cytology in the diagnosis of dry eye ocular surface disease.
      Meibography is a technique to observe the Meibomian gland morphological structure. Reduced Meibomian gland function as assessed by infrared meibography has been reported in pSS.
      • Chen X.
      • Utheim Ø.A.
      • Xiao J.
      • et al.
      Meibomian gland features in a Norwegian cohort of patients with primary Sjőgren`s syndrome.

      7.3 Imaging of lacrimal glands

      MRI and CT scans are investigative techniques mostly used to differentiate between benign and malignant lesions, often when lacrimal glands present with unilateral swelling. There is an increased incidence of B-cell lymphomas in pSS, and rarely these occur in the lacrimal gland.
      • Palamar M.
      • Ozsan N.
      • Sahin F.
      Bilateral Lacrimal Gland Lymphoma in Sjőgren Syndrome.
      In this situation, MRI is superior to CT, but there is a paucity of studies regarding its potential use as a diagnostic tool in pSS. MRI may be used to measure inflammation, glandular size, and fat deposition, and it is possible that newer and more advanced MRI modalities can be of diagnostic benefit in pSS.
      • Izumi M.
      • Eguchi K.
      • Uetani M.
      • et al.
      MR features of the lacrimal gland in Sjogren's syndrome.
      ,
      • Kawai Y.
      • Sumi M.
      • Kitamori H.
      • Takagi Y.
      • Nakamura T.
      Diffusion-weighted MRI microimaging of the lacrimal glands in patients with Sjogren's syndrome.
      ,
      • Tonami H.
      • Matoba M.
      • Yokota H.
      • Higashi K.
      • Yamamoto I.
      • Sugai S.
      CT and MR findings of bilateral lacrimal gland enlargement in Sjogren syndrome.

      7.4 Ultrasound (sonography)

      Salivary gland ultrasonography is widely used to assess major salivary gland involvement and response to treatment.
      • Baldini C.
      • Luciano N.
      • Tarantini G.
      • et al.
      Salivary gland ultrasonography: a highly specific tool for the early diagnosis of primary Sjogren's syndrome.
      ,
      • Zhou M.
      • Song S.
      • Wu S.
      • et al.
      Diagnostic accuracy of salivary gland ultrasonography with different scoring systems in Sjőgren's syndrome: a systematic review and meta-analysis.
      The literature concerning ultrasound of lacrimal glands in pSS is scant,
      • Cornec D.
      • Saraux A.
      • Jousse-Joulin S.
      • et al.
      The Differential Diagnosis of Dry Eyes, Dry Mouth, and Paratidomegaly: A Comprehensive Review.
      ,
      • Giovagnorio F.
      • Pace F.
      • Giorgi A.
      Sonography of lacrimal glands in Sjogren syndrome.
      but the method has been used to detect as used in other conditions affecting the lacrimal glands, such as solid lesions and dacryocysts.
      • Machado M.A.C.
      • Silva J.A.F.
      • Garcia E.A.
      • Allemann N.
      Ultrasound parameters of normal lacrimal sac and chronic dacrocystitis.
      ,
      • Takagi Y.
      • Nakamura H.
      • Origuchi T.
      • et al.
      IgG4-related Mikulicz`s disease: ultrasoundography of the salivary and lacrimal glands for monitoring the efficacy of corticosteroid therapy.
      Elastography is used to detect fibrosis in the pancreas and should be explored in pSS.

      8. Ocular treatment options

      Ocular treatment for DED can be divided into topical, mechanical, systemic, and surgical Table 5. Only some of these options have been investigated specifically for pSS.
      Table 5Treatment options for dry eye in pSS
      Topical/local treatment
       Acetylcysteine significantly improved conjunctival and corneal staining, mucous shreds, and filaments, but subjective ailments showed no significant difference.
      • Absolon M.J.
      • Brown C.A.
      Acetylcysteine in kerato-conjunctivitis sicca.
      ,
      Also includes patients with other causes than pSS for having dry eyes.
      ,
      Does not distinguish between pSS and sSS.
       NSAIDs can be useful in resolving symptoms of ocular discomfort in SS patients.
      • Aragona P.
      • Stilo A.
      • Ferreri F.
      • Mobrici M.
      Effects of the topical treatment with NSAIDs on corneal sensitivity and ocular surface of Sjogren's syndrome patients.
      Does not distinguish between pSS and sSS.
       Topical corticosteroids, topical autologous serum, and topical cyclosporine gave a significant improvement in visual acuity and fluorescein score but did not affect Schirmer's score, tear breakup time, or rose bengal score.
      • Hyon J.Y.
      • Lee Y.J.
      • Yun P.Y.
      Management of ocular surface inflammation in Sjogren syndrome.
       Topical corticosteroids combined with topical artificial tear substitute had a beneficial effect on the subjective and some objective parameters when compared to the combination of NSAIDs and artificial tear substitute in SS patients.
      • Avunduk A.M.
      • Avunduk M.C.
      • Varnell E.D.
      • Kaufman H.E.
      The comparison of efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on dry eye patients: a clinical and immunocytochemical study.
      Also includes patients with other causes than pSS for having dry eyes.
       Treatment using topical corticosteroid (0.1% fluorometholone) provided faster improvement in the symptoms of ocular dryness in SS patients compared with topical cyclosporine 0.5%. But there was significant improvement in Ocular Surface Disease Index score for both groups.
      • Lin T.
      • Gong L.
      Topical fluorometholone treatment for ocular dryness in patients with Sjogren syndrome: a randomized clinical trial in China.
      Does not distinguish between pSS and sSS.
       Topical 0.05% cyclosporine A is an effective treatment option for keratoconjunctivitis sicca due to pSS.
      • Deveci H.
      • Kobak S.
      The efficacy of topical 0.05 % cyclosporine A in patients with dry eye disease associated with Sjogren's syndrome.
      Does not distinguish between pSS and sSS.
       Topical 0.03% tacrolimus eye drop improved tear stability and ocular surface status in cases of inflammatory or SS-related dry eye.
      • Moscovici B.K.
      • Holzchuh R.
      • Sakassegawa-Naves F.E.
      • et al.
      Treatment of Sjogren's syndrome dry eye using 0.03% tacrolimus eye drop: Prospective double-blind randomized study.
      Does not distinguish between pSS and sSS.
       Lifitegrast improved inferior corneal staining score and subjective complaints of DED.
      • Holland E.J.
      • Whitley W.O.
      • Sall K.
      • et al.
      Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials.
      Does not specify whether the patients had pSS or isolated DED.
      Mechanical/surgical treatment
       Punctal plugs improved tear film stability and elongate the breakup time better than artificial tears.
      • Qiu W.
      • Liu Z.
      • Ao M.
      • Li X.
      • Wang W.
      Punctal plugs versus artificial tears for treating primary Sjogren's syndrome with keratoconjunctivitis SICCA: a comparative observation of their effects on visual function.
      Includes only patients with pSS.
       Thermodynamic punctum plug insertion can be effective for treatment of severe aqueous tear deficiency when preservative-free tears are not sufficient.
      • Egrilmez S.
      • Aslan F.
      • Karabulut G.
      • Kabasakal Y.
      • Yagci A.
      Clinical efficacy of the SmartPlug in the treatment of primary Sjogren's syndrome with keratoconjunctivitis sicca: one-year follow-up study.
      Includes only patients with pSS.
       Gas-permeable scleral contact lenses had a positive impact on tear osmolarity and van Bijsterveld score and symptoms.
      • Weber S.L.P.
      • De Souza R.B.
      • Gomes J.A.P.
      • Hofling-Lima A.L.
      The Use of the Esclera Scleral Contact Lens in the Treatment of Moderate to Severe Dry Eye Disease.
      Also includes patients with other causes than pSS for having dry eyes.
       Injection of platelet-enriched plasma adjacent to the lacrimal gland was found to be safe and effective in increasing lacrimal production and improving ocular staining, secondary to severe dry eye.
      • Avila M.Y.
      Restoration of human lacrimal function following platelet-rich plasma injection.
      Also includes patients with other causes than pSS for having dry eyes.
       Surgical techniques using mayor salivary glands to provide a substitute for tears have been reported.
      • Guerrissi J.O.
      • Belmonte J.
      Surgical treatment of dry eye syndrome: conjunctival graft of the minor salivary gland.
      Also includes patients with other causes than pSS for having dry eyes.
       Implanting a pump-reservoir unit under the subcutaneous tissue of the abdomen to provide artificial tears to the ocular surface dramatically improved signs and symptoms of DED.
      • Murube J.
      • Murube E.
      • Chenzhuo L.
      • Rivas L.
      Subcutaneous abdominal artificial tears pump-reservoir for severe dry eye.
      Also includes patients with other causes than pSS for having dry eyes.
      Systemic treatment
       Hydroxychloroquine show conflicting evidence on effect on ocular symptoms.
      • Gottenberg J.E.
      • Ravaud P.
      • Puechal X.
      • et al.
      Effects of hydroxychloroquine on symptomatic improvement in primary Sjogren syndrome: the JOQUER randomized clinical trial.
      • Yavuz S.
      • Asfuroglu E.
      • Bicakcigil M.
      • Toker E.
      Hydroxychloroquine improves dry eye symptoms of patients with primary Sjogren's syndrome.
      Includes only patients with pSS.
       Mycophenolate sodium treatment resulted in subjective improvement of ocular dryness and a reduced demand for artificial tear supplementations. No significant alterations of objective parameters for dryness of eyes were observed.
      • Willeke P.
      • Schluter B.
      • Becker H.
      • Schotte H.
      • Domschke W.
      • Gaubitz M.
      Mycophenolate sodium treatment in patients with primary Sjogren syndrome: a pilot trial.
       Pilocarpine tablets gave improvement of tear meniscus height and symptoms for dryness.
      • Ibrahim O.M.
      • Dogru M.
      • Kawashima S.
      • Wakamatsu T.H.
      • Tsubota K.
      • Fujishima H.
      Visante optical coherence tomography and tear function test evaluation of cholinergic treatment response in patients with sjőgren syndrome.
      Includes only patients with pSS.
       Systemic omega-6 essential fatty acid gave a statistically significant improvement of corneal fluorescein staining and symptoms of DED.
      • Aragona P.
      • Bucolo C.
      • Spinella R.
      • Giuffrida S.
      • Ferreri G.
      Systemic omega-6 essential fatty acid treatment and pge1 tear content in Sjogren's syndrome patients.
      Includes only patients with pSS.
       A systematic review and meta-analysis of rituximab for pSS found no significant differences between the groups on Schirmer's test, and only one study significantly improved the lissamine green score.
      • Souza F.B.
      • Porfirio G.J.
      • Andriolo B.N.
      • Albuquerque J.V.
      • Trevisani V.F.
      Rituximab Effectiveness and Safety for Treating Primary Sjogren's Syndrome (pSS): Systematic Review and Meta-Analysis.
      Includes only patients with pSS.
       No significant changes in lacrimal function were found in pSS during infliximab therapy.
      • Mariette X.
      • Ravaud P.
      • Steinfeld S.
      • et al.
      Inefficacy of infliximab in primary Sjogren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjogren's Syndrome (TRIPSS).
      Includes only patients with pSS.
       No significant changes in lacrimal function were found in pSS during belimumab therapy.
      • De Vita S.
      • Quartuccio L.
      • Seror R.
      • et al.
      Efficacy and safety of belimumab given for 12 months in primary Sjogren's syndrome: the BELISS open-label phase II study.
      Includes only patients with pSS.
      pSS, primary Sjögren syndrome.
      The follow-up time was often short (1–3 months) and/or poorly specified in the topical/local treatment group.
      Also includes patients with other causes than pSS for having dry eyes.
      Does not distinguish between pSS and sSS.
      Does not specify whether the patients had pSS or isolated DED.
      § Includes only patients with pSS.

      8.1 Tear substitutes

      First-line therapy is lubrication with tear substitutes, followed by anti-inflammatory eye drops. Finding the optimal lubrication is a matter of trial and error, as none of the tear supplements is clearly superior.
      • Ciurtin C.
      • Ostas A.
      • Cojocaru V.M.
      • Walsh S.B.
      • Isenberg D.A.
      Advances in the treatment of ocular dryness associated with Sjogrens syndrome.
      ,
      • Foulks G.N.
      • Forstot S.L.
      • Donshik P.C.
      • et al.
      Clinical guidelines for management of dry eye associated with Sjogren disease.
      Industry-sponsored studies tend to favor the artificial tears of the sponsoring company.
      • Moshirfar M.
      • Pierson K.
      • Hanamaikai K.
      • Santiago-Caban L.
      • Muthappan V.
      • Passi S.F.
      Artificial tears potpourri: a literature review.
      Different lubricants vary in their viscosity, lipid content, and level of hydration. Active ingredients include hydroxypropyl methylcellulose, carboxy methylcellulose, polyvinyl alcohol, hyaluronic acid, and liquid polyols.
      • Moshirfar M.
      • Pierson K.
      • Hanamaikai K.
      • Santiago-Caban L.
      • Muthappan V.
      • Passi S.F.
      Artificial tears potpourri: a literature review.
      Artificial tears with stronger mucoadhesive properties showed best effect with regard to contrast sensitivity in pSS patients,
      • Zhang Y.
      • Potvin R.
      • Gong L.
      A study of the short-term effect of artificial tears on contrast sensitivity in patients with Sjogren's syndrome.
      while data from the British Sjögren's Syndrome Association suggest a general preference toward viscous preparations being instilled less frequently and lasting longer.
      • Bhojwani R.
      • Cellesi F.
      • Maino A.
      • Jalil A.
      • Haider D.
      • Noble B.
      Treatment of dry eye: an analysis of the British Sjogren's syndrome association comparing substitute tear viscosity and subjective efficacy.
      Solutions that are more viscous offer longer relief but cause blurred vision and discomfort. Ophthalmic inserts containing, for example, hydoxypropyl cellulose may be used if the patients seek a longer lasting alternative.
      • Luchs J.I.
      • Nelinson D.S.
      • Macy J.I.
      Group LaCS
      Efficacy of hydroxypropyl cellulose ophthalmic inserts (LACRISERT) in subsets of patients with dry eye syndrome: findings from a patient registry.
      This allows for the inserts to dissolve throughout the day, and thereby provide continuous lubrication.
      • Kumari A.
      • Sharma P.K.
      • Garg V.K.
      • Garg G.
      Ocular inserts - Advancement in therapy of eye diseases.
      Preservative-free artificial tears are recommended to avoid local toxicity.
      • Coursey T.G.
      • De Paiva C.S.
      Managing Sjogren's Syndrome and non-Sjogren Syndrome dry eye with anti-inflammatory therapy.
      The common preservative, benzalkonium chloride, is known to cause tear film instability, ocular surface changes, epithelial apoptosis, conjunctival inflammation, and subconjunctival fibrosis.
      • Fraunfelder F.T.
      • Sciubba J.J.
      • Mathers W.D.
      The role of medications in causing dry eye.
      Healthy natural tears have a plethora of components such as nutrients, vitamins, growth factors, and fibronectin that are also present in serum. Autologous serum can be prepared as eye drops and is found to inhibit the release of proinflammatory cytokines and increase the number of goblet cells and mucin in conjunctiva. Eye drops made from autologous serum may protect the ocular surface against damage in pSS patients
      • Pan Q.
      • Angelina A.
      • Zambrano A.
      • et al.
      Autologous serum eye drops for dry eye.
      and is effective as treatment for severe pSS. There are standard kits approved by the Federal Drug Administration to prepare plasma-related eye drops; however, local challenges with production may limit its use in some areas of the world.

      8 .2 Anti-inflammatory eye drops

      The primary effect of NSAIDs is cyclooxygenase inhibition, thereby impairing production of proinflammatory prostaglandins, but eye drops containing NSAIDs are seldom used for treating DED.
      • Akpek E.K.
      • Lindsley K.B.
      • Adyanthaya R.S.
      • Swamy R.
      • Baer A.N.
      • McDonnell P.J.
      Treatment of Sjogren's syndrome-associated dry eye an evidence-based review.
      ,
      • Sy A.
      • O'Brien K.S.
      • Liu M.P.
      • et al.
      Expert opinion in the management of aqueous Deficient Dry Eye Disease (DED).
      Topical corticosteroids main mechanism is to switch off proinflammatory genes.
      • Rhen T.
      • Cidlowski J.A.
      Antiinflammatory action of glucocorticoids--new mechanisms for old drugs.
      Long-term use is not recommended because of side effects like glaucoma and cataract, as well as reactivation of herpes simplex virus. The guidelines of the US Federal Drug Administration limit the use of topical steroids to two weeks.

      8.3 Immunosuppressive eye drops

      Cyclosporine and tacrolimus inhibit calcium-dependent events in T-cells, thereby inhibiting the migration of immune cells, the activation of T-cells, and thus the release of proinflammatory cytokines.
      • Matsuda S.
      • Koyasu S.
      Mechanisms of action of cyclosporine.
      ,
      • Moscovici B.K.
      • Holzchuh R.
      • Sakassegawa-Naves F.E.
      • et al.
      Treatment of Sjogren's syndrome dry eye using 0.03% tacrolimus eye drop: Prospective double-blind randomized study.
      Cyclosporine comes as Restasis® (0.05%) and Ikervis® (0.1%) and may take weeks of administration before an effect occurs. Approximately one in five patients report discomfort upon installation, which limits their tolerance and utility. Cyclosporine was superior to vehicle for inflammation reduction and change in fluorescein staining of the cornea after 6 months use in DED,
      • Leonardi A.
      • Van setten G.
      • Amrane M.
      • et al.
      Efficacy and safety of 0.1% cyclosporine A cationic emulsion in the treatment of severe dry eye disease: a multicenter randomized trial.
      but we are not aware of clinical trials in humans with head-to-head comparison of cyclosporine and tacrolimus for DED. A combination of different anti-inflammatory eye drops may be needed to optimize the treatment of DED.
      • Lin T.
      • Gong L.
      Topical fluorometholone treatment for ocular dryness in patients with Sjogren syndrome: a randomized clinical trial in China.

      8.4 Systemic treatment

      Systemic drug treatment with conventional immunomodulating drugs has not convincingly demonstrated beneficial effects on the ocular manifestations of pSS.
      • Saraux A.
      • Pers J.O.
      • Devauchelle-Pensec V.
      Treatment of primary Sjőgren syndrome.
      Pilocarpine and cevimeline are cholinergic and parasympathomimetic/anti-muscarinic agents, respectively. Systemic treatment with these drugs is not approved for DED, although some patients find improvement. Biological drugs are not approved for treatment of pSS but are used off label in severe cases and have been tested in clinical trials. Efficacy for ocular manifestations have not been demonstrated for belimumab,
      • De Vita S.
      • Quartuccio L.
      • Seror R.
      • et al.
      Efficacy and safety of belimumab given for 12 months in primary Sjogren's syndrome: the BELISS open-label phase II study.
      a monoclonal antibody against B-cell activating factor or for the tumor necrosis factor-α inhibitor infliximab,
      • Mariette X.
      • Ravaud P.
      • Steinfeld S.
      • et al.
      Inefficacy of infliximab in primary Sjogren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjogren's Syndrome (TRIPSS).
      while the CD20-inhibitory monoclonal antibody rituximab seems to have a discrete effect in improving lacrimal gland function, according to a meta-analysis.
      • Souza F.B.
      • Porfirio G.J.
      • Andriolo B.N.
      • Albuquerque J.V.
      • Trevisani V.F.
      Rituximab Effectiveness and Safety for Treating Primary Sjogren's Syndrome (pSS): Systematic Review and Meta-Analysis.
      The novel anti-CD40 monoclonal antibody CFZ533 was tested in 41 patients with clinically active pSS with results suggesting efficacy.
      • Fisher B.
      • Zeher M.
      • Ng W.F.
      • et al.
      The Novel Anti-CD40 Monoclonal Antibody CFZ533 Shows Beneficial Effects in Patients with Primary Sjögren's Syndrome: A Phase IIa Double-Blind, Placebo-Controlled Randomized Trial.
      DED was not assessed, but patients did report improvement in European Sjőgren's Syndrome Patient Reported Index,
      • Seror R.
      • Ravaud P.
      • Mariette X.
      • et al.
      EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjogren's syndrome.
      which includes symptoms from dry eyes. In addition, epratuzumab, a humanized anti-CD22 monoclonal antibody, was tested in an open-label phase I/II study for pSS. Fifty-three percent of patients responded with improvement in a composite endpoint that included Schirmer testing.
      • Steinfeld S.D.
      • Tant L.
      • Burmester G.R.
      • et al.
      Epratuzumab (humanized anti-CD22 antibody) in primary Sjőgren's syndrome: an open-label phase I/II study.

      8.5 Surgical treatment

      Minor surgical procedures like punctal plug, punctal occlusion, and tarsorrhaphy may have positive effects and are, in our experience, beneficial for patients. More invasive procedures like major salivary gland transplantation or the use of subcutaneous reservoirs should be reserved for the most severe cases.
      • De Andres J.
      • Garcia-Delpech S.
      • Perez V.L.
      • et al.
      Bilateral infusion pump implants as therapy for refractory corneal ulcers in a patient with CREST syndrome: an interdisciplinary approach.

      8.6 Newer drugs

      Lifitegrast (Xiidra®) was recently (2016) approved by the FDA as the first new DED drug in more than 13 years. Lifitegrast works by blocking the interaction between intercellular adhesion molecule-1 and lymphocyte functional associated antigen-1, which is critical for the migration of antigen-presenting cells to the lymph nodes as well as CD4+ T cell activation and migration to the ocular surface. In four large multicenter, randomized, controlled trials, lifitegrast has proven to be effective in controlling both the signs and symptoms of dry eye with minimal side effects.
      • Holland E.J.
      • Whitley W.O.
      • Sall K.
      • et al.
      Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials.
      Many new drugs are in the pipeline for DED treatment, and by February, 2019, 495 studies were listed on ClinicalTrials.gov under this topic.

      9. Methods of literature search

      A PubMed search was performed to identify relevant articles (with no time restrictions) using the search terms: “primary Sjőgren's syndrome” in combination with “dry eye” or “DED” or ophtalmology” or “lacrimal” or “keratoconjunctivitis sicca” or “tear”. Searches were performed on January 12, 2017 and updated on February 28, 2019.
      Articles were excluded if they were not referenced in English. Emphasis was given to RCTs, meta-analysis, original research, and prospective studies.

      10. Disclosures

      The authors report no commercial or proprietary interest in any product or concept discussed in this article.

      Acknowledgments

      The authors are grateful to Dr. Markéta Jenssen for performing lacrimal gland biopsies, Professor Emilius Janssen for preparing photographs of lacrimal gland tissue, and Professor Kathrine Skarstein for the illustration of focus score in minor salivary gland tissue biopsies. Professor Malin V. Jonsson has been of great help for the description of focus scoring and has contributed photographs of germinal center–like structures in minor salivary glands.

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