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Background:Several large randomised controlled trials (RCTs) in primary Sjögren’s syndrome (pSS) failed to demonstrate drug efficacy.1-4 Many of these trials used ESSDAI as primary endpoint, showing large but similar response rates in active treatment and placebo groups.1,3,4 Given the heterogeneous nature of pSS, there is need for a composite endpoint including multiple clinically relevant parameters.Objectives:To develop and validate the Composite of Relevant Endpoints in Sjögren’s Syndrome (CRESS).Methods:A multidisciplinary team of pSS experts selected clinically relevant items and measurements to include in the CRESS. Definition of response of CRESS items was based on clinical relevance, previously defined minimal clinically important improvement (MCII) and data of the single-centre ASAP-III (abatacept) trial.1 CRESS was validated in three independent RCTs: TRACTISS (rituximab) trial2, multi-centre abatacept trial3 and ETAP (tocilizumab) trial4. CRESS response rates were assessed at the primary endpoint visit of all four trials.Results:Five complementary items were selected to form CRESS: systemic disease activity, patient-reported symptoms, tear gland, salivary gland and serological item. Definition of response per item is presented in Table 1. Total CRESS response was defined as response on ≥3 of 5 items. Since not all trials have ocular staining score or salivary gland ultrasonography (SGUS) available, the concise CRESS (cCRESS) was developed simultaneously, leaving Schirmer’s test and unstimulated whole saliva flow for the tear and salivary gland items, respectively. In the ASAP-III trial, CRESS response rates were 24/40 (60%) for abatacept vs. 7/39 (18%) for placebo at week 24 (pTable 1.CRESS items and definition of responseItemsMeasurementsDefinition of responseSystemic disease activityClinESSDAIScorePatient-reported symptomsESSPRIDecrease of ≥1 point or ≥15%Tear gland*Schirmer/OSS**-If abnormal Schirmer (≤5 mm) at baseline: increase of ≥5 mm in Schirmer-Or if abnormal OSS (≥3 points) at baseline: decrease ≥2 points in OSS-Or if both Schirmer/OSS normal scores at baseline: no change to abnormal in bothSalivary gland*UWS/SGUSIncrease of ≥25% in UWS (or if score is 0 at baseline, any increase)Or decrease of ≥25% in total Hocevar score (SGUS)SerologicalRF/IgGDecrease of ≥25% in RFOr decrease of ≥10% in IgGCRESS responderResponder on ≥3 of 5 itemsOcular Staining Score (OSS), Unstimulated whole salivary flow (UWS), Salivary gland ultrasonography (SGUS), Rheumatoid factor (RF), Immunoglobuline G (IgG)*Concise CRESS (cCRESS): CRESS without OSS and SGUS, leaving Schirmer and UWS for tear and salivary gland items, respectively**Mean of both eyesIn the external validation trials, cCRESS response rates for TRACTISS were: 33/67 (49%) rituximab vs. 20/66 (30%) placebo at week 48 (p=0.026). CRESS response rates (without SGUS) for the multi-centre abatacept trial were: 41/92 (45%) abatacept vs. 30/95 (32%) placebo at week 24 (p=0.067). cCRESS response rates (without rheumatoid factor) for ETAP were: 10/55 (18%) tocilizumab vs. 13/55 (24%) placebo at week 24 (p=0.482) (Figure 1A-D). Compared to ESSDAI MCII of ≥3 points decrease, CRESS was able to approximately halve placebo response rates in RCTs with high baseline ESSDAI scores (>5) (Figures 1E-H).Conclusion:CRESS shows lower placebo response rates compared to ESSDAI MCII, which is crucial for demonstrating treatment efficacy. With the CRESS, higher response rates in abatacept and rituximab treated patients compared to placebo were found in RCTs which previously showed negative primary endpoint results. CRESS confirmed that no differences were found for almost all outcome measures between tocilizumab and placebo,4 with low response rates. The CRESS is a well-balanced, feasible, composite endpoint for use in clinical trials in pSS patients.References:[1]Van Nimwegen 2020;9913(19):1–11[2]Bowman 2017;69(7):1440–50[3]Baer (doi:218599)[4]Felten (doi:21846)Acknowledgements:The authors would like to acknowledge all contributors of the included trials.Disclosure of Interests:Suzanne Arends: None declared, Liseth de Wolff: None declared, Jolien F. van Nimwegen Speakers bureau: Bristol Myers Squibb, Consultant of: Bristol Myers Squibb, Gwenny M. Verstappen: None declared, Jelle Vehof: None declared, Michele Bombardieri Consultant of: MedImmune, GlaxoSmithKline, Grant/research support from: MedImmune, Simon J. Bowman Consultant of: AstraZenecea/MedImmune, Bristol Myers Squibb, Celgene, Eli Lilly, Glenmark, GlaxoSmithKline, MTPharma, Novartis, Ono, Pfizer, Takeda, UCB, XTLBio, Elena Pontarini: None declared, Alan Baer Consultant of: Bristol Myers Squibb, Sanofi, VielaBio, Novartis, Marleen Nys Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Jacques-Eric Gottenberg Grant/research support from: Bristol Myers Squibb, Pfizer, Renaud FELTEN: None declared, Neelanjana Ray Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Arjan Vissink: None declared, Frans G.M. Kroese Speakers bureau: Bristol Myers Squibb, Roche and Janssen-Cilag, Consultant of: Bristol Myers Squibb, Grant/research support from: Unrestricted grants from Bristol Myers Squibb, Hendrika Bootsma Speakers bureau: Bristol Myers Squibb and Novartis, Consultant of: Bristol Myers Squibb, Roche, Novartis, Medimmune, Union Chimique Belge, Grant/research support from: Unrestricted grants from Bristol Myers Squibb and Roche

Durch die Untersuchung der Harder'schen Druse und der Tranendruse beim Hirsch fanden wir bei einem Hirsch einen Tumor an der Tranendruse. Durch die pathohistologischen Befunde und durch verschiedene Farbungsmethoden (Hamatoxylin-Eosin, Trichrom-Methode nachMallory, Kombinationsfarben mit Alzianblau pH 2,5 und PAS-Methode sowie Immunozytochemischer Methode) stellten wir fest, das die Tumorzellen uberwiegend polygonal sind und eine ausgepragte Karyorrhexie sowie Karyopyknose aufweisen. Auserdem handelt es sich um ein Adenom der Tranendruse, das epithelialer Herkunft ist.

Third eyelid covers the medial canthus of the eye and consists of T-shaped flap like cartilage and tear gland, both are helpful in protection of eye. Prolapsed gland appeared as a dark pink to reddish mass and misdiagnosed as a tumor and treated like a tumor in which gland is excised out. The present report describes a case of cherry eye (prolapse of third eyelid) in 18 months old Cocker spaniel. The case was treated by adopting massage method to replace the third eyelid back to its place followed by administration of eye drops. The treatment method was successful as there was no recurrence when the animal was followed-up for 3 months.

The lysozyme concentration in human tears is an important parameter for tear gland function. The decline of lysozyme in tears reflects lacrimal gland destruction. In Sjögren's patients, lacrimal gland destruction parallels labial salivary gland destruction. The objective of this study was to determine whether human tear lysozyme that was frozen on Schirmer strips at -20 degrees C for several years maintained activity and whether there was a linear relation with inflammatory changes in labial salivary glands.A total of 200 frozen Schirmer strips were processed. They were collected from 20 randomly selected patients each year of five consecutive years, all attending the UCSF Sjögren's Clinic. The tear lysozyme in the Schirmer strips was measured by a colorimetric assay. The average lysozyme concentration each year was calculated and compared. One third of the patients underwent labial salivary gland biopsy. The correlation was calculated between the tear lysozyme concentration and the lymphocytic focus scores in biopsy specimens.No significant difference of average lysozyme concentration in the Schirmer strips was found when the five different years of collection were compared. The linear relation between the tear lysozyme concentrations and the focus score in labial salivary gland biopsies showed a coefficient of r = -0.41. The linear relation between other diagnostic measurements, like Schirmer test, tear breakup time, or rose bengal staining pattern, and the focus score was lower.Human tear lysozyme in Schirmer strips can be stored at -20 degrees C for at least five years. There is little difference in lysozyme activity of frozen compared to unfrozen specimens. The lysozyme concentration in tears correlates better with the lymphocytic focus score in labial salivary gland biopsy than does clinical assessment and is therefore a parameter for the actual degree of tear gland destruction.

Tear lysozyme and tear lactoferrin are enzymes synthesized by the lacrimal gland. Their concentration in human tears reflects tear gland function. Tear gland dysfunction can lead to ocular surface disease. We developed a colorimetric lysozyme assay. The objective of this study was to determine the diagnostic power and the clinical application of this assay that allows rapid and precise quantification of tear lysozyme.Tear specimens of 120 eyes (30 Sjögren's patients and 30 controls) were collected using standardized filter paper discs. Tear lysozyme concentration was determined using p-nitrophenyl penta-N-acetyl-beta-chitopentaoside as substrate in the colorimetric assay. The results were compared to clinical findings and to two commonly used tests, the Micrococcus agar diffusion assay for tear lysozyme and the tear lactoferrin immunodiffusion assay.The colorimetric assay showed a good dose-response relationship. The use of the assay as a method of diagnosing aqueous tear deficiency, using the clinical findings and the medical history as gold standard, demonstrated 85% sensitivity and 92% specificity. The results of the colorimetric assay when compared with the Micrococcus agar diffusion assay showed a linear relationship of r=0.77; when compared with the lactoferrin immunoassay r=0.73.The colorimetric assay is simple to perform and does not require sophisticated laboratory equipment and personnel. Results can be precisely quantified within one hour after tear collection. The diagnostic power of the test is comparable to previously reported assays for lysozyme and lactoferrin and will be useful in the diagnosis of ocular surface disease.

As early as 1992, Fleming reported the presence of lysozyme in the tear fluid.1 Other proteins have also been reported, notably lactoferrin2 and tear-specific prealbumin.3,4 All these proteins are major components of the lacrimal fluid. Their presence under both normal and pathological conditions have been well documented.5–9 The tear proteins are synthesized by the lacrimal gland10 and, in degenerations of the tear gland, the concentration of tear proteins in the lacrimal fluid decreases.

The causes of keratoconjunctivitis sicca (KCS) are manifold. Cicatricial, nutritional, neurogenic — both acquired and congenital — and exposure factors can be present alone or in any given combination. In this study, the evaluation of the clinical tests in keratoconjunctivitis sicca is limited to those forms of KCS that are caused by a decrease in the tear gland function, be it as a result of autoimmune inflammatory reactions or as a result of involution.

This short monograph on the histopathology of the tear gland is based on the author's extensive investigations. The upper tear glands obtained at 500 autopsies in addition to biopsy specimens were studied. These findings are compared with those reported in the literature and give a full description of the different phases of the histologic changes in normal and diseased glands. The division into twenty chapters with some subdivisions does not make for organic coherence but facilitates consultation by the reader. With reference to the histologic changes, the chapter on onkocytes is of interest, although the pathologic significance of these cells is not clear. The description of the development of clusters of lymphocytes in the normal gland, the death of epithelial cells and the process of atrophy will be appreciated by the pathologist who deals principally with biopsy specimens. Emphasis must be placed on the author's opinion that

The objective sign of disease of the tear passages, viz: the overflow of tears, varies in degree in different patients. From the history and by the personal examination, it can be learned that while the eyes of some patients water continuously as long as they are awake, others notice the watering only when exposed to wind, smoke or dust, or on using their eyes under the condition of eye strain. In this class of patients the tears accumulate only while some stimulus excites the tear gland; but in the first mentioned class the activity of the tear gland is a continuous one. As far as we know, the secretion of the lachrymal gland is, however, not a continuous one under normal circumstances. Thus it has been noticed in congenital, absolute impermeability of the tear passage and after surgical obliteration of the tear sac, that the tears appear only when some