WO2002084300A2 - Diagnostic du syndrome de sjogren - Google Patents

Diagnostic du syndrome de sjogren Download PDF

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WO2002084300A2
WO2002084300A2 PCT/NL2002/000249 NL0200249W WO02084300A2 WO 2002084300 A2 WO2002084300 A2 WO 2002084300A2 NL 0200249 W NL0200249 W NL 0200249W WO 02084300 A2 WO02084300 A2 WO 02084300A2
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parotid
patients
stimulated
test
sodium
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PCT/NL2002/000249
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WO2002084300A3 (fr
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Wouter Warner Iwe Kalk
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De Boeringstichting Oral And Maxillofacial Research Fund
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/84—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving inorganic compounds or pH
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis

Definitions

  • the invention relates to the field of diagnosis of Sj ⁇ gren's syndrome.
  • Sj ⁇ gren's syndrome is considered an autoimmune exocrinopathy resulting in, amongst many other manifestations, tear and salivary gland dysfunction. Since the etiopathogenesis of SS remains unclear, the diagnosis of SS is still based on the presence of characteristic signs and symptoms. A variety of diagnostic tests is currently in use, but none of these tests detects changes pathognomonic for SS. Therefore, different combinations of test criteria have been proposed for the diagnosis of SS.
  • diagnosis of Sj ⁇ gren's syndrome (SS) is mainly based on questioning and extensive examining a possible patient as regards to oral and/or ocular dysfunctions (Vitali et al, 1993, 1996).
  • salivary gland function Assessment of for example salivary gland function is, therefore, of potential diagnostic significance (Benedek-Spat, 1975; Mandel and Baurmash, 1976; Ben-Aryeh et al, 1981; Fox et al, 1985; Schi ⁇ dt and Thorn, 1989; Thorn et al, 1989; Daniels, 1989; Mandel, 1990; Atkinson et al, 1990; Atkinson, 1993; Pennec et al, 1993; Vissink et al, 1993).
  • Methods for determining salivary gland (dys)function include salivary flow rate measurements (sialometry) and analysis of salivary composition (sialochemistry), for which whole saliva (oral fluid) is most frequently used. The accuracy of these techniques, however, is disputed.
  • glandular sahva Several distinct alterations in flow rate and composition of glandular saliva have been reported in SS-patients, not only when compared with healthy controls (Mandel and Baurmash, 1976; Atkinson et al, 1990; Atkinson et al, 1993; Vissink et al, 1993). These alterations are not observed or less obvious when using whole sahva.
  • the use of glandular sahva for diagnosing SS is hampered by the lack of univocal salivary reference values.
  • sialometry and sialochemistry of, be it whole or glandular, stimulated or unstimulated, sahva is at present (e.g. Vitali and Bombardieri, Ann. Med. Interne 149:12-16, 1998 wishing to select the most sensitive and specific tests for Sjogrens syndrome) still considered to be of little value and only to be diagnostic for (the oral component of) SS when major changes in salivary secretion and composition have occurred.
  • the present invention among others provides thresholds (cut-off points) for relevant variables of glandular secretions for diagnosing SS and to construct and evaluate an easily applicable diagnostic approach for SS, and is especially useful in screening approaches for SS.
  • the invention provides a method for determining an alteration in a secretory gland sample wherein said alteration is associated with Sj ⁇ gren's syndrome comprising testing said sample for the presence of an elevated sodium level, for example, when sodium is elevated to about 10, preferably about 15, more preferably to higher than about 20 mM/1, the individual from which the sample was obtained may be further tested the propensity to manifest Sj ⁇ gren's syndrome, since it is likely that said individual has such propensity.
  • the invention provides a method for determining an alteration in a secretory gland sample wherein said alteration is associated with Sj ⁇ gren's syndrome comprising testing said sample for the presence of an elevated chloride level, for example, when chloride is elevated to about 20, preferably to about 25, more preferably to higher than about 30 mM/1, the individual from which the sample was obtained may also be further tested the propensity to manifest Sj ⁇ gren's syndrome since it is likely that said individual has such propensity.
  • an elevated chloride level for example, when chloride is elevated to about 20, preferably to about 25, more preferably to higher than about 30 mM/1
  • the invention provides a method for determining an alteration in a secretory gland sample wherein said alteration is associated with Sj ⁇ gren's syndrome comprising testing said sample for the presence of a lowered phosphate level for example, when phosphate is lowered to about 4.5, preferably to about 3.5, or even 2.5 more preferably to lower than about 2, and particularly to about 1 mM/1, the individual from which the sample was obtained may also be further tested the propensity to manifest Sj ⁇ gren's syndrome since it is likely that said individual has such propensity.
  • Preferred is a method as provided herein for determining an alteration in a secretory gland sample wherein said alteration is associated with Sj ⁇ gren's syndrome comprising testing said sample for the presence of an elevated sodium and chloride level, as explained more in detail in de detailed description.
  • Combining test results for an elevated sodium and/or chloride level with lowered phosphate level also provides even more valuable information.
  • the invention provides the insight that with SS patients sodium and/or chloride levels is such secretions are generally elevated, whereas phosphate levels can at the same time be lowered, as compared to healthy controls or patients not suffering from SS.
  • the invention provides a method wherein said secretory gland sample comprises saliva.
  • said invention provides a method for testing for these alterations in saliva samples, and more preferably for sahva samples obtained from parotid and/or submandibular/sublingual salivary glands.
  • the method as provided by the invention can of course also be directed at secretion samples obtained from other secretory glands implicated in SS.
  • the invention also provides a test device for use in a method according to the invention, preferably provided with means to detect (or preferably to determine the concentration) both sodium and chloride in a sample, or provided with means to detect both sodium or chloride and phosphate in a sample, or all three parameters, in a sample.
  • a test device for determining an alteration in a secretory gland sample wherein said alteration is associated with Sj ⁇ gren's syndrome, preferably wherein said test device comprises a test strip. Test strips provide the simplest handling.
  • Test strips as provided herein preferably comprise various reactions zones, for example one for sodium, one for chloride, and advantageously, one for phosphate, allowing testing for SS with enhanced specificity and sensitivity.
  • the reaction zones are wetted with a sample solution, such as saliva, by simple dipping or spotting. After the given time has elapsed, the colouring of the reaction zone(s) is for example compared with a colour scale to determine the quantity (to determine the concentration) of the analyte tested.
  • the invention thus provides a method for screening for the propensity to manifest Sj ⁇ gren's syndrome comprising use of a method or of a test device according to the invention, and, as further explained in the detailed description without hmiting the invention thereto, a non-invasive method for diagnosing Sj ⁇ gren's syndrome.
  • the diagnostic work-up for SS carried out in all patients, included: subjective complaints of oral and ocular dryness (table 1), sialography, histopathology of salivary gland tissue, serology (SS-A- and SS-B antibodies) and eye tests (Rose Bengal staining and Schirmer tear test).
  • table 1 subjective complaints of oral and ocular dryness
  • sialography histopathology of salivary gland tissue
  • serology serology
  • Eye tests Rose Bengal staining and Schirmer tear test
  • the revised European classification criteria for Sj ⁇ gren's syndrome (Vitali et al, 1993, 1997) were used as reference standard for the diagnosis of SS, categorising patients as primary and secondary SS and non-SS patients.
  • the first one-hundred patients - referred between September 1997 and March 1999 - participated in a study, in which sialometrical and sialochemical variables of potential diagnostic value have been identified. In the present study these patients served as Observation group' to define cut-off points and
  • the Observation group' consisted of 58 SS-patients (33 primary SS and 25 secondary SS; male/female ratio: 1/8, mean age 53 years, SD 14, range 21 to 84) and 42 patients testing negative for SS (male/female ratio: 1/20, mean age 55 years, SD 17, range 20 to 81)(table 2).
  • the 'test group' consisted of 7 SS-patients (2 primary, 5 secondary SS; male/female ratio: 1/6, mean age 62 years, SD 10, range 46 to 76) and 13 non-SS patients (male/female ratio: 0/13, mean age 55 years, SD 11, range 36 to 76).
  • xerogenic drugs i.e. antihypertensives, beta-blockers, antihistamines, and psychotropics, was relatively frequent in all patients (Observation group': SS 45%, non-SS 55%; 'test group': SS 57%, non-SS 54%).
  • the univariate analysis consisted of selecting cut-off points from ROC-curves of the relevant diagnostic indicators and combining these into a definition for a positive diagnosis of SS.
  • the multivariate analysis (in which the diagnosis of SS is a descriptive of a set of jointly relevant diagnostic indicators) consisted of the construction of a logistic regression model, including variables stepwise backward by likelihood ratio (Miettinen et al, 1998). It predicts the true state (SS or non-SS) of a patient. Diagnostic indicators and tests were evaluated by ROC-curve and likelihood ratio.
  • SS Sj ⁇ gren's syndrome
  • ESR erythrocyte sedimentation rate
  • CRP C-reactive protein
  • IgG and IGA immunoglobulins
  • Cut-off points for a positive diagnosis of SS were selected from ROC-curves of the potentially relevant sialometrical and sialochemical variables (figure 1, table 6). The cut-off points were selected with emphasis on specificity (up to 1.00) in order to compensate for specificity loss, which will inevitably occur when parameters are combined as test for SS.
  • sialochemical variables were combined with sialometrical variables. This resulted in four tests with high specificity and moderate sensitivity (table 8). By combining sialometrical and sialochemical variables, all patients could be classified (i.e. no loss of cases due to missing data).
  • the selected test definitions and test formulas had on average equal sensitivity and specificity in the 'test group' compared to the Observation group'.
  • 15% of the patients in the test group could not be diagnosed due to missing data.
  • the selected test definitions cut-off point
  • sialometrical and sialochemical variables can contribute to the diagnosis of Sj ⁇ gren's syndrome (SS). Some have greater diagnostic potential than others, as can be determined by the likelihood ratio, as well as by the shape of a Receiver- Operating Characteristic (ROC) curve. High potential is indicated by a high likelihood ratio and by a ROC curve that approaches the upper left corner of the diagram.
  • SS Sj ⁇ gren's syndrome
  • Variables can be combined by applying their cut-off points into a set of criteria for a diagnosis of SS, but also by using a logistic regression model that predicts the true state of a patient (SS or non-SS) based upon the selected variables.
  • the univariate method the cut-off point approach — has the advantage that the sensitivity and specificity of the test can be adjusted to its purpose (e.g. screening, diagnosis) by selecting the proper cut-off points.
  • the multivariate method the logistic regression approach - has the advantage of using the full (joint) discriminative potency of the variables included and correcting for their mutual influences. This method, however, has the limitation that if any variable is missing the test cannot be carried out, since all variables are required in the formula.
  • the impaired applicability of the logistic regression model was counterbalanced by a higher likelihood ratio (likelihood ratio of 21 versus 17 of cut-off point approach). Both approaches (logistic regression and cut-off point) proved adequate for diagnosing SS using only two or three sahvary variables.
  • the logistic regression approach, having the highest likelihood ratio, is the best option for diagnosing individual patients, while the cut-off point approach, being more universally applicable, may have greater value for diagnosing series of patients.
  • test 14 accurately predicts the presence or absence of SS.
  • the cut-off point criteria (table 8: test 7) can be used as an alternative to diagnose the patient.
  • glandular sialometry and sialochemistry have been useful methods that contribute to the differentiation of sahvary gland diseases.
  • glandular sialometry and sialochemistry have become clinically apphcable methods that, when combined, form a reliable diagnostic technique for SS. Since the collection of sahva takes only few minutes and is noninvasive, and the analysis requires no laboratory other than for routine blood testing, we feel that glandular sialometry and sialochemistry will replace other, more invasive, diagnostic techniques for SS.
  • SS Patients with SS differed clearly from the patients tested negative for SS, showing lower submandibular/sublingual (SM/SL) flow rates and a markedly changed sahvary composition of parotid- and SM/SL sahva. Besides changes in sahvary flow rate and composition, distinct sialometrical profiles were observed, characteristic for either early or late sahvary manifestation of SS, or for the xerogenic side effect from medication.
  • SM/SL submandibular/sublingual
  • glandular sialometry and sialochemistry are not only useful instruments to differentiate SS from other sahvary gland disease in chnical practice, but also have great potential as diagnostic criteria for SS, reveahng distinct sialometrical and sialochemical changes as well as profiles. Being simple, safe (non-invasive) and sensitive (early disease detection) glandular sialometry and sialochemistry encompass three major advantages compared to other oral tests for SS.
  • the diagnostic work-up for SS was carried out in all patients and included the following aspects: subjective complaints of oral and ocular dryness (table 1), sialography, histopathology of sahvary gland tissue, serology (SS-A- and SS-B antibodies) and eye tests (Rose Bengal staining and Schirmer tear test).
  • the duration of oral symptoms was assessed, defined as the time from first complaints induced by or related to oral dryness until referral. 'Short duration' was defined as less than one year, and long duration' as more than two years of oral symptoms.
  • sahvary assessments were performed in absence of acute sialadenitis. If chnical signs of acute inflammation were present, sahvary assessment was postponed until chnical signs had subsided for at least six weeks. Glandular salivas were collected in a standardised manner. In brief, patients were instructed not to eat, drink or smoke during ninety minutes preceding the sialometrical assessment. All assessments were performed at a fixed time of the day, in this study between one and three o'clock PM, in order to minimise fluctuations related to a circadian rhythm of sahvary secretion and composition. All assessments were performed by the same observer.
  • Glandular salivas were collected in preweighed plastic tubes from both individual parotid glands by using modified Lashley cups (Carlson-Crittenden cups), and simultaneously from the submandibular/subhngual (SM/SL) glands by syringe aspiration. Sahva from the SM/SL glands was collectively aspirated, as separate aspiration is rather difficult in chnical practice due to the close anatomical relationship between the orifices of both glands and the frequent presence of communicating ducts between the submandibular and sublingual main ducts.
  • modified Lashley cups Carlson-Crittenden cups
  • Unstimulated sahvary secretions were collected during five minutes, followed by collection of stimulated secretions during ten minutes.
  • the sahvary glands were stimulated with citric acid solution (2% weight/volume) apphed with a cotton swab to the lateral borders of he tongue at 30-second intervals. Mixing of he acid solution apphed to the tongue and SM/SL sahva poohng anteriorly in the floor of the mouth (orifices of the SM/SL glands) was carefully avoided.
  • Lag phase defined as the time from first acid apphcation on the tongue until first visible sahva secretion (in the tubes connected to the cups) was recorded for both parotid glands.
  • sialochemical analysis was performed.
  • the following sahvary components were quantified: sodium, potassium, chloride, calcium, phosphate, urea, total protein and amylase.
  • Sodium and potassium ions were measured flame photometrically with lithium ions as a standard (3000 ppm).
  • Chloride ions were measured by titration with silver ions.
  • Calcium ions were measured spectrophotometrically at 577 and 600 nm after complexing with o-cresolphthalein.
  • Inorganic phosphate was measured at 340 and 383 nm after addition of molybdate and reduction with bisulphite in the presence of p- methylaminephenolsulfate .
  • Urea was measured at 340 nm after addition of urease/glutamate dehydrogenase.
  • Total protein was measured at 604 nm after addition of pyrogallol.
  • Amylase was quantified by the method of Pierre and Nadj.
  • SS Sj ⁇ gren's syndrome
  • Group A patients with primary SS, comprised three men and 30 women (male/female ratio: 1/10; mean age of 51 years; SD 16; range 21 to 84).
  • Group B patients with secondary SS, comprised four men and 21 women (male/female ratio: 1/5; mean age of 54 years; SD 12; range 25 to 78).
  • Group C patients tested negative for SS, comprised two men and 40 women (male/female ratio: 1/20; mean age of 55 years; SD 17; range 20 to 81) (table 2).
  • a fourth group, group D comprised 36 non-medicated healthy subjects without a history of sahvary gland diseases. This group served as historical controls for sialometry and sialochemistry, assessed with identical methods as used in this study.
  • Lag phase was increased significantly in groups A, B and C compared to group D (table 4) and was inversely related to flow rate (rparotid -0.51, P ⁇ 0.01).
  • Mean stimulated parotid flow rate in groups A, B and C was reduced as compared to normal (group D) (figure 2, table 14).
  • Patients in group B had significantly higher stimulated parotid flow rate compared to patients in group A (figure 2, table 14).
  • Unstimulated and stimulated submandibular/subhngual (SM/SL) flow rates were reduced in groups A and B as compared to SM/SL flow rates in groups C and D (figure 2, table 14).
  • Sialochemistry Sialochemical results hsted in table 5 are hmited to stimulated sahva samples, as the volume of unstimulated sahva samples was insufficient for full sialochemical assessment in the majority o the patients studied (A: 75%, B: 76%, C: 36%, D: 0%). In eight percent of the patients in this study, sialochemistry was not performed due to absence of measurable sahvary secretion (A: 18%, B: 8%, C: 0%, D: 0%). With regard to calcium and urea concentrations, no significant differences were observed between the four groups.
  • groups A and B mean sodium and chloride concentrations in parotid sahva were increased eight fold and two fold respectively, compared to the concentrations in group C (figure 3).
  • groups A and B the mean phosphate concentration in SM/SL sahva was decreased to two-third of the concentration in group C (figure 3).
  • the total amount of amylase being secreted (U/min) was markedly less in groups A, B and C compared to group D.
  • Total protein concentration in parotid sahva was increased in groups A, B and C compared to group D, but did not differ significantly between groups A, B and C.
  • groups A and B the sialochemical electrolyte changes in SM/SL sahva paralleled the changes in parotid sahva.
  • Sahvary composition did not differ significantly between the patients of groups A and B.
  • group C significant changes in sahvary composition were observed compared to healthy controls (group D).
  • Sialoadenosis is a parenchymatous sahvary gland disorder due to secretory and metabolic disturbances of the acinar parenchyma, which can be clinicaUy reflected by xerostomia and the presence of a bilateral chronic or recurrent painless swelling ofthe sahvary glands, particularly the parotid glands.
  • Sodium retention dysfunction syndrome can be chnicaUy reflected by xerostomia and recurrent unilateral painless sweUing of a parotid gland for a few hours. It has been suggested to be related to impaired gland perfusion, which may occur due to homeostatic mechanisms of the blood supply in favour of other organ.
  • duct ceUs are impaired in their function by the periductal lymphocytic infiltration, which is present in the major sahvary glands affected by SS.
  • autoantibodies directed against duct cells cause impairment of electrolyte transport in duct ceUs.
  • the unaltered levels of potassium and calcium in SS do not necessarily oppose this theory of ductal dysfunction, but may indicate that their transport differs from the normal active ductal transport of sodium, chloride and phosphate.
  • sialometrical profiles characteristic for either early or late sahvary manifestation of SS, or the side effect of drugs might be very useful in diagnosing SS.
  • the early profiles are important for detecting the presence of SS shortly after disease onset when other symptoms still may be inconspicuous.
  • the early and late profiles seem useful for staging the disease regarding its oral component, comparable with the use of sialography for staging glandular changes in SS.
  • the profile characteristic for xerogenic drug usage is useful to reveal the presence of a suppressive drug-effect on the secretory function of sahvary glands.
  • sialometry and sialochemistry as diagnostic instruments varies under certain chnical conditions.
  • sialochemistry is often useful, since sialochemical changes - reflecting autoimmune attack on secretory ceUs - usually precede sahvary gland dysfunction in SS.
  • sialometry is highly diagnostic for SS. Therefore, it is advisable to combine sialometry and sialochemistry as diagnostic instruments, and assess their joint diagnostic value in an early as weU as a progressed phase of SS.
  • glandular sialometry and sialochemistry is useful to differentiate SS from other sahvary gland disease, reveahng not only separate changes in sahvary flow rate and composition but also characteristic sialometrical profiles.
  • sialometrical and sialochemical results if obtained at aU, are taken into account when deciding whether additional (more invasive) diagnostic procedures are required.
  • cut-off values for the relevant parameters need to be formulated and analyzed in addition to this survey.
  • sialochemical variables might be added to the hst of markers for SS, such as cytokines, interleukins, hyaluronic acids and certain proteins which are currently under investigation.
  • markers for SS such as cytokines, interleukins, hyaluronic acids and certain proteins which are currently under investigation.
  • some of these markers lack the direct relationship to loss and dysfunction of exocrine gland tissue, which is the major outcome of SS, but merely reflect complex inflammatory processes or co-processes in the disease. Therefore, these markers may have more use in the understanding of the immunopathogenesis of SS rather than in the diagnosis of SS.
  • sialometry probably has the potency to be used as a parameter for disease progression of SS (at least regarding the oral component).
  • a long- term prospective study is still required.
  • SM/SL submandibular/subhngual
  • SS Sj ⁇ gren's syndrome
  • Chloride is for example detected by reacting with silver ions, decolorizing red- brown sUverchromate (Merckoquant ® Chloride, Merck).
  • Phosphate is for example detected by reacting with molybdate ions in a solution acidified with sulfuric acid, which is reduced to phosphomolybdenum blue (PMB)(Merckoquant ® Phosphate, Merck).
  • PMB phosphomolybdenum blue
  • Sodium is for example detected by reaction with uranyl potassium ferrocyanide to form uranyl sodium acetate, thereby changing the colour from red-brown to greenish.
  • the accuracy of the test by using the sahva test-strip is an estimate, based upon a previous study using laboratory techniques for sialochemical analysis.
  • the test-strip can be used for parotid sahva detection only, as weU as for parotid- and SM/SL sahva detection.
  • the test has an estimated sensitivity of 56 and specificity of 95 percent by reading chloride and sodium concentrations; when both parotid and SM/SL sahva drops are apphed the test reaches a sensitivity of 92 and a specificity of 62 percent.
  • test-strip is particularly useful for general practitioners, gynecologists and dentists.
  • the test can used to support the decision whether or not referral to a speciahst is required among patients with chnical symptoms or signs suspect for SS.
  • the test-strip can also be used in a hospital setting by internists and rheumatologists, to quickly screen among certain patients for oral signs of SS, comparable with the use of the Schirmer test-strip for ocular signs. Combined use of both screening tests further increases the sensitivity for SS.
  • the sahvary glands need to be stimulated during two minutes. This can be achieved by asking the patient to chew (mint or citric) flavoured gum during two minutes before samphng. This stimulation is required to prevent incorrect outcomes, resulting from changed sahvary composition from stasis of sahva in the sahvary ducts.
  • the mouth After the chewing gum is removed from the mouth, the mouth must be rinsed with water. The inside of a cheek is exposed, and dried with a cotton swab foUowed by expressing a drop of sahva out at the opening of the Stensen duct.
  • This opening is located at the inner cheek adjacent to the second upper molar.
  • the drop of sahva is harvested with a sahva pipette, and apphed on the strip at the parotid site. After some seconds required for a chemical reaction the first test result can be read (by a marked change of colour).
  • a drop of SM/SL sahva is harvested with another (clean) sahva pipette, after drying the floor of the mouth with a cotton swab and expressing a drop of sahva out at the opening of the Wharton's duct.
  • This opening is located under the tongue paramedian in the floor of the mouth.
  • the drop of sahva is apphed on the strip at the SM/SL site, after which the final test result can be read.
  • a negative test result both SM/SL and parotid sahva drops applied
  • a positive test result does not without any doubt prove the presence of SS, but indicates that there is a significant chance that SS is present, and prompts for referral to a speciahst for further diagnostic testing.
  • Sj ⁇ gren's syndrome causes that, initiaUy, only subtle changes in the exocrine glands take place that are difficult to detect with routine diagnostics.
  • Chronic inflammation of the sahvary glands causes a decrease of sahvary secretion only after months to years.
  • radiographic alterations as demonstrated with sialography, develop very slowly from disease onset.
  • the inflammatory reaction in the sahvary glands itself can be detected, however, by changes in the sahvary composition. Dentists and general practitioners can detect such changes simply by using a saliva test-strip.
  • Table 4 Composition of stimulated glandular salivas (mean ⁇ SD) of SS-positive patients (SS) and SS-negative patients (non-SS) in the 'observation group'.
  • Statistical test used independent sample T-test. Significance marked with *.
  • Cl-diff 95% confidence interval ofthe difference (note: if zero is not included in the interval the difference is significant).
  • SM/SL(stimulated) sodium >10 mmol/L or m SM/SL(stimulated) chloride >20 mmol/L or 0.71 0.81 3 84 0.74 0.78 z_ SM SL(stimulated) phosphate ⁇ 2.50 mmol/L m m
  • LR likelihood ratio
  • PPV positive predictive value
  • SM/SL submandibular/sublingual
  • Sialometrical and sialochemical variables w 6. Stimulated SM/SL flow ⁇ 0.05 ml/min or 1.00 0.66 ⁇ 100 1.00 0.68 c Parotid(stimulated) sodium ⁇ 20 mmol/L z! 7. Stimulated SM/SL flow ⁇ 0.05 ml/min or 0.95 0.71 14 100 0.95 0.70 c Parotid(stimulated) sodium ⁇ 20 mmol/L or m Parc4id(stimulated) chloride ⁇ 30 mmol/L
  • Stimulated SM/SL flow ⁇ 0.05 ml/min or 0.90 0.78 8 100 0.92 0.75 m t Parotid(stimulated) sodium ⁇ 20 mmol/L or ⁇ > Parotid(stimulated) chloride ⁇ 30 mmol/L or
  • LR likelihood ratio
  • PPV positive predictive value
  • SM/SL submandibular/sublingual
  • LR likelihood ratio
  • PPV positive predictive value
  • LNR log
  • SM/SL submandibular/sublingual
  • IgG is elevated in order to improve the sensitivity.
  • IgG ⁇ 15 Stimulated SM/SL flow ⁇ 0.05 ml/min 0.95 0.53 11 100 0.94 0.61
  • IgG ⁇ 15 Parotid(s1imulated) sodium ⁇ 20 mmol L 1.00 0.69 ⁇ 90 1.00 0.74
  • IgG> 15 Par ⁇ tid(stimulated) sodium ⁇ 10 mmol/L
  • IgG ⁇ 15 Parotid(stimulated) sodium ⁇ 20 mmol/L or 0.95 0.83 17 100 0.96 0.80 c Stimulated SM/SL flow ⁇ 0.05 ml/min m
  • IgG>15 Parotid(stimulated) sodium ⁇ IO mmol/L or f o> Stimulated SM SL flow ⁇ 0.20 ml min
  • IgG ⁇ 15 Parotid(stimulated) sodium ⁇ 20 mmol L or 0.90 0.86 9 100 0.93 0.83
  • Parotid(stimulated) chloride ⁇ 30 mmol/L or Stimulated SM SL flow ⁇ 0.05 ml min IgG>15: Parotid(stimulated) sodium ⁇ IO mmol/L or
  • IgG ⁇ l 5 Parotid(stimulated) sodium ⁇ 20 mmol/L or 0.88 0.91 8 100 0.91 0.88
  • IgG>15 Parotid(stimulated) sodium ⁇ IO mmol/L or Parotid(stimulated) chloride ⁇ 30 mmol/L or Stimulated SM SL flow ⁇ 0.20 ml/min or Parotid lag phase >2.20 min
  • LR likelihood ratio
  • PPV positive predictive value
  • SM SL submandibular/sublingual m
  • LR likelihood ratio
  • PPV positive predictive value
  • LNR log
  • SM/SL submandibular/sublingual
  • Criteria cut-off points
  • test formulas specificity sensitivity LR N PPV* NPV* test (logistic regression) for classifying SS
  • IgG ⁇ 15 Parotid(stimulated) sodium ⁇ 20 mmol/L or 0.86 0.83 20 0.71 0.92 Stimulated SM/SL flow ⁇ 0.05 ml/min
  • IgG>15 Parotid(stimulated) sodium ⁇ IO mmol/L or Stimulated SM/SL flow ⁇ 0.20 ml/min
  • LR likelihood ratio
  • Parotid flow rate (mL/min gland) N.D. ⁇ 0.03 >0.03 SM/SL flow rate (mL/min/SMSL-glands) N.D. ⁇ 0.03 >0.03
  • Parotid flow rate (mL min/gland) ⁇ 0.05 0.05-0.10 ⁇ O.IO* SM/SL flow rate (mL/min/SMSL-glands) ⁇ 0.05 0.05-0.20 ⁇ 0.20
  • Parotid flow rate (mlJmin/gland) 0.12* ⁇ o.i3 0.24* ⁇ 0.25 0.19* ⁇ 0.15 0.52 ⁇ 0.42
  • SM/SL flow rate (mL/min/SM/SL-glands) 0.24** ⁇ 0.28 0.26* ⁇ 0.35 0.42 ⁇ 0.28 0.46 ⁇ 0.24

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Abstract

L'invention se rapporte au diagnostic du syndrome de Sjögren. Le syndrome de Sjögren (SS) est considéré comme une exocrinopathie auto-immune se traduisant, entre autres manifestations, par une dysfonction des glandes lacrymales et salivaires. L'invention concerne une méthode permettant d'identifier dans échantillon de glande sécrétoire une altération associé au syndrome de Sjögren, et consistant à rechercher la présence de sodium, de chlorure et/ou de phosphate dans l'échantillon.
PCT/NL2002/000249 2001-04-17 2002-04-16 Diagnostic du syndrome de sjogren WO2002084300A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2771850C1 (ru) * 2021-06-25 2022-05-12 федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный медико-стоматологический университет имени А.И. Евдокимова" Министерства здравоохранения Российской Федерации (ФГБОУ ВО МГМСУ им. А.И. Евдокимова Минздрава России) Способ забора слюны для исследования секреторной функции околоушных желез в виде контролируемой динамической сиалометрии

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Title
KALK W W I ET AL: "Sialometry and sialochemistry: Diagnostic tools for Sjogren's syndrome." ANNALS OF THE RHEUMATIC DISEASES, vol. 60, no. 12, December 2001 (2001-12), pages 1110-1116, XP008000537 ISSN: 0003-4967 *
MENSTELL S ET AL: "SIALOCHEMISTRY IN SJOGREN'S SYNDROME" LARYNGO- RHINO- OTOLOGIE, vol. 69, no. 6, 1990, pages 320-321, XP008000535 ISSN: 0935-8943 *
NAHIR A M ET AL: "CHEMICAL ANALYSIS OF WHOLE SALIVA IN SJOGREN'S SYNDROME" ANNALS OF THE RHEUMATIC DISEASES, vol. 46, no. 9, 1987, pages 654-657, XP008000534 ISSN: 0003-4967 *
STUCHELL R N ET AL: "CLINICAL UTILIZATION OF SIALOCHEMISTRY IN SJOGRENS SYNDROME" JOURNAL OF ORAL PATHOLOGY, vol. 13, no. 3, 1984, pages 303-309, XP008000533 ISSN: 0300-9777 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2771850C1 (ru) * 2021-06-25 2022-05-12 федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный медико-стоматологический университет имени А.И. Евдокимова" Министерства здравоохранения Российской Федерации (ФГБОУ ВО МГМСУ им. А.И. Евдокимова Минздрава России) Способ забора слюны для исследования секреторной функции околоушных желез в виде контролируемой динамической сиалометрии

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