Preliminary Diagnostic Criteria for Sitigren's Syndrome

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mia defined by subjective complaints, Schirmer's test {5 mm/5 min or positive rose-bengal staining on slit lamp examination, 2) xerostomia defined by subjective ...
ScandJ Rheumatology1986;Suppl. 6l:22-25

PreliminaryDiagnosticCriteriafor Sitigren'sSyndrome and H . M. MOU TS OP OU LOS I F . N. SK O P O U L I,IA. A . D R O S O S ,IT. P A P A IOA N N OU 2 zDepartment of Statistics, From the tDepartment of Medicine, School of Medicine, and the School of Mathematics, Uniuersity of loannina, Ioannina, Greece

Although Sjogren's syndrome (SS) is a very common autoimmune disease there are no uniformally accepted diagnostic criteria. In this study we evaluated various clinical parameters as criteria for this disorder. Fifty-two patients with sicca complaints but no evidence of other autoimmune rheumatic disorders were studied. These patients were further subdivided into definite primary SS (primSS) (n: l9) and possible primary SS (n : 33). The patients of the definite group fulfilled 213of the following criteria: l) xerophthalmia defined by subjective complaints, Schirmer's test {5 mm/5 min or positive rose-bengal staining on slit lamp examination, 2) xerostomia defined by subjective complaints and parotid flow rate (l ccl5 mm/gland and,3) presence or history of parotid gland enlargement. In all patients the histology of labial minor salivary glands showed round cell infiltrates >2+ (Tarpley's classification). The clinical manifestations of definite primary SS were compared to those of patients with possible primary SS. In addition,49 patients with rheumatoid arthritis (RA) and suspected secondary SS were evaluated. Eleven patients were initially classified as definite secondary SS in association with RA (lip biopsy >2+ and ll2 of the criteria: xerophthalmia and xerostomia) and the remaining 38 as possible secondary SS with RA. Estimation of the frequency and significance of all variables within the subgroups, as well as the specificity, sensitivity and misclassification error rate suggestedthat: I) Definite primSS can be diagnosed in the absence of any other autoimmune disease, labial biopsy with histologic lesion >2+ and presence of either parotid gland enlargement (specificity 94Vo, total misclassification error rate 7 Vo) or subjective xerostomia (specificity 85 Vo, total misclassification error rate 12Va) or positive rose-bengal staining (specificity 82 7o, total misclassification error rate 13 Vo) andII) Definite secondary SS (sec^lS) in association with RA can be diagnosed in a RA patient with labial biopsy )2+ and subjective xerophthalmia (specificity 97 Vo, total misclassification error rate 27o).

Investigators working

with Sjogren's syndrome use various terminology

of the disorder (primary and several

SS, sicca syndrome,

sets of clinical

rnanifestations,

autoimmune laboratory

for the subgroups

exocrinopathy, and histologic

secondary findings

for

SS) the

diagnosis of this entity (2, 4, 5). In this studywe madean attemptto definethe most prominentparametersas diagnostic criteria for the primary and secondaryforms of the syndrome.

MATERIALS AND METHODS Patients Fifty-two patients suspected of having primary Sjogren's syndrome (primSS), and 49 patients with classical rheumatoid arthritis (RA) and manifestations of SS participated in this study. Xerophthalmia was considered present if the patient had affirmatively answered half of the questions published by Moutsopoulos et al. (6) (subjectiue xerophthalmia) and a positiue Schirmer's lesl ((5 mm/5 min), or keratoconjunctivitis sicca on slit lamp examination after rose-bengal staining. Xerostomia was considered present if the patient had affirmatively answered half of the pertinent questions (6) (subjectiue xerostomict) and a decreased stimulated parotid flow rate (0. Group rrr: Definite sec.s,s(n 1l). The patients had RA, fulfiiled 112 oithe following criteria (c) xerophthalmia, (b) xerostomiaand had a labial biopsy )2-r. Group rY: Possiblesecss (n 38).The patients had RA, furfilred112ofthe abovecriteriaand had a biopsy>0 labialbiopsy >2+ without subjectivesicca compraints. Methods For eachvariableor combinationof variables definedabove,sensitivity,specificityand misclassification error rate were calculated(1). Linear discriminantanalysiswas appliedto confirm the results usingthe BMDP 7M procedure.

RESULTS Table I shows the sensitivity, specificity and misclassification error rate of each variable and combination of variables within groups of primSS patients. It appears that the most sensitive and specific variables are PGE, subjective xerostomia and positive rose-bengal staining' It is of interest to note that combination of different variables does not decrease considerably the misclassificationelror rate. In Table II, the sensitivity, specificity and misclassification error rate of individuals variables and combination of different variables within groups of secSS patients are given. It appears that the most sensitive and specific variable in the secSS patients is subjective xerophthalmia' Combination of different variables does not significantly decrease the misclassification error rate. In contrast, salivary glands manifestations in secSS patients are very infrequent.

Table r' Classification criteria-Primary group I and II patients)

sidgren's syndrome patients (based on comparison between

Criteria l . Lip biopsy > 2 + 2 . Lip biopsy > 2 + J . Lip biopsy> 2 + 4 . Lip biopsy > 2 + 5 . Lip biopsy > 2 +

and parotid gland enlargement and subj. xerostomia a n d r o s e - b e n g a ls t a i n i n g and parotid flow and parotid gland enlargement and

6.Lip biopsy )2+

;::';'"..-,,i;i:lTXt",".gemenr and

7. Lip biopsy )2+ 8' Lip biopsy >2+ 9. Lip biopsy >2*

0. Lip biopsy)2+

subjective xerostomia and rose-bengal staining and subjective xerostomla and parotid grand enrargement and parotid flow and subjective xerostomia and parotid flow and rose-bengal staining and parotid flow

Sensitivity Specificity (:%) (%\

Total misclassif. error rate (Vo)

89 95 95 79

7 t2 13 17

9 85 82 85

4

100

9l

l0 l3

79 74

94 9l

l2 15

23

24

F. N. Skopouliet al.

Table lL Clus.sificationcriteria-secondary S.idgrens svndrome-Rheumatoid arthritis patients (based on (ompurison betuteengroup III and group IV pntients) Sensitivity (%)

Criteria

l . [ . i pb i o p s y> 2 + 2 . L i p b i o p s y) 2 + 3 . L i p b i o p s y2 2 + 4 . L , i pb i o p s y > 2 + - s .I - i p b i o p s y > 2 + 6. [-ipbiopsy>2+ 7. Lip biopsy >2+ 8. Lip biopsy)2* 9. Lip biopsy )2+

100 a n d s u b j e c t i v ex e r o p h t h a l m i a a n d s u b - i e c t i v ex e r o p h t h a l m i aa n d r o s e - b e n g a l 9l staining a n d s u b j e c t i v ex e r o p h t h a l m i aa n d S c h i r m e r ' s 'test tll al a n d r o s e - b e n g asl t a i n i n C 73 a n d r o s e - b e n g a ls t a i n i n ga n d S c h i r m e r ' s t e s t til a n d S c h i r m e r ' st e s t 63 and parotid flow 9 a n d s u b j e c t i v ex e r o s t o m i a t) and parotid gland enlargement

Specificity (%)

Total misclassif. error rate (Vc)

91 100

2

100 19 84 8l 89 91 r00

t8 l8 l6 l8 22 22

I

The results of discriminant analysis showed the following: l) In primSS patients three parameters were selected successively: parotid gland enlargement, lip biopsy and rosebengal staining, 2) for secSS patients two parameters were selected successively:subject i v e x e r o p h t h a l m i aa n d r o s e - b e n g a sl t a i n i n gt e s t .

DISCUSSION-CONCLU SIONS The primary purpose of this analysis was to develop diagnostic criteria for determining whether a patient can be classified as having definite pnmSS or definite secSS in association with RA. This was based on the following variables: subjective xerophthalmia, Schirmer's test, rose-bengalstaining test. subjective rerostomia, parotid flow rate, parotid g l a n de n l a r g e m e n at n d l a b i a l m i n o r s a l i v a r l ' g l a n db i o p s y ' .P o s i t i v el a b i a l b i o p s y ( > 2 + ) w a s used as a prerequisile diagnostic variable for both primary' and secondary definite Sjog r e n ' s s y n d r o m e . T h i s w a s a p p l i e d a s a s i n e q u a n o n d i a g n o s t i cc r i t e r i o n f o r S j o g r e n ' s s y n d r o m e b e c a u s ei t r u l e s o u t j t h e r p a t h o l o g i c e n t i t i e s t h a t m i m i c S j o g r e n ' s s y n d r o m e ( s a r c o i d o s i sa, m y l o i d c l s i sl,i p o p r o t e i n e m i a g . r a n u l o m a t o u sd i s e a s e se, t c . ) ( 2 ) . O t h e r i n v e s tigators have shown that labial histopathologr is highlr specific and sensitive for the d i a g n o s i so f S j o g r e n ' ss y n d r o m e ( 3 ) . Analysis of our data shows that variables like Schirmer's test I and parotid flow rate h a v e l o w s p e c i f i c i t ya n d s e n s i t i v i t yf o r S S . T h u s . w e e x c l u d e d t h e m f r o m t h e d i a g n o s t i c criteria. In contrast. rose-bengalstaining test seems to be the most useful examination to establishthe subjective xerophthalmia of patients r,"ith S-logren'ssyndrome. S u b j e c t i v ex e r o p h t h a l m i ai s t h e m o s t c o m m o n s t ' m p t o m i n p a t i e n t s w i t h d e f i n i t e s e c ondary SS in association with RA instead of subjective rerostomia and PGE which have very low incidence in these patients. On the other hand in primary SS, PGE and subjective xerostomia are the most common clinical manifestations.On the basis of our statistical analysiswe can conclude that: l) Definite primSS can be diagnosedin the absenceof any other autoimmune rheumatic diseaseand in the presenceof either recurrent parotid gland enlargement, or subjective xerostomia, or positive rose-bengal staining in addition to p o s i t i v em i n o r s a l i v a r yg l a n d b i o p s y e 2 + ) . 2 ) D e f i n i l e . r e r ' . l Sa n d R A c a n b e d i a g n o s e di n the presence of classical or definite RA, subjective xerophthalmia and positive minor s a l i v a r yg l a n d b i o p s y ( > - 2 + ) .

Criteria for Sjogren's syndrome

ACKNOWLEDGEMENT The authors wish to thank Mrs A. Kyriazi for her computer programming assistance, Dr R. C. Kitridou for her suggestions and Ms E. E. Papanikolaou for secretarial assisiance.

REFERENCES I' Armitage'P': Statistical Methodsin MedicalResearch. BlackwellScientificpublications, oxford, 2 ' B l o c h ,K . J . . B u c h a n a nw , . w . , w o h l , M . J . & B u n i m ,J . J . : S j o g r e n , s y n d r o m ea: c r i n i c a r , pathologicaland serologicalstudy of sixty-twocases.Medicinetg-;i;;r.r iq, ft1, tgss. 3' Daniels'T' E': Labial ialivary giand biopsyin Sjogren'ssyndrome:assessment as a diagnostic criterionin 362suspected .ur.r. ArthritisRheum27:147, r9g4. o R', Frost-Larsen. K', Isager,H. & Prause,J. U.: Sjcigren's syndrome.Allergy 36:139, Hitnt*e' 5 ' M o u t s o p o u l o sH, . M . , w e b e r , B . L . , v l a g o p o u r o sT, . p . , c h u s e d ,T . M . & D e c k e r , J. L.: Differencesin the clinical manifestation, Jf ,i..u ,ynorome in the presenceand absence of rheumatoidarthritis.Am J Med 66:733, 1979. 6' MoutsopouloH s ,. M . . K l i p p e r ,J . H . , p a v r i d i s , N . , w o r f , R . o . , S w e e t J, . 8 . , S t e i n b e r gA, . D., chu' F' c' & Tarpley,T'M.: correlative histologicand serologicfindingsof siccasyndrome in patiertswith systemiclupuserythematosus. ArthritisRheum 23:37,19g0. 7' Tarpley'T' M" Anderson'L. G. & white, c. L.: Minor salivaryglandinvolvement in Sjcigren,s syndrome.Oral Surg37:64, 1974.

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