Sjgrens Syndrome

1
Sjögrens Syndrome
Classification Criteria
Extraglandular Manifestations
Clinical Follow-up

• Systemic Therapy

Claudio Vitali, MD Dept. of Internal Medicine and
Section of Rheumatology Piombino, Italy
2
Sjögrens Syndrome - Definition

• Sjögren's syndrome (SS) is defined as an
  autoimmune disease of the exocrine glands,
  involving in particular the salivary and lacrimal
  glands.
• It may occur alone (primary SS), or in
  association with a variety of connective tissue
  diseases and autoimmune disorders (secondary SS).
  
• The spectrum of presentation of the disorder is
  very broad, ranging from the local consequences
  of exocrine gland dysfunction to major,
  life-threatening systemic complications such as
  vasculitis, and renal or lung involvement.

3
Sjögrens Syndrome - Associations

• Rheumatoid arthritis
• Systemic Lupus
• Scleroderma
• Mixed Connective Tissue Disease
• Primary Biliary Cirrhosis
• Myositis
• Vasculitis
• Thyroiditis
• Chronic Active Hepatitis
• Mixed Cryoglobulinaemia

4
Sjögrens Syndrome
Classification Criteria
Extraglandular Manifestations
Clinical Follow-up

• Systemic Therapy

5
Sjögrens Syndrome
Extraglandular Manifestations
Classification (Diagnostic) Criteria
Clinical Follow-up

• Systemic Therapy

6
(No Transcript)
7
(No Transcript)
8
(No Transcript)
9
Types of Criteria for Rheumatic Diseases(from
Fries JF, et al. Arthritis Rheum, 1994)
10
Classification Criteria for SjSIssues

• Introductory Remarks
• History
• European/American classification criteria
• Impact of different classification criteria on
  the Scientific Community
• Performance of different classification criteria
  sets

11
Classification Criteria for Sjögrens
SyndromeIntroductory Remarks

• Conceptually, classification criteria are the
  same as diagnostic criteria. This is particularly
  true when sensitivity and specificity of
  classification criteria were both close to 100.
• However, classification criteria are usually not
  perfect and a certain proportion of patients is
  always misclassified.
• Thus, classification criteria do not have the
  medical standing of a diagnosis and the physician
  is the only one who can establish a diagnosis for
  an individual patient.

12
Classification Criteria are not aimed at the
Diagnosis
13
Classification Criteria are a Communication Tool
14
(No Transcript)
15
Classification Criteria for Sjögrens
Syndrome Historical Overview
16
San Diego Classification Criteria for SjS (Fox
RI et al., 1986)

• Histopathology of minor salivary (or lacrimal)
  glands (focus score 2)
• Salivary gland involvement
• Symptomatic xerostomia plus
• Decreased Unstimulated and Stimulated whole
  salivary gland flow
• Ocular involvement
• Positivity of Schirmers I test (lt9 mm/5min)
• plus Increased Staining with Rose Bengal test
  (or fluorescin test)
• Autoantibodies
• Presence of anti-Ro/La antibodies or
• Presence of ANA or
• Presence of RF
• Exclusions
• Pre-existing lymphoma
• Graft-versus-host disease
• Acquired Immunodeficiency disease
• Sarcoidosis

17
The Mosaic of Different Classification Criteria
Sets
included
not included
18
The application of different diagnostic criteria
over the years has led to a heterogeneous group
of patients being given the diagnosis of
SjS. There is an increasing need to establish
internationally recognized criteria for the
diagnosis of SjS, both to provide common basis
for defining patients for studies and to clarify
case-by-case clinical diagnosis. Proceedings of
2nd International Symposium on SS (San Antonio,
Texas, 1989). J Autoimmun 1989 2 529-41
19
Pisa, September 1988 Meeting of the Experts
20
Preliminary criteria for the classification of
Sjögren's syndrome. Results of a prospective
concerted action supported by the European
Community. Vitali C, Bombardieri S, Moutsopoulos
HM, et al. Arthritis Rheum 1993 36 340-7
21
Assessment of the European classification
criteria for Sjögren's syndrome in a series of
clinically defined cases. Results of a
prospective multicentre study. Vitali C,
Bombardieri S, Moutsopoulos HM, et al. Ann Rheum
Dis 1996 55 116-22.
22
Venice, December 1999 VIIth International
Symposium on SjS
23
Classification Criteria for Sjögrens
Syndrome The European American Revision of the
Classification Criteria
24
Classification Criteria for Sjögrens Syndrome
25
(No Transcript)
26
Classification Criteria for Sjögrens
syndromeNew Rules for the Classification
27
Classification Tree for Primary SjS
sensitivity 96.05 specificity 94.2
28
Classification Criteria for Sjögrens
SyndromeAgreement on the Exclusion Criteria
29
Classification criteria for Sjögren's syndrome a
revised version of the European criteria proposed
by the American-European Consensus Group.
Vitali C, Bombardieri S, Jonsson R,
Moutsopoulos HM, Alexander EL, Carsons SE,
Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer
SR, Talal N, Weisman MH. Ann Rheum Dis 2002 61
554-8.
30
Classification Criteria for Rheumatic Diseases
31
Classification Criteria for Sjögrens
Syndrome The Impact of the Different
Classification Criteria Sets on the Scientific
Community
32
Number of Citations in the Medical Journals of
Different Classification Criteria Sets proposed
for Sjögrens SyndromeSource ISI-Web of Science
(Jan 1990-May 2004)
33
Classification Criteria for Sjögrens
Syndrome The Performance of Different
Classification Criteria Sets
34
Study Population
35 Patients with Clinically Defined Primary SjS
(1 Male, mean age 58.9 yrs.) 54 Disease
Controls 20 Patients with other CTDs, without
Secondary SjS (1 Male, mean age 49.0 yrs.) 34
Patients with Sicca Complaints, but without SjS
(5 Males, mean age 50.8 yrs.)
35
Classification CriteriaSensitivity - Definition
Prevalence of true patients which meet the
criteria designed to correctly classify patients
as having that disease.
TP TPFN
x100
36
Sensitivity of the Different Classification
Criteria Sets
plt.05 plt.01 plt.001






37
Classification CriteriaSpecificity - Definition
Prevalence of normal (or disease) controls which
do not meet the criteria designed to correctly
classify patients as having a given disease.
TN TNFP
x100
38
Specificity of the Different Classification
Criteria Sets

39
Classification CriteriaPositive Predictive Value
- Definition
Prevalence of cases which meet the criteria for a
given disease, which are true patients with that
disease.
TP TPFP
x100
40
Positive Predictive Value of the Different
Classification Criteria Sets

41
Classification CriteriaNegative Predictive Value
- Definition
Prevalence of cases which do not meet the
criteria for a given disease, which do not suffer
from that disease.
TN TNFN
x100
42
Negative Predictive Value of the Different
Classification Criteria Sets
plt.05 plt.01 plt.001






43
Classification CriteriaAccuracy - Definition
TNTP TNTPFNFP
x100
44
Accuracy of the Different Classification Criteria
Sets
plt.05 plt.01 plt.001






45
Concluding Remarks

• American-European Classification Criteria are
• the only validated,
• the most reliable,
• and
• the most widely accepted
• tool presently available for the classification
  of patients with primary and secondary Sjögrens
  syndrome.

46
Sjögrens Syndrome
Classification Criteria
Extraglandular Manifestations
Clinical Follow-up

• Systemic Therapy

47
Sjögrens Syndrome
Classification Criteria
Extraglandular Manifestations
Clinical Follow-up

• Systemic Therapy

48
SjS - Manifestazioni Cliniche Extraghiandolari
49
SjS - Alterazioni Sierologiche
50
Cutaneous involvement of patients with primary
SjS

• Cutaneous vasculitis
• SS associated small vessel vasculitis
•      Cryoglobulinaemic vasculitis
•      Urticarial vasculitis
•      Other leucocytoclastic vasculitis
• SS associated medium vessel vasculitis
• b) Other cutaneous processes
• Ro associated, polycyclic, photosensitive
  cutaneous lesions (SCLE)
• Erythema nodosum
• Livedo reticularis
• Thrombocytopenic purpura
• Lichen planus
• Vitiligo
• Nodular vasculitis
• Cutaneous amyloidosis
• Annular granuloma
• Granulomatous panniculitis

51
Pulmonary Involvement in primary SjS

• Various studies have recently described the
  predominance of bronchial/bronchiolar involvement
  rather than interstitial disease.
• Bronchiolar abnormalities is present in one third
  of the patients, with a higher frequency of air
  trapping in lower lobes.
• Small airway disease is the main functional
  disorder.
• Large and/or small airway disease was the
  predominant computed tomography scan pattern in
  more than 50 of patients.

52
Renal Disease in Patients with primary
SjS.Altered Renal Parameters and Renal Biopsies
No Altered renal parameters Proteinur
ia 55/198 28 Distal RTA 31/237 13 Low
creatinine clearance 29/182 16 Renal
biopsy Tubulointerstitial nephritis 16/27 59 G
lomerulonephritis 12/27 44 Membranoproliferat
ive 6/12 50 Mesangial proliferative 5/12 4
2 Membranous 1/12 8
53
Central Nervous System Involvement in primary
SjS. Clinical Features recently described

• Multiple sclerosis-like disease
• Myelopathy
•     Acute myelitis
•     Chronic myelopathy
• Central pontine myelinolysis
• Parkinsonism
• Painful tonic/dystonic spasms
• Bells palsy
• Optic neuritis
• CNS vasculitis
• CNS T cell lymphoma
• Cerebral amyloid angiopathy

54
Sensorineural hearing loss in patients with
primary SjS prevalence and immunological markers
  No Hearing loss ANA Anti-Ro/SSA
aCL Tumiati et al57 30 14 (47) 14 (100) 14
(100) 9 (64) Ziavra et al58 40 9
(23) 9(100) 7 (78) 1 (11) Boki et al59
48 7 (15) Hatzopoulos et al 22 8
(36) Total 140 38 (27) 23 (100) 21
(91) 10(43) Results are shown as No ().
55
Haematological Abnormalities in Patients with
primary SjS Recent Studies
  Prevalence References No/total No
() a) Red blood cell count Normocytic
anaemia 118/641 (18.4) 5, 62 Haemolytic
anaemia Isolated cases 62, 63 b) White blood
cell count Leucopenia 116/628 (18.5) 5, 62,
64 Lymphopenia 23/268 (8.6) 62 Neutropenia
19/268 (7.1) 62 Eosinophilia 31/268
(11.6) 62 Chronic agranulocytosis Isolated
cases 62, 63, 65, 66 c) Platelet
count Thrombocytopenia 55/479 (11.5) 62,
64 d) Other abnormalities Raised ESR (gt50 mm/1st
h) 82/380 (21.6) 62 Hypergammaglobulinaemia 19
1/585 (32.6) 5, 62, 67 Antiphospholipid
antibodies 24/184 (13) 62
56
Current Concepts in the Extraglandular
Expression of primary SjS (I)
 a) Cutaneous involvement Prognostic
significance of cryoglobulinaemia and purpura Ro
associated, polycyclic/photosensitive lesions
(SCLE-like) b) Pulmonary involvement High
frequency of bronchial/bronchiolar disease
(3050) Insidious and slow progression of
pulmonary disease c) Renal involvement Indolent
subclinical course of TIN Demonstration of
glomerulonephritis in 44 of pts biopsied Key
role of cryoglobulinaemia in SS related GMN d)
Neurological involvement Increased cerebral
white matter lesions Insidious course and poor
response to treatment of PSN Autonomic
disturbances (abnormal responses to CV tests)
57
Current Concepts in the Extraglandular
Expression of primary SjS (II)
 e) Lymphoproliferative involvement Prevalence
of 4 of lymphoma in cross sectional
studies Lymphadenopathy, purpura, and neuropathy
as clinical markers of lymphoproliferation Lym
phopenia, reduced complement, cryoglobulins,
and mIgs as analytical markers Salivary
glands as the main site of lymphoma Higher
prevalence of extranodal involvement f)
Miscellaneous Sensorineural hearing loss in
nearly 25 of patients Rare occurrence of
symptomatic cytopenias Fatigue
58
Sjögrens Syndrome
Classification Criteria
Extraglandular Manifestations
Clinical Follow-up

• Systemic Therapy

59
Sjögrens Syndrome
Classification Criteria
Extraglandular Manifestations
Clinical Follow-up

• Systemic Therapy

60
Types of Criteria for Rheumatic Diseases(from
Fries JF, et al. Arthritis Rheum, 1994)
61
Types of Criteria for Rheumatic Diseases(from
Fries JF, et al. Arthritis Rheum, 1994)
62
from Fries JF, et al. Arthritis Rheum, 1994
63
Disease activity in SLE is like pornography. It
is hard to define, but the experts recognise it
when they see it. J. Decker
64
Definition of Disease Activity

• The clinical course of CTDs is usually marked by
  episodes of flares in which clinical features of
  organ or system involvement become evident.
• Each flare of the disease may lead to damage and
  failure of the involved organ or system, if not
  reverted by adequate treatment.
• Activity can be considered a continuous and
  reversible concept, varying from zero to maximum
  activity.
• Severity is obviously an additional factor in
  activity judgement, since an active patients with
  severe manifestations is usually classified as
  more active than a patient with milder clinical
  features.

65
Definition of Disease Damage

• The concept of damage implies the concept of
  irreversibility of a lesion.
• Damage is a cumulative outcome measure which is
  usually stratified according to the severity of
  the considered lesions.
• For instance, renal failure or brain
  derangements, as final results of a long-lasting
  renal involvement or previous vascular accident,
  are severe outcomes and, consequently, obtain a
  higher value when the cumulative damage is
  measured.

66
STUDY PROTOCOL
67
Study Protocol (I)Enrolment of Patients

• Multicenter study in Italy
• Patients with primary SjS (according to Am-Eu
  Criteria)
• At least 50 of patients with some degree of
  disease activity, at the enrolment time (T0)
• In active patients a second clinical observation
  after 3 months (T1)

68
Study Protocol (II)Data Collection

• Standardised clinical chart (106
  clinical/serological variables subdivided in 15
  domains)
• Definition of any single item in a specific
  glossary
• Items derived from BILAG-SjS, ECLAM-SjS,
  SLICC-SjS
• BILAG scoring system for reversible items
  (absent, same, new, improving, worse).
• Y/N option for irreversible items
• Schirmers-I test and Unstimulated Whole Saliva
  Collection

69
Study Protocol (III)Scoring Patients for
Disease Activity and Damage

• The Observer from each Center had to judge every
  patient for the degree of disease activity and
  disease-related damage
• The Physicians Global Assessment was given only
  on the basis of his/her clinical evaluation at
  the end of the observation and after the data
  record
• A nominal scale and a numerical scale (from 0 to
  10) were used to classify/score each patient for
  both disease activity and damage, and represent
  the golden standard for each entity, respectively

70
Study Protocol (IV)Data Analysis (1 step)

• Univariate analyses to select variables which
  significantly correlated with activity and damage
  scores, respectively.
• Multivariate models for activity and damage
  (i.e., multiple linear regressions where the
  Observers numerical scores for activity and
  damage were used as dependent variables).
• b coefficients in the models were considered as
  indicative for the relative weights of the
  different items in the scales (stratification for
  severity)

71
Study Protocol (V) Data Analysis (2 step)

• Once scoring systems for activity and damage had
  been built, activity and damage levels were
  re-calculated accordingly.
• Construct validity of the scales was assessed
  by
• Simple regression analysis against Observers
  scores (Pearsons R), given at T0 and T1.
• Normality of the distribution of differences
  between the calculated scores and the
  corresponding given scores (Shapiro-Wilks test
  W ).

72
Study Protocol (VI) Data Analysis (3 step)

• Sensitivity to change (responsiveness) of SjSDAI
  was assessed by
• Simple regression analysis between T0-T1
  variation (D) of Observers scores and the
  corresponding overtime variation of SjSDAI scores
  (Pearsons R).
• The accuracy of SjSDAI of selecting patients
  classified by the Observer as active or very
  active, from those defined as inactive or mildly
  active, was tested by
• ROC curve analysis

73
RESULTS
74
Study Population

• 12 participating centres
• 206 patients with primary SjS
• 5 Males and 201 Females
• Age ranging from 19 to 84 yrs. (mean 55.4 yrs.)
• Disease duration ranging from 1 to 43 yrs. (mean
  8.86 yrs.)
• In 121 out of the 206 patients a second clinical
  observation was performed after 3 months

75
Results Activity
76
(No Transcript)
77
Activity - Multiple Linear Regression
Dependent variable Activity Score
(0-10) Independent variables b coefficient
t p Pleural/pulmonary manifestations
(new/worse) 0.506 15.028 0.000 Arthritis or
ingravescent arthalgia 0.328 9,692 0.000 Vasculiti
s 0.242 6.888 0.000 Lymphnode/spleen
enlargement 0.240 7,384 0.000 Active renal
involvement (excl. stable disease) 0.187 5,737 0.0
00 Fever 0.183 5,528 0.000 Fatigue
(presence) 0.176 3.793 0.000 Major salivary gland
swelling (new/worse) 0.154 4.684 0.000 Peripheral
neuropathy (recent onset) 0.095 2.735 0.007 Leuko/
lymphopenia 0.076 2.294 0.023 Fatigue
(new/worse) 0.059 1.630 0.105 r 0.894 p lt
0.0001
78
Sjögrens Syndrome Disease Activity Measurement
(SjSDAI)
79
SjSDAI Scoring System
Item Definition Score 1. Constitutional
complaints a. Fever gt38C, not due to
infections 1 b. Fatigue Sufficiently severe
to affect normal activities 1 c D of
fatigue New appearance or worsening of fatigue
1   2. Glandular complaints a. D of salivary
gland swelling New appearance or increasing
swelling of 3 major salivary glands (not
due to infection or stones)   3. Articular
complaints Any of the following 2 a.
Artrhitis Inflammatory joint pain in one or more
joints b. Evolving arthralgias New appearance
or worsening of joint pain without signs of
articular inflammation (with exclusion of
other causes of joint/muscle pain)
  4. Hematological features a.   
Leuko/lymphopenia lt3500 / lt1000 cmm 1 b.   
Lymphnode/spleen enlargement Clinically palpable
lymphnode/spleen 2   5. Pleural-pulmonary
complaints Any of the following 4 a.   
Pleurisy Confirmed by imaging, not due to
infection b.    Pneumonia (segmental or
interstitial) Ground glass aspects on CT scan,
not due to infection   6.
Vasculitis a. D of vasculitis New
appearance or worsening of vasculitis 3
(i.e., diffuse cutaneous vasculitis or palpable
purpura)   7.  Active renal involvement Any of
the following 2 a.    New or worsening
proteinuria more than 0.5 gr/day b.   
Increasing serum creatinine above the normal
limits c.    New or worsening nephritis
glomerular or interstitial, histologically
defined   8. Peripheral neuropathy Recent onset
(lt 6 months), by nerve conduction studies 1

80
Correlation between Given and Calculated SjSDAI
Scores 1 observation (206 patients)
Given Score
R 0.872 p lt 0.0001
Calculated Score (SjSDAI)
boxes interquartile range dark lines median
value whiskers extreme values
81
Correlation between Given and Calculated SjSDAI
Scores at 2observation (121 patients)
Given Score
R 0.817 p lt 0.0001
Calculated Score (SjSDAI)
boxes interquartile range dark lines median
value whiskers extreme values
82
Distribution of Differences (Obs Scores SjSDAI
Scores)
W 0.933 plt0.0001
W 0.927 plt0.0001
N of cases
1st observation time (206) pts.
2nd observation time (121) pts.
83
Sensitivity to Change of SjSDAI
D of given scores 1 vs 2 observation
R 0.683 p lt 0.0001
D of calculated scores (SjSDAI) 1 vs 2
observation
boxes interquartile range dark lines median
value whiskers extreme values
84
Sensitivity 86.5 Specificity 87.6
AUC Area Under the Curve
85
Results Damage
86
(No Transcript)
87
Damage - Multiple Linear Regression
Dependent variable Damage Score
(0-10) Independent variables b coefficient
t p Lymphoproliferative disease
0.425 9.395 0.000 Pleuro-pulmonary fibrosis
0.339 7.133 0.000 Schirmers I-test lt5 mm/5min
0.257 5.602 0.000 CNS involvement (long
lasting) 0.158 3.428 0.001 UWSC lt1.5/15
min 0.146 3.169 0.002 Ocular lesions
0,146 3.021 0.003 Stable renal involvement
0.142 3.056 0.003 Dental loss
0.125 2.630 0.009 Peripheral neuropathy (long
lasting) 0.115 2.451 0.015 r
0.778 p lt 0.0001
88
Sjögrens Syndrome Disease Damage Index (SjSDDI)
89
SjSDDI Scoring System
Item Definition Score 1.    Oral/salivary
damage a. salivary flow impairment UWSC lt 1.5
ml/15 min, by standard method (24,25) 1 b.
Loss of teeth Complete or almost complete
1   2.    Ocular damage a. tear flow
impairment Schirmers-I testlt5 mm/5min, by
standard method (24,25) 1 b. structural
abnormalities Corneal ulcers, cataract, chronic
blepharitis 1   3. Neurological damage a.
CNS involvement Long lasting stable CNS
involvement 2 b. Peripheral neuropathy Long
lasting stable peripheral nerve 1
or autonomic system impairment   4.
Pleural-pulmonary damage Any of the following
2 - Pleural fibrosis (confirmed by imaging)
- Interstitial fibrosis (confirmed by
imaging) - Significant irreversible functional
damage (by spirometry)   5. Renal impairment Any
of the following 2 - Stably raised serum
creatinine or reduced GFR - Tubular
acidosis (urinary pHgt6 and serum
bicarbonatelt15mmol/L in two
consecutive tests) - Nephrocalcinosis
(confirmed by imaging)   6. Lymphoproliferative
disease Any of the following 5 (clinically
and histologically confirmed) - B cell
lymphoma - Multiple myeloma -
Waldenstroms macroglobulinaemia
90

Correlation between Given and Calculated SjSDDI
Scores (206 patients)
R 0.760 p lt 0.0001
Given Score
boxes interquartile range dark lines median
value whiskers extreme values
Calculated SjSDDI Score
91
Distribution of Differences (Obs Scores SjSDDI
Scores)
W 0.940 plt0.0001
N of cases
92
Conclusions (I)

• In the present study specific scoring scales for
  disease activity (SjSDAI) and damage (SjSDDI) in
  SjS are firstly defined.
• The construct validity SjSDAI has been
  demostrated by testing this scale
• in the totality of the enrolled patients
• in a part of the patients re-evaluated after 3
  months.

93
Conclusions (II)

• Sensitivity to change (responsiveness) of SjSDAI
  has been showed by its ability to appreciate
  overtime variation of disease activity.
• Accuracy of SjSDAI in selecting active/very
  active patients (i.e., patients who probably need
  a more aggressive therapeutic approach) has also
  been verified.

94
Conclusions (III)

• A valid definition of damage in SjS is also
  obtained by applying SjSDDI.

95
Aknowledgements

• Patronage
• Italian Society of Rheumatology
• Protocol preparation
• Simon Bowman
• Database management and analysis
• Gianluigi Palombi

• Patients and data collection (in alphabetic order
  by the city)
• Covelli M (Bari)
• Franceschini F (Brescia)
• Govoni M (Ferrara)
• Benucci M (Florence)
• Maddali Bongi S (Florence)
• Del Papa N, Maglione W (Milan)
• Migliaresi S, Orefice M (Naples)
• Epis O, Montecucco C (Pavia)
• Gerli R (Perugia)
• Baldini C, Bombardieri S, Tavoni A (Pisa)
• Priori R, Valesini G (Rome)
• De Vita S (Udine)

96
Types of Criteria for Rheumatic Diseases(from
Fries JF, et al. Arthritis Rheum, 1994)
97
Mortality and its Predictors in primary SjS

• The standardized mortality ratio was 1.15 (95 CI
  0.86-1.73) compared with the general
  population.
• In incident cases, the probability of LPD was
  2.6 at 5 years and 3.9 at 10 years.
• Mortality rates were significantly higher in
  patients with low C4 levels (hazard ratio HR
  4.39, 95 CI 2.18-8.83).
• LPD was independently predicted by the presence
  (at the 1st visit) of
• parotid enlargement (HR 5.21, 95 CI 1.76-15.4)
  
• palpable purpura (HR 4.16, 95 CI 1.65-10.5)
• low C4 levels (HR 2.40, 95 CI 0.99-5.83)

Ioannidis JPA et al Arthritis Rheum, 2002
98
(No Transcript)
99
Theander E, et al, Arthritis Rhem, 2004
100
Possible Predictors of Death in Primary SjS
Variable HR (95 CI) P Male sex 1.28
(0.50-3.27) 0.61 MSGB 2.14 (1.07-4.25) 0.031
SSA/SSB positive 1.33 (0.73-2.40) 0.35 AECC
fulfilled 1.61 (0.86-3.02) 0.14 IgG gt17.5
gm/liter 1.12 (0.54-2.32) 0.76 IgM gt1.6
gm/liter 1.46 (0.69-3.09) 0.33 C3lt0.83
gm/liter 2.68 (1.30-5.52) 0.007 C4lt0.2
gm/liter 2.70 (1.27-5.70) 0.009 Low C3 and C4
3.00 (1.44-6.29) 0.003 at diagnosis HR
hazard ratio ANA antinuclear antibody AECC
American-European consensus criteria
Theander E, et al, Arthritis Rhem, 2004
101
Prognostic Subgroups in primary SjS

• Patients with low C4 levels, major salivary gland
  enlargement, palpable purpura may be classified
  as having a high-risk disease syndrome (type I
  autoimmune epithelitis).
• This group comprises 20 of the current primary
  SS diagnoses.
• Patients without these predictors (80 of all
  primary SS diagnoses) may be reassured that they
  have a low-risk (type II) form of primary SS that
  carries no increased risk of death.

102
CD4 T-lymphocytopenia as Predictor of LPD
Theander E, et al, Ann Rheum Dis, 2006
103
Sjögrens Syndrome
Classification Criteria
Extraglandular Manifestations
Clinical Follow-up

• Systemic Therapy

104
Sjögrens Syndrome
Classification Criteria
Extraglandular Manifestations

• Systemic Therapy

Clinical Follow-up
105
Evidence Based Treatment of SjSA Review of RCTs
using the Cochrane Approach

• Since 1978, 34 RTCs (testing 15 different
  therapeutic modalities) have been published.
• A trend towards larger sample size and improved
  quality of trials has been observed.
• There is evidence that muscarinic agonists
  (pilocarpine, cevimeline) and local IFN-a improve
  glandular function and symptomatology.
• Topical treatment with Cyclosporin eye drops
  shows anti-inflammatory effects and improves
  ocular symptoms, but results on tear secretion
  rate are conflicting.
• Systemic treatment with steroids and
  antimalarians downregulates markers of immune
  system activation, without evidence of any short-
  or long-term clinical benefit.
• Low dose oral azathioprine is ineffective and
  prone to side effects.
• K. Asmussen, VIII International Symposium on SS,
  Kanazawa, Japan, May 16-18 2002.

106
Evidence Based Treatment of SjSA Review of RCTs
using the Cochrane Approach
Conclusions No RCTs testing pharmacological
intervention in SjS have demonstrated
significant, stable and clinically meaningful
modification or remission of the disease
activity. Therefore, current treatment
principles remain palliative. K. Asmussen, VIII
International Symposium on SS, Kanazawa, Japan,
May 16-18 2002.
107
New therapeutic agents for the treatment of
patients with primary SjS
  Dose Number of patients treated References Mus
carinic agents Pilocarpine 5 mg/6 h po 127
(primary associated SS) 81 5 mg/12 h po 27
(primary SS) 82 Cevimeline 30 mg/8 h po 25
(primary associated SS) 83 62 (primary
associated SS) 84 Biological agents Infliximab 3
mg/kg ev 4 (SS associated with RA) 88 1
(primary SS neuropathy) 89 16 (primary
SS) 86, 87 5 mg/kg ev 54 (primary
SS) 90 Etanercept 25 mg/12 h sc 15 (primary
SS) 91 Rituximab 375 mg/m2 ev 1 (primary SS
lymphoma) 98 1 (primary SS
lymphoma) 99 IFNa 150 IU/8 h po 300 (primary
SS) 94
108
Pilocarpine in SjS

• Clinical studies with pilocarpine (Salagen)
  tablets have demonstrated significant subjective
  and objective benefit for xerostomia and related
  oral symptoms at doses of 20 mg/day or more.
• Symptomatic relief of xerophthalmia and other
  xeroses due to SjS may also occur.
• Data from human and animal models suggest that
  regular use of pilocarpine may not only improve
  patient quality of life, but potentially prevent
  complications as well.

109
Cevimeline (Evoxac) in SjS

• Approved by FDA for the treatment of dry mouth
• In comparison with pilocarpine has
• a longer half-life (about 5.0 vs. 1.5 hours)
• a higher specificity for muscarinic M3 receptor
  (salivary and lacrimal glands) than for M2
  receptor (heart and lung) by about 10-fold,
• this suggesting a theoretical benefit for its
  use.

110
Anti-TNFa Therapy in SjS

• In a open trial infliximab (3 infusions, 3 mg/kg)
  showed to improve unstimulated salivary flow and
  restore the normal aquasporin-5 distribution in
  minor salivary glands in a small number of
  patients with SS.
• In a single centre open pilot study on 15
  patients. etanercept (25mg twice weekly during 12
  weeks) showed to improve fatigue and reduce ESR
  and CRP levels. No effects were observed on the
  function of lacrimal and salivary glands.

111
Inefficacy of infliximab in primary Sjogren's
syndrome results of the randomized, controlled
Trial of Remicade in Primary Sjogren's Syndrome
(TRIPSS). Mariette X, Ravaud P, Steinfeld S,
Baron G, Goetz J, Hachulla E, Combe B, Puechal X,
Pennec Y, Sauvezie B, Perdriger A, Hayem G, Janin
A, Sibilia J. Arthritis Rheum 2004 50 1270-6.
112
Rituximab treatment in patients with primary
Sjogren's syndrome an open-label phase II study.
Pijpe J, van Imhoff GW, Spijkervet FK,
Roodenburg JL, Wolbink GJ, Mansour K, Vissink A,
Kallenberg CG, Bootsma H. Arthritis Rheum. 2005
Sep52(9)2740-50.
113
THERAPEUTIC GUIDELINES IN SJÖGREN'S SYNDROME

• Extraglandular manifestations (1)
• 1. arthralgias/ arthritis
• - NSAID's
• - steroids (low dosage)
• - anti-malarians
• 2. Raynaud's phenomenon
• - vaso-active drugs (Ca-antagonists)
• 3. haemocytopenia (usually mild forms)
• 4. vasculitis (purpura, peripheral
  neuropathies, etc.)
• - steroids (low/medium dosage)

114
THERAPEUTIC GUIDELINES IN SJÖGREN'S SYNDROME

• Extraglandular manifestations (2)
• 5. Myositis
• - steroids (high dosage or pulse)
• - MTX or cyclophosphamide (pulse)
• 6. Interstitial lung involvement (in active
  phase )
• - steroids (high dosage or pulse)
• - cyclophosphamide (daily dose or pulse )
• 7. Tubulointerstitial nephritis
• - steroid (medium/high dosage)
• - bicarbonates to correct acidosis in a late
  phase

115
THERAPEUTIC GUIDELINES IN SJÖGREN'S SYNDROME

• Extraglandular manifestations (3)
• 8. Fatigue and depression
• Steroids (low dosage) are indicated in the case
  of late morning or early afternoon fatigue, often
  associated with flulike symptoms and probably
  related to disease activity and production of
  specific cytokines (IL-1, TNF-a).
• Psychoactive drugs in the case of early morning
  fatigue, often associated with poor sleep and
  fibromyalgia symptoms. Benzodiazepine agents to
  induce sleep and antidepressant drugs lacking
  anticholinergic effects (fluoxetine, fluvoxamine,
  etc.) can be tried.

116
Lymphoproliferative Disorders in SjS

• - Pseudolymphoma
• - plasma cell granuloma
• - Castleman's disease
• - Waldenstrom's macroglobulinaemia
• - multiple myeloma
• - B cell lymphoma
• Surveillance
• Clinical follow up and monitoring of warning
  signals
• Collaborations with Dpts. of Haematology and
  Oncology

117
Clinical Follow up and Monitoring of Warning
Signals

• persistent falling of gammaglobulins and
  evolution to hypogammaglobulinaemia (hypo-IgG)
• sudden increase of gammaglobulins with mIgs
• appearance or increase of cryoglobulins (and
  cryoglobulinemic purpura)
• presence or appearance of low complement
• falling or disappearance of autoantibodies
• reduced resistence to bacterial infections
• sudden (recurrent) swelling of one or both
  parotid glands

118
Conclusions

• Am-Eu classification criteria for SjS are highly
  accurate and reliable. So, these can be also used
  as diagnostic criteria in clinical practice.
• Activity and damage criteria are now available.
  These can be useful in following-up patients with
  glandular and extra-glandular manifestations of
  the disease, and in monitoring the effects of
  therapy.
• Some clinical and serological markers have been
  identified which are able to predict the
  likelihood of LPD development and to select
  patients at highest risk of death.
• Systemic treatment of SjS is often based only on
  empirical data. More consistent arguments exist
  on the use of muscarinic agonists. Promising data
  are emerging on some biological agents.

119
Grazie per l'attenzione