Sjogrens Syndrome When your tears are more than precious
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A Patients Perspective
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Sicca is Misery
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The Doctors response? Its a chronic disease for which we have
NO cure. Its life-style threatening NOT really life-
threatening
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Overview Historical Background Epidemiology Clinical
Manifestations Classification Criteria Mechanisms and Pathogenesis
Evidence Based Therapeutic Options Novel Therapies Being
Studied.
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Historical background 1882 Leber described filamentary
keratitis 1888 Mikulicz described a patient with bilateral lacrimal
and parotid enlargement. 1933 Henrik Sjgren described the
association of filamentary keratitis with arthritis. 1953 Morgan
and Castleman noted the commonality between the glandular
enlargement described by Mikulicz and the keratitis described by
Sjgren Sjgren's syndrome (SS)
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Historical background, ctd: 1980 Talal introduced the term
autoimmune exocrinopathy Skopouli and Moutsopoulos introduced the
term autoimmune epitheliitis
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Henrik Samuel Conrad Sjogren 1933
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Sjogrens Syndrome Epidemiology Autoimmune disease targeting
lacrimal and salivary glands. Can be Primary or secondary. Mostly
women, aged 40-50 years. 1 Currently 50% of SS patients are
undiagnosed. Early onset (
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Sjogrens Syndrome Clinical Pearls
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Primary Sjogrens Syndrome Clinical Symptoms Clinical
HallmarksExtraglandular Features Dry eyes Dry mouth Anti Ro Anti-La
Neurological complications Dry nose Pulmonary involvement Liver
complications GI complications Dry skin Vasculitis
Arthralgia/Arthritis Peripheral neuropathy Fatigue
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Classification Criteria Primary Sjogrens Syndrome 1. Ocular
Symptoms (at least one) Symptoms of dry eyes for at least 3 months
A foreign body sensation in the eyes Use of artificial tears 3 or
more times per day II. Oral Symptoms (at least one) Symptoms of dry
mouth for at least 3 months Recurrent or persistently swollen
salivary glands Need for liquids to swallow dry foods Vitali C,et
al. Ann Rheum Dis.2002;61:554-558
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Classification Criteria Primary Sjogrens Syndrome:
III.objective Ocular Signs (at least one) Abnormal Schirmers test,
(without anesthesia; 5 mm/5 minutes) Positive vital dye staining of
the eye surface IV.Positive histopathology of minor salivary
glands: Lip biopsy showing focal lymphocytic sialoadenitis (focus
score 1 per 4 mm 2 ) V. objectiveOral Signs (at least one)
Unstimulated whole salivary flow (1.5 mL in 15 minutes) Abnormal
parotid sialography Abnormal salivary scintigraphy VI. anti Ro
and/or anti La antibodies Vitali C,et al. Ann Rheum
Dis.2002;61:554-558
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Classification Criteria Primary Sjgrens syndrome diagnosis: Any
4 of the 6 criteria, must include either item IV (Histopathology)
or VI (Autoantibodies) Any 3 of the 4 objective criteria (III, IV,
V, VI) Secondary Sjgrens syndrome diagnosis: Well-defined major
connective tissue disease One symptom (I or II) plus 2 of the 3
objective criteria (III, IV and V) is indicative of secondary
SS.
Proposed SS classification criteria 2012: at least 2 of the
following 3 objective features: 1. Positive serum anti-SSA/Ro
and/or anti-SSB/La or (positive rheumatoid factor and ANA titer
1:320) 2. Labial salivary gland biopsy exhibiting focal lymphocytic
sialadenitis with a focus score 1 focus/4 mm2 3.
Keratoconjunctivitis sicca with ocular staining score 3 (assuming
that individual is not currently using daily eye drops for glaucoma
and has not had corneal surgery or cosmetic eyelid surgery in the
last 5 years)
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Proposed SS classification criteria 2012: Prior diagnosis of
any of the following conditions would exclude participation in SS
studies or therapeutic trials because of overlapping clinical
features or interference with criteria tests: History of head and
neck radiation treatment Hepatitis C infection Acquired
immunodeficiency syndrome Sarcoidosis Amyloidosis Graft versus host
disease IgG4-related
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CLASSIFICATION CRITERIA
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Differential Diagnosis MedicationsAnticholinergic drugs Past
treatmentsPast head/neck radiation Systemic DiseaseSarcoidosis
Hepatitis C HIV/AIDS Graft-versus-host disease Pre existing
lymphoma RA SLE Systemic sclerosis Primary biliary cirrhosis
Diabetes Mellitus CMV or other Herpes virus
Sjogrens syndrome Clinical pearls 25% of SS pts may have no
detectable salivary flow 55% with dry skin at presentation. Ss pts
also have increased recurrent sinusitis, chronic cough, recurrent
oral candidiasis, indigestion, constipation, dysphagia and
dysgeusia
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Sjogrens syndrome Clinical pearls 45% of SS pts have thyroid
dysfunction. SS is 10 times higher in autoimmune thyroiditis pts.
Raynauds in 13% of SS Over half of SS pts will have subclinical
muscle inflammation. Over half will have arthralgia. Depression is
very common in SS pts. Fatigue if profound, significantly limiting
the activities of more than half the patients Voulgarellis M&
AG Tziousfas.Nat Rev Rheum 2010. Bayetto&Logan. Austral Dental
j. 2010
Sjogrens Syndrome Clinical Pearls High risk of lymphoma
development and therefore high mortality rates : 1. Severe
involvement of exocrine glands 2. Vasculitis 3. Low C4levels 4.
Cryoglobulinemia Malignant lymphoma may be at 44 times higher than
the general population.
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Sjogrens Syndrome Clinical Pearls pSS associated lymphomas:
Often develop in mucosal locations where pSS is active Mostly
B-cell non-Hodgkin lymphomas (NHL) with a predominance of the low
grade, marginal zone MALT histological type. Royer, B. et al.
Lymphomas in patients with Sjgren's syndrome are marginal zone
B-cell neoplasms, arise in diverse extranodal and nodal sites, and
are not associated with viruses. Blood90, 766775 (1997).
Voulgarelis, M. et al. Prognosis and outcome of non-Hodgkin
lymphoma in primary Sjgren syndrome. Medicine (Baltimore)91, 19
(2012).
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Sjogrens syndrome Clinical pearls: Vascuiltis One of the more
common extragladular manifestations. Approximately half with
subcutaneous vasculitis have only one episode. Associated with more
severe SS disease. Therapy for vasculitis: steroids. IVIG may be
affective Scofield RH.Curr Rheum report.2011
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Sjogrens syndrome Clinical pearls: Sjogrens syndrome Clinical
pearls: Neuropathy Neurological manifestations in PSS varies from
10 to 60%. Sensory neuropathy is the most common. Patients with
neuropathy are more likely to have palpable purpura, vasculitis,
cryoglobulinemia, monoclonal gammopathy, and lymphoma. Usually a
late event associated with systemic disease. Mechanism is unclear
Chai & Logigian. Curr Opin Neurol2010, Pavlakis et al. J Neurol
Neurosurg Psych 2011, Sene et al. Medicine 2011
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Sjogrens syndrome Neuropathy
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Sjogrens associated neuropathy Sjogren, 1935: Case 9: Bilateral
chronic otitis media; Bilateral VII nerve neuritis. In my previous
work, I noticed that decreased sensation of the conjunctiva and the
cornea sometimes occurs. This variable and very inconstant symptom
results from the local histological modifications and must not be
considered as a trigeminal nerve involvement. Other sensory
impairment in the territory of the trigeminal nerve was not
observed.
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Sjogrens associated neuropathy Sheldon,1939: Case report: there
have developed during the same period: 1. Mental changes, for which
she has been a voluntary inmate in the Staffordshire County Asylum.
The symptoms are mostly of a delusional type and are cheerful in
character. 2. Epileptic fits.
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Sjogrens associated neuropathy Weber,1945: described nonocular
features of SS in several case reports, 2 of them with nervous
system involvement Coverdale,1948: described patients with SS "with
unusual' constitutional features," one of whom had neurological
manifestations: Mr A... aged 68 years... made no complaint of these
disabilities (xerostomia and xerophthalmia) until a few months ago
when he had a cerebral hemorrhage with hemiplegia and his eyes
became worse.
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Sjogrens associated neuropathy Attwood and Poser, 1961: first
detailed case of neurological manifestations in SS. a patient with
multiple cranial nerve palsies, sensory polyneuropathy, and
cerebellar syndrome. Then, a few isolated cases of sensorimotor
polyneuropathy were very briefly mentioned.
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Kaltreider and Talal, 1969: the first accurate work on
peripheral neuropathy in SS: 109 cases reviewed over 10 yrs.
frequency of peripheral neuropathy in SS (8.25%) Clinical pattern:
5 sensorimotor polyneuropathies, 2 sensory polyneuropathies, 2
multiple mononeuropathies. 1 Trigeminal sensory neuropathy Sicca
complex preceded neurological manifestations in 9 of 10 pts,
intervl=4yrs. Sjogrens associated neuropathy
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Horwich et al,1977 Malinow et al, only in 1986: first
histopathological documentation of dorsal root ganglionitis in
subacute sensory neuronopathy associated with Sjgren's
syndrome
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Peripheral neuropathy associated with SS: Sjogren1935Bilateral
facial palsy, transient sensory changes Attwood and
Poser1961Peripheral neuropathy and multiple cranial neuropathies(
III, V,VII, X,XII) Talal1967Peripheral neuropathy
Gumpel1969Peripheral neuropathy Kaltreider and Talal1969Peripheral
and trigeminal neuropathy Pittsley and Talal1980Peripheral and
cranial neuropathy Alexander1981,1982 peripheral S&M
polyneuropathy, cranial neuropathy, MNM,CTS
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Peripheral neuropathy associated with SS:
Peyronnard1982Sensorimotor neuropathy Malinow1986Pure sensory
neuropathy And so on....and so on...
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CNS involvement in SS: Sheldon1939Seizures
Weber1945Internuclear opthalmoplegia,ptosis, mental changes, Sz
Coverdale1948Hemiplegia Heaton1959Sz,Hemianopsia
Kaltreider1969Seizures Stolze19692 cerebrovascular accidents in 139
pts with SS Kaltreider and Talal19691 pt with CNS vasculitis of 109
SS
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CNS involvement in SS: Viala and Masson1970Hemiparesis, ataxia
Shearn1971Peivascular lymphocytic infilterates Steinberg,Green and
Talal1971Thrombootic thrombocytopenic purpura Monda1979Ataxia,
nystagmus Alexander19818 SS pts with CNS symptoms: hemiparesis,
aseptic ME, acute transverse myelitis, SAH, progressive myelopathy
Molina1985Same findings in 50 SS pts with inflammatory vascular
disease
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CNS involvement in SS: Alexander198620% of SS have CNS symptoms
Malinow1986Sz, movement disorders, aseptic meningitis, cognitive
dysfunction, spinal cord dysfunction Rutan1986Transverse myelitis
Drosos1989No CNS symptoms in 52 pts with primary SS
Hietaharju199022% of CNS symptoms in 44 primary SS pts
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CNS involvement in SS: Spezialetti199359% of CNS symptoms in 48
primary SS pts Moutsopoulus19931 in 300 pts (the lowest)
Tajima19973 of 21 primary SS pts. Wingerchuk DM1999NMO Anaya20023
0f 120 pts with primary SS (MS like, complicated migraine, optic
neuritis)
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Other Extraglandular Features of SS: Skin: Xerosis Raynauds and
cutaneous vasculitis Annular erythema Erythema nodosum Livedo
reticularis Lichen planus Vitiligo Cutaneous amyloidosis Granuloma
annulare Angular cheilitis
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Other Extraglandular Features of SS: Pulmonary manifestations:
Xerotrachea Pulmonary vascular disease / PAH. ILD: NSIP, LIP,UIP,
organizing pneumonia Follicular bronchiolitis. Nodular lymphoid
hyperplasia Lymphoma Pulmonary nodular amyloidosis
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Other Extraglandular Features of SS: Interstitial nephritis:
Fanconi syndrome Distal (type 1) RTA Nephrogenic Hypokalemia
Glomerular disease: MPGN MN Renal Involvement
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Other Extraglandular Features of SS: Urinary Bladder:
Interstitial cystitis: dysuria urinary frequency nocturia
urgency
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Other Extraglandular Features of SS: GIT: Dysphagia. Nausea,
epigastric pain, and dyspepsia Atrophic gastritis Achlorhydria /
pernicious anemia Celiac disease LIVER: PBC Portal tract fibrosis
Idiopathic portal hypertension. Chronic active hepatitis !!!!
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Pathogenesis of Sjogrens Syndrome
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Pathogenesis of Sjogrens syndrome Voulgarelis, M. &
Tzioufas, A. G. (2010) Pathogenetic mechanisms in the initiation
and perpetuation of Sjgrens syndrome Nat. Rev. Rheumatol.
doi:10.1038/nrrheum.2010.118
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Genetics, Genomics and viral infections Genetics: mutations in
: IRF5 (IFN regulatory factor 5) STAT4 (signal transducer and
activator of transcription 4), a protein involved in the type II
IFN pathway. BLK (encoding B-lymphocyte kinase) IL12A (encoding
IL-12 subunit ) TNIP1 (encoding TNFAIP3-interacting protein 1)
CXCR5 (CXC chemokine receptor 5) Association of muscurinic receptor
3 gene variants. Genomics: gene expression profiles show an
elevated interferon signature. Voulgarellis M,et al Nat Rev
Rheumatol 2010;6:529-537, Appel S,et al, Ann Rheum Dis
2011;70:1327-9, LowHZ,et al. Arthritis Res Ther 2011;13:218,
Scofield RH. Curr Opin Rheumatol 2009; 21: 448-453
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Table 1 Polymorphic genes associated with pSS Nocturne, G.
& Mariette, X. (2013) Advances in understanding the
pathogenesis of primary Sjgrens syndrome Nat. Rev. Rheumatol.
doi:10.1038/nrrheum.2013.110
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Genetics, Genomics and viral infections Viral Infections: EBV
Human T lymphotrophic virus type 1 Hepatitis C virus. Coxsacki
virus. Retroviruses. NONE Could be Replicated. Is the virus
stimulus not detectable at the stage of the disease? Voulgarellis
M,et al Nat Rev Rheumatol 2010;6:529-537, Appel S,et al, Ann Rheum
Dis 2011;70:1327-9, LowHZ,et al. Arthritis Res Ther 2011;13:218,
Scofield RH. Curr Opin Rheumatol 2009; 21: 448-453
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Genetics, Genomics and viral infections Fas-deficient C57BL/6
lpr/lpr mice Salivary gland infilterates without CMV 3 mo
genetically predisposed to development of systemic autoimmunity
with glomerulonephritis, but without salivary gland involvement
Sialotropic CMV Fleck, M., Kern, E. R., Zhou, T., Lang, B. &
Mountz, J. D. Murine cytomegalovirus induces a Sjgren's
syndrome-like disease in C57Bl/6-lpr/lpr mice. Arthritis Rheum.41,
21752184 (1998).
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Pathogenesis of Sjogrens syndrome
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Dendritic Cells: Found in salivary glands of patients Increased
IFN signature Cytokines: Increase in proinflammatory cytokines
(IL1b, IL6, IL7, IL10,IFNg,TNF) TH1 cytokines found to dominate
early phase TH2 dominated late phase
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Pathogenesis of Sjogrens syndrome CYTOKINES
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Pathogenesis of Sjogrens syndrome T cells: Increased Th17 cells
in salivary glands Potential defect in Tregs( as disease advances
numbers of Treg drops) T cell cytokines: TH1 cytokines dominate in
early SS disease stage. TH2 cytokines dominate in later SS disease
stage Upregulation of IL6 results in Th17 cells forming germinal
centers in salivary glands
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Pathogenesis of Sjogrens syndrome B cells: Migrate to the
salivary gland due to increased cytokines and chemo attractants.
Formation of ectopic germinal centers. Increased activation of B
cells. Autoantibodies: Hypergammaglobulinemia Production of
anti-RF, anti-Ro(SSA),and/or anti-La(SSB) Blys(BAFF): B cell
stimulator Upregulated expression Plays a key role in development
of germinal centers
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Autoantibodies 80-90% of primary SS pts will have at least one
of anti-Ro, anti-La and/or RF. Anti Ro/La are linked with : 1.
Earlier disease onset 2. Increased disease severity 3. Longer
disease duration 4. Extraglandular involvement.
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Autoantibodies Targets of autoantibodies: Ro52(TRIM21) : an
interferon inducible gene which serves as a negative feedback
regulator of proinflammatory cytokines. Muscrinic M3 acetylcholine
receptors. alpha-fodrin (an actin-binding protein) Islet cell
autoantigen Voulgareliis M&AG Tziousfas. Nat Rev Rheum2010,
Al-Hasimi et al,J Oral Pathol Med 2001, Jonnson et al, immunology
letters 2011
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Pathogenesis of Sjogrens syndrome Voulgarellis M,et al.Nat Rev
Rheumtol. 2010;6:529-537
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Figure 1 Schematic representation of the pathophysiology
processes hypothesized to underlie pSS, based on our current
understanding Nocturne, G. & Mariette, X. (2013) Advances in
understanding the pathogenesis of primary Sjgrens syndrome Nat.
Rev. Rheumatol. doi:10.1038/nrrheum.2013.110
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Treatment of Sjogrens syndrome
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Typically treat symptoms: Moisturizing eye drops Eye ointments
at night Mouth gels, sprays, and specialized washes Artificial
saliva
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Sjogrens syndrome Treatment: Evidence Based Medicine Overall
quite modest Between 1986 and 2010, 1,791 publications in Medline
and EMBASE referring to Sjogrens syndrome. Of these 37 are
controlled trials and 19 are prospective cohort studies. Majority
focus on symptoms of dry eyes or dry mouth. Large trials also
include patients with sicca. Ramos-Casals,et al.JAMA
2010;304:452-60
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Sjogrens syndrome Treatment; Ocular treatment Topical NSAIDs(
0.1% diclofenac or 0.1% indomethacin) may decrease corneal
sensitivity. Topical steroids may help while being used but no
sustained relief. Punctal occlusion. Ramos-Casals,et al. JAMA
304:452-60
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Sjogrens syndrome Treatment; Ocular treatment 3 placebo
controlled trials using topical cyclosporin in 1451 subjects with
moderate to sever dry eyes: Subjective and objective improvement
(p