Sjogren’s Syndrome When your tears are more than precious.

Sjogrens Syndrome When your tears are more than precious

A Patients Perspective

Sicca is Misery

The Doctors response? Its a chronic disease for which we have NO cure. Its life-style threatening NOT really life- threatening

Overview Historical Background Epidemiology Clinical Manifestations Classification Criteria Mechanisms and Pathogenesis Evidence Based Therapeutic Options Novel Therapies Being Studied.

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)

Historical background, ctd: 1980 Talal introduced the term autoimmune exocrinopathy Skopouli and Moutsopoulos introduced the term autoimmune epitheliitis

Henrik Samuel Conrad Sjogren 1933

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 (

Sjogrens Syndrome Clinical Pearls

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

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

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

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.

Secondary Sjogrens syndrome clinical symptoms Clinical Hallmarks: Dry eyes Dry mouth Autoimmune disorders: Rheumatoid arthritis SLE Scleroderma

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)

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

CLASSIFICATION CRITERIA

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

Symptoms associated with SS: extraglandular manifestations FatiguePeripheral neuropathy Primary biliary cirrhosis FibromyalgiaRenal tubular acidosis GI symptoms FeverMyositisRespiratory diseases ArthralgiasChronic hepatitisPsychosis SynovitisPurpuraLymphadenopathy RaynaudsVasculitisSplenomegaly Depressionlymphoma Autoimmune thyroiditis

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

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

SS: Increased lymphoma risk DisorderNo. of studies All NHL: Ever/Never (%) Controls: Ever/Never (%) OR (95% CI) RA12504/11735 (4.3) 556/15222 (3.7) 1.06 (0.87-1.29) Psoriasis7278/7460 (3.7) 279/10122 (2.8) 1.16 (0.98-1.38) SLE1157/12034 (0.5) 26/15237 (0.2) 2.69 (1.68-4.30) Sjogrens syndrome852/8178 (0.6) 8/10543 (0.0) 6.56 (3.1-13.9) Primary823/8176 (0.3) 5/10543 (0.0) 4.75 (1.79-12.6) Secondary829/8178 (0.4) 3/10543 (0.0) 9.57 (2.9-31.6) Scleroderma74/7616 (0.1) 7/10093 (0.1) 0.69 (0.2-2.4) Ekstrom Smedby,et al.Blood 2008;111:4029-38

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.

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).

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

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

Sjogrens syndrome Neuropathy

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.

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.

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.

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.

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

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

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

Peripheral neuropathy associated with SS: Peyronnard1982Sensorimotor neuropathy Malinow1986Pure sensory neuropathy And so on....and so on...

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

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

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

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)

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

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

Other Extraglandular Features of SS: Interstitial nephritis: Fanconi syndrome Distal (type 1) RTA Nephrogenic Hypokalemia Glomerular disease: MPGN MN Renal Involvement

Other Extraglandular Features of SS: Urinary Bladder: Interstitial cystitis: dysuria urinary frequency nocturia urgency

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 !!!!

Pathogenesis of Sjogrens Syndrome

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

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

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

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

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).

Pathogenesis of Sjogrens syndrome

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

Pathogenesis of Sjogrens syndrome CYTOKINES

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

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

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.

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

Pathogenesis of Sjogrens syndrome Voulgarellis M,et al.Nat Rev Rheumtol. 2010;6:529-537

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

Treatment of Sjogrens syndrome

Typically treat symptoms: Moisturizing eye drops Eye ointments at night Mouth gels, sprays, and specialized washes Artificial saliva

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

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

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

Sjogren’s Syndrome When your tears are more than precious.

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