Sjögren's Syndrome Clinical, Pathogenetic & Aspects Dept. of Pathophysiology Medical School National University of Athens Greece Sjögren's Syndrome Clinical, Pathogenetic & Aspects Athanasios G. Tzioufas, MD Alexandria, 1st ELAR, April 2013

Sjögren's Syndrome - Autoimmune Epithelitis Female disease ♀/♂ : 9/1 Common 0.5-1% of adult females 4th -5th decade of life Slowly progressive

Sjögren's Syndrome - Autoimmune Epithelitis The frequency distributions of ages at onset of symptoms & at diagnosis of primary Sjögren's syndrome 5 10 15 20 25 30 35 40 45 1-10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90 AGE % OF PATIENTS At diagnosis Onset Pavlidis et al, J Rheumatol 1998; 2, 9:5

Sjögren's Syndrome - Autoimmune Epithelitis Center of autoimmune disorders alone (primary) with other (secondary) Wide clinical spectrum organ-specific systemic neoplasia Prototype autoimmune disease humoral cellular

Association of Sjögren's syndrome with other autoimmune rheumatic diseases

Sjögren's syndrome - Immunopathology Lymphocytic infiltration of the affected epithelial tissues Autoantibodies-immune complex mediated disease

Autoantibodies to cellular autoantigens in pSS by IVTT and RIA Autoantibody to: Percent Ro 60 66 Ro 52 49 La 57 Calreticulin 20 Carbonic anhydrase II 11 M3R VAMP-2 4 a-fodrin U1RNP 2 Nucleolin Calpastatin NPY Τα αυτοαντισώματα έναντι ενός Ro/SSA και La/SSB απαντώνται κυρίως σε ασθενείς με σύνδρομο Sjögren, αλλά και σε ασθενείς με συστηματικό ερυθηματώδη λύκο και σπανιότερα σε ασθενείς με ρευματοειδή αρθρίτιδα και αδιαφοροποίητο αυτοάνοσο νόσημα. Οι πρωτεΐνες Ro/SSA και La/SSB ανευρίσκονται μαζί στα κυτταροπλασματικά ριβουνοκλεοπρωτεϊνικά σύμπλοκα Ro/La RNP. H απόκριση έναντι La/SSB θεωρείται ειδική για το σύνδρομο Sjögren. Tzioufas et al Arthritis Rheum 58 :S791, 2008

Sjögren's Syndrome – Autoimmune Epithelitis Antibodies to Ro and La cellular antigens Ro (SSA) Unknown Function La (SSB): transcription factor Initiation and termination of RNA-polymerase III transcription Gottlieb E et al., EMBO J., 1989; 8:841 Maraia RJ, Proc Natl Acad Sci USA, 1996; 93:3383 Maturation of pre-tRNAs and other RNA-polymerase III transcripts Fan H et al., Mol Cell Biol 1998; 18:3201

Sjögren's Syndrome – Autoimmune Epithelitis Autoimmune Phenomena: Lesion Activated infiltrating cells B cells T cells helper/memory LFA.1/HLA-DR+ Dendritic cells in advanced lesions Activated epithelium HLA-DR c-myc proinflammatory cytokines lymphoid chemokines co-stimulatory/adhesion molecules autoantigens Labial Minor SG Skopouli et al, J Rheumatol. 1991, Yiannopoulos et al J Clin Immunol, 1992 Manoussakis et al Arthritis Rheum, 1999, Tzioufas et al J Autoimmunity, 1999, Xanthou et al, Clin Exp Immunol. 1999, Xanthou et al Arthritis Rheum, 2001

Autoimmune Epithelitis Endocrine Stress EPITHELIUM EPITHELIUM Persistent Virus Genetic Make-up EPITHELIUM La/SSB La/SSB MHC-II EXOSOMES FasL Cytokines/ Chemokines ICAM.1 CK receptor Fas CD40 MHC-II B7 APOPTOSIS B Ag-Presentation T B DC Ag-Release T

Sjögren's Syndrome - Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement difficulty with chewing, swallowing excessive fluid use Subjective: Objective: Dry mouth Intermittent parotid gland enlargement Dry oral mucosa – mouth ulcers Tongue Teeth Parotid gland enlargement Tests red devoid of epithelium cracked “crocodile skin” multiple caries early loss

Sjögren's Syndrome – Autoimmune Epithelitis

Sjögren's Syndrome - Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement difficulty with chewing, swallowing excessive fluid use Subjective: Objective: Dry mouth Intermittent parotid gland enlargement Dry oral mucosa – mouth ulcers Tongue Teeth Parotid gland enlargement Tests red devoid of epithelium cracked “crocodile skin” multiple caries early loss

Sjögren's syndrome – Autoimmune Epithelitis

Sjögren's Syndrome - Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement difficulty with chewing, swallowing excessive fluid use Subjective: Objective: Dry mouth Intermittent parotid gland enlargement Dry oral mucosa – mouth ulcers Tongue Teeth Parotid gland enlargement Tests red devoid of epithelium cracked “crocodile skin” multiple caries early loss

Sjögren's Syndrome – Autoimmune Epithelitis Parotid gland enlargement

Sjögren's Syndrome - Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement difficulty with chewing, swallowing excessive fluid use Subjective: Objective: Dry mouth Intermittent parotid gland enlargement Dry oral mucosa – mouth ulcers Tongue Teeth Parotid gland enlargement Tests red devoid of epithelium cracked “crocodile skin” multiple caries early loss

Sjögren's Syndrome – Autoimmune Epithelitis Salivary flow: Parotid Whole Stimulated Unstimulated (≤1.5ml/15min)

Sjögren's Syndrome – Autoimmune Epithelitis Salivary gland biopsy Chilsom focus score (≥ 1 foci/4mm2 )

Sjögren's Syndrome - Autoimmune Epithelitis Glandular manifestations Lacrimal Gland Involvement “gritty” “sandy” Foreign body sensation Lack of tearing  “sticky” eyelids Conjunctival injection Lacrimal gland enlargement (rare) Keratoconjuctivitis sicca Subjective: Objective:

Sjögren's Syndrome - Autoimmune Epithelitis Schirmer's test (≤5mm/5min) Rose-Bengal staining (≥4: van Bijsterveld’s scoring system)

Sjögren's Syndrome - Autoimmune Epithelitis The American-European Consensus Group classification criteria Subjective (Positive = a positive response to at least one of the three following questions) I. Ocular symptoms: Have you had daily, persistent, troublesome dry eyes for more than 3 months? Do you have a recurrent sensation of sand or gravel in the eyes? Do you use tear substitutes more than three times a day? II. Oral symptoms: Have you had a daily feeling of dry mouth for more than 3 months? Have you had recurrently or persistently swollen salivary gland as an adult? Do you frequently drink liquids to aid in swallowing dry food? Vitali C et al., Ann Rheum Dis. 2002;61:554

Sjögren's Syndrome - Autoimmune Epithelitis The American-European Consensus Group classification criteria Objective III. Ocular signs (positive result in at least one of the following tests) Schirmer’s I test Rose-Bengal score or another ocular dye score IV. Histopathology  focus score ≥1 V.  Salivary gland involvement (positive result in at least one of the following tests) Unstimulated salivary flow Parotid sialography Salivary scintigraphy VI. Autoantibodies: Ro(SSA) and/or La(SSB) Vitali C et al., Ann Rheum Dis. 2002;61:554

Sjögren's Syndrome - Autoimmune Epithelitis The American-European Consensus Group classification criteria Rules for classification: Definitive primary SS presence of any four of the six items in patients without any potentially associated disease Secondary SS item‑1 or item‑2 plus any two from items 3, 4, 5 in patients with a potentially associated disease (another connective tissue disease) Vitali C et al., Ann Rheum Dis. 2002;61:554

Sjögren's Syndrome - Autoimmune Epithelitis The American-European Consensus Group classification criteria Exclusion criteria: prior head and neck irradiation pre-existing lymphoma acquired immunodeficiency disease (AIDS) hepatitis C infection sarcoidosis graft‑versus‑host disease sialoadenosis drugs (neuroleptic, anti‑depressant, anti‑hypertensive, parasympatholytic) Vitali C et al., Ann Rheum Dis. 2002;61:554

Primary Sjögren's Syndrome-systemic manifestations Clinical manifestations at diagnosis & end of follow-up (261 patients) Diagnosis End of follow-up patients (%) Arthralgia/arthritis 70 75 Raynaud’s phenomenon 41 48 Purpura 10 11 Pulmonary involvement (small airway disease) 19 23 Primary biliary cirrhosis 4 Renal involvement interstitial 7 9 glomerulonephritis 0.4 2 Peripheral Neuropathy 1 Lymphoproliferative disorders Skopouli et al., Semin Arthritis Rheum 2000; 29: 296

Primary Sjögren's Syndrome-systemic manifestations Clinical manifestations at diagnosis & end of follow-up (261 patients) Diagnosis End of follow-up patients (%) Arthralgia/arthritis 70 75 Raynaud’s phenomenon 41 48 Purpura 10 11 Pulmonary involvement (small airway disease) 19 23 Primary biliary cirrhosis 4 Renal involvement interstitial 7 9 glomerulonephritis 0.4 2 Peripheral Neuropathy 1 Lymphoproliferative disorders Skopouli et al., Semin Arthritis Rheum 2000; 29: 296

Sjögren’s Syndrome Epithelial involvement – Clinical evidence Labial Minor SG Kidney Liver Lung Systemic Manifestations Frequency (%) Pulmonary involvement small airway disease 23 Renal involvement interstitial 9 Liver involvement billiary cirrhosis 4 Skopouli et al., Semin Arthritis Rheum 2000 Moutsopoulos HM. Clin Immunol Immunopathol. 1994 28

Primary Sjögren's Syndrome-systemic manifestations Clinical manifestations at diagnosis & end of follow-up (261 patients) Diagnosis End of follow-up patients (%) Arthralgia/arthritis 70 75 Raynaud’s phenomenon 41 48 Purpura 10 11 Pulmonary involvement (small airway disease) 19 23 Primary biliary cirrhosis 4 Renal involvement interstitial 7 9 glomerulonephritis 0.4 2 Peripheral Neuropathy 1 Lymphoproliferative disorders Skopouli et al., Semin Arthritis Rheum 2000; 29: 296

Clinical spectrum of primary Sjögren's syndrome

Sjögren's Syndrome - Autoimmune Epithelitis Algorithm for the diagnosis If positive Sjögren's Syndrome Dry mouth Dry eyes Salivary gland enlargement Raynaud’s phenomenon Purpura Renal tubular acidosis or Eye & salivary gland tests Serology If any positive

Sjögren's syndrome – treatment. Progress of the last decade Understanding of the natural history Insights into pathogenetic mechanisms New biologics-experience from other diseases Outcome measures

Sjögren’s Syndrome Therapy Collaboration Rheumatology Ophthalmology Oral medicine – Dentistry Other medical specialties

Current treatments for dry mouth Thanou-Stavraki and James, 2008

Current and experimental treatments for dry eyes Thanou-Stavraki and James, 2008

Sjögren's Syndrome – conventional DMARDs Sicca Manifestations Immunomodulation: Methotrexate (Clin Exp Rheumatol 1996, 4:555) Azathioprine (J Rheumatol 1998; 25:896-899) Nandrolone decanoate (Clin Exp Rheumatol 1988, 6:53) Cyclosporine A (Ann Rheum Dis 1986, 45:732)

Sjögren's Syndrome – Biologic therapies Sicca Manifestations Immunomodulation: Anti-TNF a Mariette et al. Arthritis Rheum. 2004 Apr;50(4):1270-6, Sankar et al.Arthritis Rheum. 2004 Jul;50(7):2240-5. IFN-a Cummins et al. Arthritis Rheum. 2003 Aug 15;49(4):585-93. Anti-CD20 Meijer et al.Arthritis Rheum. 2010 Apr;62(4):960-8.

JAMA, July 28, 2010—Vol 304, No. 4 38

Treatment of Sjögren's syndrome Empirical Symptomatic Therapeutic regimens used successfully in other systemic diseases (particularly SLE and RA) Lack of control trials

Sicca features Xerostomia Xerophthalmia Other sicca features FIRST STEP Topical therapies Saliva substitutes (1+/B) Preservative-free artificial tears (1++/B) Topical measures (4/D) Topical ocular vit. A/glycols (2+/B) Topical 0.05% Cyclosporine A (1++/B) SECOND STEP Systemic therapies N-acetylcysteine (1+/B) N-acetylcysteine* (4/D) Pilocarpine Cevimeline (1++/A) Pilocarpine Cevimeline (1++/A) Pilocarpine (1++/B) Plug insertion (1+/B) * For ENT sicca features

Sjögren's Syndrome -Therapy Parenchymal organ involvement Lungs, Kidneys, Liver Slow process Usually does not lead to organ failure Skopouli et al., Semin Arthritis Rheum. 2000, 29:296 Lack of controlled therapeutic trials Corticosteroids ineffective-dangerous? Anecdotal reports with azathioprine, MMF, IVIG

Sjögren's Syndrome -Therapy Systemic Vasculitis Corticosteroids Cyclophosphamide Plasmapheresis IVIg Others

Extraglandular involvement Joint Pulmonary Renal Vasculitic Neurological Life-threatening Arthralgia Arthritis Bronchial Interstitial Tubular Glomerular CNS Multineuritis Polyneuropathy Ataxic neuronop HCQ NSAIDs Inhaled tx Cortic. Bic/K replac. MP Cortic. IVIG HCQ CYC Cortic. CYC RTX Pex Aza RTX MTX MPA/CyA PA/Aza Pex RTX RTX RTX First-line therapy Second-line therapy Third-line therapy Refractory cases

Treatment options-Summary Sicca manifestations Dry eyes topical 0.05% cyclosporine (twice daily) severe refractory ocular dryness May add topical NSAIDs Dry mouth Pilocarpine Cevimeline Systemic manifestations No clear benefits from HCQ GC Other immunosuppressive RTX is promising for some situations Vasculitis Glomerulonephritis Arthritis

Collaborators-Dept of Pathophysiology-UOA E Kapsogeorgou M Manoussakis F Skopouli M Voulgarelis HM Moutsopoulos