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Sjogren
- 3. Sjögren's Syndrome Clinical, Pathogenetic& Aspects Athanasios G. Tzioufas, MD Dept. of Pathophysiology Medical School National University of Athens Greece Alexandria, 1st ELAR, April 2013
- 4. Sjögren's Syndrome -Autoimmune Epithelitis Female disease ♀/♂ : 9/1 Common 0.5-1% of adult females 4th -5th decade of life Slowly progressive
- 5. Sjögren's Syndrome -Autoimmune Epithelitis The frequency distributions of ages at onset of symptoms & at diagnosis of primary Sjögren's syndrome 0 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 %OFPATIENTS At diagnosisAt diagnosis OnsetOnset Pavlidis et al, J Rheumatol 1998; 2, 9:5
- 6. 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
- 7. Association of Sjögren'ssyndrome with other autoimmune rheumatic diseases
- 8. Sjögren's syndrome -Immunopathology Lymphocytic infiltration of the affected epithelial tissues Autoantibodies-immune complex mediated disease
- 9. Autoantibodies to cellularautoantigens in pSSAutoantibodies to cellular autoantigens in pSS by IVTT and RIAby IVTT and RIA Autoantibody to: Percent Ro 60 66 Ro 52 49 La 57 Calreticulin 20 Carbonic anhydrase II 11 M3R 11 VAMP-2 4 a-fodrin 4 U1RNP 2 Nucleolin 0 Calpastatin 0 NPY 0 Tzioufas et al Arthritis Rheum 58 :S791, 2008
- 10. 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 Antibodies to Ro and La cellular antigens
- 11. 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 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 Labial Minor SG
- 12. EPITHELIUMEPITHELIUM Endocrine StressStress Autoimmune Epithelitis EXOSOMES DC DC Ag-Release T T T T T T T T T Ag-Presentation B B B B BB EPITHELIUMEPITHELIUM Persistent Virus GeneticMake-up CD40 APOPTOSIS Fas Fas L B7 T B Cytokines/ Chemokines ICAM.1 CK recepto r EPITHELIUMEPITHELIUM La/SSB La/SSB MHC-II MHC-II
- 13. Sjögren's Syndrome -Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement Dry mouth Intermittent parotid gland enlargement Dry oral mucosa – mouth ulcers Tongue Teeth Parotid gland enlargement Tests Subjective: Objective: difficulty with chewing, swallowing excessive fluid use red devoid of epithelium cracked “crocodile skin” multiple caries early loss
- 14. Sjögren's Syndrome –Autoimmune Epithelitis
- 15. Sjögren's Syndrome -Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement Dry mouth Intermittent parotid gland enlargement Dry oral mucosa – mouth ulcers Tongue Teeth Parotid gland enlargement Tests Subjective: Objective: difficulty with chewing, swallowing excessive fluid use red devoid of epithelium cracked “crocodile skin” multiple caries early loss
- 16. Sjögren's syndrome –Autoimmune Epithelitis
- 17. Sjögren's Syndrome -Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement Dry mouth Intermittent parotid gland enlargement Dry oral mucosa – mouth ulcers Tongue Teeth Parotid gland enlargement Tests Subjective: Objective: difficulty with chewing, swallowing excessive fluid use red devoid of epithelium cracked “crocodile skin” multiple caries early loss
- 18. Sjögren's Syndrome –Autoimmune Epithelitis Parotid gland enlargement
- 19. Sjögren's Syndrome -Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement Dry mouth Intermittent parotid gland enlargement Dry oral mucosa – mouth ulcers Tongue Teeth Parotid gland enlargement Tests Subjective: Objective: difficulty with chewing, swallowing excessive fluid use red devoid of epithelium cracked “crocodile skin” multiple caries early loss
- 20. Sjögren's Syndrome –Autoimmune Epithelitis Salivary flow: Parotid Whole Stimulated Unstimulated (≤1.5ml/15min)
- 21. Sjögren's Syndrome –Autoimmune Epithelitis Salivary gland biopsy Chilsom focus score (≥ 1 foci/4mm2 )
- 22. Sjögren's Syndrome -Autoimmune Epithelitis Glandular manifestations Lacrimal Gland Involvement Subjective: Objective: Foreign body sensation Lack of tearing “sticky” eyelids Conjunctival injection Lacrimal gland enlargement (rare) Keratoconjuctivitis sicca “gritty” “sandy”
- 23. Sjögren's Syndrome - AutoimmuneEpithelitis Schirmer's test (≤5mm/5min) Rose-Bengal staining (≥4: van Bijsterveld’s scoring system)
- 24. (Positive = apositive 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 Subjective
- 25. 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) Sjögren's Syndrome - Autoimmune Epithelitis The American-European Consensus Group classification criteria Objective
- 26. Rules for classification: Definitiveprimary 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
- 27. Exclusion criteria: prior headand 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 Sjögren's Syndrome - Autoimmune Epithelitis The American-European Consensus Group classification criteria
- 28. Primary Sjögren's Syndrome-systemicmanifestations Clinical manifestations at diagnosis & end of follow-up (261 patients) Skopouli et al., Semin Arthritis Rheum 2000; 29: 296 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 4 Renal involvement interstitial 7 9 glomerulonephritis 0.4 2 Peripheral Neuropathy 1 2 Lymphoproliferative disorders 2 4
- 29. Primary Sjögren's Syndrome-systemicmanifestations Clinical manifestations at diagnosis & end of follow-up (261 patients) Skopouli et al., Semin Arthritis Rheum 2000; 29: 296 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 4 Renal involvement interstitial 7 9 glomerulonephritis 0.4 2 Peripheral Neuropathy 1 2 Lymphoproliferative disorders 2 4
- 30. Sjögren’s Syndrome Epithelial involvement– Clinical evidence 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 Labial Minor SG Kidney Liver Lung
- 31. Primary Sjögren's Syndrome-systemicmanifestations Clinical manifestations at diagnosis & end of follow-up (261 patients) Skopouli et al., Semin Arthritis Rheum 2000; 29: 296 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 4 Renal involvement interstitial 7 9 glomerulonephritis 0.4 2 Peripheral Neuropathy 1 2 Lymphoproliferative disorders 2 4
- 32. Clinical spectrum ofprimary Sjögren's syndrome
- 33. 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 or Eye & salivary gland tests Serology If any positive
- 34. 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
- 35. Sjögren’s Syndrome Therapy Collaboration Rheumatology Ophthalmology Oral medicine– Dentistry Other medical specialties
- 36. Current treatments fordry mouth Thanou-Stavraki and James, 2008
- 37. Current and experimentaltreatments for dry eyes Thanou-Stavraki and James, 2008
- 38. 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)
- 39. 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.
- 40. JAMA, July 28,2010—Vol 304, No. 4
- 42. Treatment of Sjögren'ssyndrome Empirical Symptomatic Therapeutic regimens used successfully in other systemic diseases (particularly SLE and RA) Lack of control trials
- 43. Sicca features Xerostomia Saliva substitutes (1+/B) Salivasubstitutes (1+/B) N-acetylcysteine (1+/B) N-acetylcysteine (1+/B) Pilocarpine Cevimeline (1++/A) Pilocarpine Cevimeline (1++/A) Xerophthalmia Preservative-free artificial tears (1++/B) Preservative-free artificial tears (1++/B) Topical ocular vit. A/glycols (2+/B) Topical ocular vit. A/glycols (2+/B) Topical 0.05% Cyclosporine A (1++/B) Topical 0.05% Cyclosporine A (1++/B) Pilocarpine Cevimeline (1++/A) Pilocarpine Cevimeline (1++/A) Other sicca features Topical measures (4/D) Topical measures (4/D) N-acetylcysteine* (4/D) N-acetylcysteine* (4/D) Pilocarpine (1++/B) Pilocarpine (1++/B) Plug insertion (1+/B) Plug insertion (1+/B) * For ENT sicca features
- 44. Sjögren's Syndrome -Therapy Parenchymalorgan 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
- 45. Sjögren's Syndrome -Therapy SystemicVasculitis Corticosteroids Cyclophosphamide Plasmapheresis IVIg Others
- 46. Joint Pulmonary RenalVasculitic Neurological Life-threatening Arthralgia Arthritis Bronchial Interstitial Tubular Glomerular CNS Multineuritis Polyneuropathy Ataxic neuronop HCQ NSAIDs HCQ Cortic. MTX RTX Inhaled tx Cortic. Aza MPA/CyA RTX Bic/K replac. Cortic. CYC PA/Aza RTX IVIG RTX MP CYC Pex RTX First-line therapy Second-line therapy Third-line therapy Refractory cases Pex Extraglandular involvement
- 47. Treatment options-Summary Systemic manifestations Noclear benefits from HCQ GC Other immunosuppressive RTX is promising for some situations Vasculitis Glomerulonephritis Arthritis Sicca manifestations Dry eyes topical 0.05% cyclosporine (twice daily) severe refractory ocular dryness May add topical NSAIDs Dry mouth Pilocarpine Cevimeline
- 48. Collaborators-Dept of Pathophysiology-UOA EKapsogeorgou M Manoussakis F Skopouli M Voulgarelis HM Moutsopoulos
Editor's Notes
- #10 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.