Sjögren's Syndrome Clinical, Pathogenetic & Aspects

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

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

3. 45 40 At diagnosis 35 Onset 30 25 % OF PATIENTS 20 15 10 5 0 1-10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90 AGE Sjögren's Syndrome - Autoimmune Epithelitis The frequency distributions of ages at onset of symptoms & at diagnosis of primary Sjögren's syndrome Pavlidis et al, J Rheumatol 1998; 2, 9:5

4. 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

5. Association of Sjögren's syndrome with other autoimmune rheumatic diseases

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

7. Autoantibodies to cellular autoantigens in pSS by IVTT and RIA Tzioufas et al Arthritis Rheum 58 :S791, 2008

8. Sjögren's Syndrome – Autoimmune EpithelitisAntibodies 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

9. Labial Minor SG Sjögren's Syndrome – Autoimmune EpithelitisAutoimmune 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

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

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

12. Sjögren's Syndrome – Autoimmune Epithelitis

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

14. Sjögren's syndrome – Autoimmune Epithelitis

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

16. Sjögren's Syndrome – Autoimmune Epithelitis Parotid gland enlargement

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

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

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

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

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

22. Sjögren's Syndrome - Autoimmune EpithelitisThe American-European Consensus Group classification criteriaSubjective (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

23. Sjögren's Syndrome - Autoimmune EpithelitisThe American-European Consensus Group classification criteriaObjective 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

24. Sjögren's Syndrome - Autoimmune EpithelitisThe 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

25. Sjögren's Syndrome - Autoimmune EpithelitisThe 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

26. Primary Sjögren's Syndrome-systemic manifestationsClinical manifestations at diagnosis & end of follow-up(261 patients) Skopouli et al., Semin Arthritis Rheum 2000; 29: 296

27. Primary Sjögren's Syndrome-systemic manifestationsClinical manifestations at diagnosis & end of follow-up(261 patients) Skopouli et al., Semin Arthritis Rheum 2000; 29: 296

28. Lung • Labial Minor SG • Liver • Kidney Sjögren’s SyndromeEpithelial involvement – Clinical evidence Skopouli et al., Semin Arthritis Rheum 2000 Moutsopoulos HM. Clin Immunol Immunopathol. 1994

29. Primary Sjögren's Syndrome-systemic manifestationsClinical manifestations at diagnosis & end of follow-up(261 patients) Skopouli et al., Semin Arthritis Rheum 2000; 29: 296

30. Clinical spectrum of primary Sjögren's syndrome

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

32. 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

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

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

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

36. Sjögren's Syndrome – conventional DMARDsSicca 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)

37. Sjögren's Syndrome – Biologic therapiesSicca 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.

38. JAMA, July 28, 2010—Vol 304, No. 4

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

41. Sicca features Xerostomia Xerophthalmia Other sicca features Topicaltherapies FIRST STEP Saliva substitutes (1+/B) Preservative-free artificial tears (1++/B) Topicalmeasures (4/D) Topical ocular vit. A/glycols (2+/B) Topical 0.05% Cyclosporine A (1++/B) Systemictherapies SECOND STEP 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

42. Sjögren's Syndrome -TherapyParenchymal 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

43. Sjögren's Syndrome -TherapySystemic Vasculitis • Corticosteroids • Cyclophosphamide • Plasmapheresis • IVIg • Others

44. Extraglandular involvement Joint Pulmonary Renal Vasculitic Neurological Life-threatening Arthralgia Arthritis Interstitial Tubular Glomerular CNS Multineuritis Polyneuropathy Ataxic neuronop Bronchial HCQ NSAIDs Inhaledtx 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

45. Systemic manifestations No clear benefits from HCQ GC Other immunosuppressive RTX is promising for some situations Vasculitis Glomerulonephritis Arthritis Sicca manifestations Dry eyes topical0.05%cyclosporine (twicedaily) severe refractory ocular dryness May add topical NSAIDs Dry mouth Pilocarpine Cevimeline Treatment options-Summary

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