Athanasios G Tzioufas MD

1. Athanasios G Tzioufas MD

2. Sj�gren's SyndromeClinical picture, adverse outcome and B-cell neoplasia Athanasios G. Tzioufas, MD Baltimore, John Hopkins Arthritis Center 5-4-2007

3. Sj�gren's Syndrome � Autoimmune Epithelitis Female disease ?/? : 9/1 Common 0.2-1% of adult females 4th -5th decade of life Slowly progressive

4. Sj�gren's Syndrome � Autoimmune Epithelitis The frequency distributions of ages at onset of symptoms & at diagnosis of primary Sj�gren's syndrome

5. Sj�gren'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 native

6. Association of Sj�gren's syndrome with other autoimmune rheumatic diseases

7. Sj�gren's syndrome � autoimmune epithelitis

8. Sj�gren's syndrome � autoimmune epithelitis

9.  (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

10.  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

11.  Rules for classification: Definitive primary SS presence of any four of the six items Presence of 3 objective criteria 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

12.  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

13. Sj�gren's Syndrome � Autoimmune Epithelitis Lymphocytic infiltrates with destruction of epithelial tissues B-lymphocytic hyperactivity

14. Sj�gren's Syndrome � Autoimmune Epithelitis

15. Anti-Ro/SSA and La/SSB in Sj�gren�s syndrome Longer disease duration Association with extraglandular manifestations (particularly vasculitis) Association with higher intensity of salivary gland infiltrates A direct pathogenetic effect has not been demonstrated

16. Primary Sj�gren's Syndrome

17. Primary Sj�gren's SyndromePulmonary Involvement

18. Primary Sj�gren's Syndrome

19. Primary Sj�gren's SyndromeRenal Involvement Interstitial nephritis (25%) Asymptomatic-subclinical Proximal tubular acidosis Distal tubular acidosis Nephrocalcinosis Glomerulonephritis (2.5%) Membranoproliferative Membranous Messangioproliferative

20. Primary Sj�gren's Syndrome

21. Primary Sj�gren's SyndromeLiver Involvement

22. Sj�gren's Syndrome � Autoimmune Epithelitis

23. Sj�gren'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

24. Systemic manifestations Periepithelial (tissue specific) Liver Lung Kidney (interstitial) Extraepithelial (systemic) Purpura Peripheral neuropathy Kidney (glom/phritis) Myositis

27. Parotid gland enlargement

28. Skin purpura

29. Mixed Monoclonal (Type II) cryoglobulinemia

32. Summary

34. Adverse outcome in Sj�gren�s syndrome So, during the next minutes I will concentrate on our current understanding for the prediction markers of lymphoma development in SS, the clinical picture of these patients and their outcomeSo, during the next minutes I will concentrate on our current understanding for the prediction markers of lymphoma development in SS, the clinical picture of these patients and their outcome

35. The definition of predictor markers of lymphoma development in SS is of vital importance for the follow up of these patients. Ideally, a predictor marker should be present��� and to be absent���.The definition of predictor markers of lymphoma development in SS is of vital importance for the follow up of these patients. Ideally, a predictor marker should be present��� and to be absent���.

36. Primary Sj�gren's SyndromeEvolution, incidence and impact Skopouli et al., Semin Arthritis Rheum 2000; 29: 296 Study Characteristics 261 patients with primary SS 1981-1995 mean follow-up time 3.6 years Evolution of the clinical picture and laboratory profile Incidence and predictors for systemic disease Impact of SS on overall survival

37. Primary Sj�gren's SyndromeClinical evolution, morbidity and mortality (261 patients) Time interval from the first symptoms to diagnosis: mean: 6 years (interquartile range:2-8 years) Follow-up from the time of diagnosis mean: 3.6 years (interquartile range: 2-5 years) Total reported duration of symptoms mean: 9.5 years (interquartile range: 5-12 years)

38. Primary Sj�gren's SyndromeManifestations referred as first symptoms and at diagnosis (261 patients)

39. Primary Sj�gren's SyndromeClinical manifestations at diagnosis and at the end of the follow-up (261 patients)

40. Primary Sj�gren's SyndromeLaboratory findings at diagnosis and at the end of the follow-up (261 patients)

41. Primary Sj�gren's SyndromeGlandular manifestations are present at the time of diagnosis Systemic manifestations Arthritis Raynaud�s phenomenon Pulmonary involvement Interstitial nephritis Liver involvement Serologic profile

42. Primary Sj�gren's SyndromeDoes it evolve ?? Systemic manifestations Glomerulonephritis Peripheral neuropathy Lymphoma

43. Primary Sj�gren's SyndromePredictors of various outcomes at time of diagnosis

45. Primary Sj�gren's SyndromeStudy characteristics Aim: Determination of incidence and predictors of adverse long-term outcomes in Sj�gren's Syndrome 723 consecutive patients with primary Sj�gren's syndrome 4384 person-years Determination of mortality rate Determination of lymphoproliferative disease rate Development of a rational predictive classification for the syndrome

46. Primary Sj�gren's SyndromeLong-term outcome 38 Lymphoproliferative disorders (4%) Probability for lymphoma development: 2.6% at 5 years 3.9% at 10 years 39 Deaths Mortality ratio: 1.15 (95% CI 0.86-1.73)

47. Primary Sj�gren's SyndromeLong-term outcome 7 out of 39 deaths was attributable to lymphoma All patients who developed lymphoma resulting in death had either: Low C4 levels or Palpable purpura at the first study visit

48. Primary Sj�gren's SyndromeOutcome of patients with SS/Lymphoma The lymphoproliferative disease was independently predicted by: Parotid gland enlargement (Hazard ratio: 5.21) Palpable purpura (Hazard ratio: 4.16) Low C4 levels (Hazard ratio: 2.40)

49. Primary Sj�gren's Syndrome

50. Primary Sj�gren's Syndrome

55. Sj�gren's Syndrome - Autoimmune Epithelitis

56. Adverse outcome in Sj�gren�s syndrome So, during the next minutes I will concentrate on our current understanding for the prediction markers of lymphoma development in SS, the clinical picture of these patients and their outcomeSo, during the next minutes I will concentrate on our current understanding for the prediction markers of lymphoma development in SS, the clinical picture of these patients and their outcome

58. Primary Sj�gren's SyndromeMilestones of lymphoproliferation 1964: Description of the first cases with lymphoma (Bunim & Talal) 1978: Increased risk of lymphoma in SS (Kassan et al) 1979: Lymphoma in SS in a B-cell lymphoma (Zulman et al) 1989-1991: Monoclonal expansion of B-cell takes place in the affected exocrine glands (Fieshlander et al, Moutsopoulos et al) 1998 - : Prediction models of poor outcome in large patient cohorts

59. Primary Sj�gren's SyndromeLimitations for studying lymphoma Low incidence of SS (0.5 � 1.4%) Risk of lymphoma (6.4 cases/1000 per year)

60. Centers that participated in the study: National University of Athens, Greece : M. Voulgarelis, U.G. Dafni, H.M. Moutsopoulos University College, London, UK : D.A. Isenberg, N. Sutcliffe Members of the European Concerted Action on Sj�gren's syndrome University of Bergen, Norway : R. Jonsson, H.J. Haga University of Vienna, Lainz Hospital, Austria : H. Kiener, J. S. Smolen, Friedrich-Alexander-Universitat, Erlangen�Nurnberg,Germany : J. R. Kalden University of Pisa, Pisa, Italy : S. Frigelli, C. Vitali University of Udine, Italy: S. De Vita, G. F. Ferraccioli, Y. Pennec Centre Hospitalier Universitaire de Brest, France : P. Youinou University Hospital MAS, Malmo, Sweden : E. Theander, R. Manthorpe

61. Primary Sj�gren's SyndromeMalignant Lymphoma (n=33)

62. Primary Sj�gren's SyndromeMalignant Lymphoma (n=33)

63. Primary Sj�gren's SyndromeMalignant Lymphoma

64. Primary Sj�gren's SyndromeMalignant Lymphoma (n=33)

65. Primary Sj�gren's SyndromeMalignant LymphomaHistological classification (WHO-REAL)

66. Primary Sj�gren's SyndromeClinical characteristics of lymphoma

67. Primary Sj�gren's SyndromeClinical characteristics of lymphomaNodal involvement

68. Primary Sj�gren's SyndromeClinical characteristics of lymphomaExtranodal involvement

69. Primary Sj�gren's SyndromeMalignant Lymphoma (n=33)

70. Primary Sj�gren's SyndromeLymphoma � Causes of death

71. Primary Sj�gren's SyndromeLymphoma � Factors of increased death risk

72. Primary Sj�gren's SyndromeLymphoma

73. Adverse outcome in Sj�gren�s syndrome So, during the next minutes I will concentrate on our current understanding for the prediction markers of lymphoma development in SS, the clinical picture of these patients and their outcomeSo, during the next minutes I will concentrate on our current understanding for the prediction markers of lymphoma development in SS, the clinical picture of these patients and their outcome

74. Sj�gren�s Syndrome - TherapySpectrum

75. Sj�gren's Syndrome -TherapyAggressive B-cell non-Hodgkin�s lymphomasCombined B-cell depletion therapy and CHOP AIMS: To evaluate� the efficacy of CHOP plus anti-CD20 6 patients with Diffuse Large B-cell Lymphoma 9 patients treated with CHOP alone Patients� outcome Clinical and serological picture of SS patients that received combination treatment

76. Sj�gren's Syndrome Aggressive B-cell non-Hodgkin�s lymphomasMain clinical, serological and histopathological features at diagnosis

77. Sj�gren's Syndrome lymphomasCombined B-cell depletion therapy and CHOP Overall survival

78. Sj�gren's Syndrome lymphomasCombined B-cell depletion therapy and CHOP Outcome Reduction of serum cryoglobulins Normalization of C4 levels during treatment

79. Sj�gren's Syndrome lymphomasCombined B-cell depletion therapy and CHOP Outcome Extraglandular manifestations vanish by the end of treatment Peripheral neuropathy (2 patients) Cutaneous vasculitis (3 patients) Sicca symptoms persist

80. Sj�gren's Syndrome high grade lymphomasCombined B-cell depletion therapy and CHOP Conclusions Combination treatment anti-CD20 and CHOP is superior to standard CHOP Non life-threatening toxicities fever & chills (2 patients) alopecia (6 patients) grade III neutropenia (5 patients) neutropenic fever (2 patients) Sustained response