Sjogrens Dr. Nicole Chau Rhem Rounds Nov 22

Sjogren‟s Syndrome and Lymphoma Rheumatology Rounds SMH Dr. Nicole Chau PGY1 November 22, 2005 Objectives To review diagnostic and clinical features of Sjogren‟s To summarize the literature on incidence and prevalence of lymphoma in Sjogren‟s patients To identify risk factors for development of lymphoproliferative disorders To identify time frame of development of lymphoma To identify risk factors for mortality Background Case 1994 Left 57yo F parotid enlargement, dry mouth, low grade fever, arthralgias; thought to have sialadenitis, given antibiotics with some relief Lymphadenopathy investigations normal Background Case 1997 Jan    Admit for low grade fever/chills, sweats, dry mouth CT CAP normal, CT head & neck showed LN, normal abdo U/S, BM Bx=reactive Hb 92, MCV 72, WBC 5 (10% lympho), CD4 90, plt 118, ESR 60, C3 0.73, C4 0.02 Background Case 1997 Mar    Admit to ICU for MSOF (renal, GI, cardiac, heme) pulmonary edema Hb 90‟s, WBC 18 left shift & 2% lympho, plt 200, bld film=microangiopathic hemolytic picture Cr 125 w/ heme granular casts & 3+ protein, + cryoglobulins, hypogammaglobulinemia Background Case 1997 June  Sjogren‟s dx, sicca, RF +, weakly + ANA, Ro, La  Cryoglobulinemia confirmed on renal bx 1997 Oct  Worsening renal function, started cyclophosphamide 100mg OD Background Case 2001 May  Started Imuran, (Prednisone induced myopathy) 2002 – 2003  Recurrent enlarged submandibular LN R>L, Odynophagia resolved with antibiotics Background Case 2003 Nov   Left submandibular swelling 2.5 x 3cm Firm enlarged parotids with discreet mass in left tail 2004 Jan FNA = inflammatory cells/indeterminate 2004 Jan FNA = inadequate sample 2004 Feb FNA = inflammatory cells 2004 Mar FNA = inflammatory cells  Mass continues to enlarge (>baseball size)…. Background Case 2004 Mar   Admitted to ENT for IV clinda and work up of left level 2 neck mass CT shows large mass w/ necrotic centers, multiple nodes >1cm  Excisional Bx = large cell lymphoproliferative process c/w anaplastic plasmacytoma Gallium scan showed multiple disease sites in bilat axilla, intraabdominal LN BM asp & bx normal, no increased Ig 2004 April   2004 May – Aug  Completes CHOP Sjogren‟s Syndrome  1892 “Mickulicz syndrome” 1933 Henrik Sjogren, Danish opthalmologist „keratoconjunctivitis sicca‟ Annual incidence ~ 4/100 000 population     Prevalence ~ 0.5% among adults 9/10 female Ann Rheum Dis 1997;56:521-5 Scand J Rheumatol 2004;33:39-43 Sjogren‟s Syndrome  Systemic autoimmune disorder characterized by lymphocytic infiltration of exocrine glands, especially lacrimal and salivary glands Defining Sjogren‟s  Criteria for international consensus and classification  NOT required for clinical diagnosis  At least nine different criteria sets proposed in past 20 years  Primary vs Secondary Lymphoctyic Infiltrates Labial Salivary Gland Biopsy To confirm diagnosis of primary Sjogren‟s syndrome  Labial salivary gland biopsy score of >1 lymphocytic focus/4mm2   False positive with SLE, AIDS, myasthenia gravis False negative with corticosteroids and smoking  New QIH method has 93% sensitivity  396 patients, reviewed for diagnosis by 5 experts, changed diagnosis from indefinite to definite in 31% Van Woerkom JM. Rheum 2005 Nov 15 (Epub ahead of print)  May make a diagnosis of lymphoma (case report)  B cell MALT lymphoma diagnosed by labial minor salivary gland biopsy in patients screened for Sjogren's syndrome. Van Mello NM et al. Ann Rheum Dis 2005 Mar;64(3):471-3 Non-exocrine Features of Sjogren‟s MSK: arthritis, arthralgia (50%) Cutaneous Vasculitis:      lower extremity purpura (palpable/nonpalpable) urticarial digital ulcers erythema multiforme livedo Raynaud‟s Resp: sinusitis, ILD, alveolitis Endocrine: autoimmune thyroiditis Non-exocrine Features of Sjogren‟s GI: dysphagia, PBC, chronic hepatitis, celiac Renal: interstitial nephritis, type 1 RTA CNS (20%): neuropsychiatric, peripheral neuropathy Heme:      anemia of CD hemolytic anemia leukopenia, thrombocytopenia type II cryoglobulins Lymphoma (First described in 1963, 3 cases of lymphoma and one Waldenstrom’s macroglobulinemia out of 58 pts with sicca syndrome) Sjogren‟s & Lymphoma  Chronic excess B cell stimulation  Salivary, lacrimal and cervical lymph nodes are the main sites of monoclonal B cell proliferation & also of SS related lymphoma Most lymphoma arises from reactive infiltrate called lymphoepithelial sialedenitis (aka benign lymphoepithelial lesion)  Monoclonal B Cell Proliferation Precedes Clinical Onset Of NHL  Immunophenotyping showed evidence of light chain restriction in B cells infiltrating salivary glands Speight PM. Eur J Cancer B Oral Oncol 1994;30B(4):244-7  Immunogenotyping detected monoclonal Ig light or heavy chain rearrangements in labial salivary gland biopsies using PCR Jordan RC. Int J Hematol 1996;64(1):47-52  Circulating monoclonal immunoglobulins were detected in nearly 20% of patients with primary SS Brito-Zeron P. Medicine 2005;84(2):90-97 Neoplastic Transformation   Mechanism unclear, multi-step process Chronic antigenic stimulation for clonal selection & expansion  Monoclonal proliferation suggests dysregulation of B cell system likely predisposing to malignant transformation Dysregulation cell cycle check points and apoptosis Tapinos NI. Arthritis Rheum 1999;42:1466 Mariette X. Leuk and Lymph 1999;33(1-2):93-99  Spectrum of Malignant Lymphoproliferation  Circulating monoclonal immunoglobulins (monoclonal gammopathy)   Free light chains Mixed monoclonal cryoglobulins   Non-Hodgkin‟s lymphoma Extranodal marginal zone B cell lymphoma (MZL) of MALT (mucosa associated lymphoid tissue) Clinical Presentation  Extraglandular spread to lung, kidney, lymph nodes, skin, bone marrow Clinically indistinguishable between lymphoma vs pseudolymphoma  „Pseudolymphoma‟ Pleomorphic cells but not meeting malignant criteria May present as:       enlarged parotids lymphadenopathy (regional and generalized) hepatosplenomegaly pulmonary infiltrates vasculitis hypergammaglobulinemia What is the risk? First Study To Assess Magnitude Of Risk Kassan et al. followed 142 pts between 1954 to 1975, average f/u 8.1 years  7 cases of NHL between 6 mos to 13 years after admission  43.8 times incidence expected in general population at the time (p<0.01)  Risk of malignant lymphoma in pts with SS is ~6.4 cases per 1000 per year Kassan et al. Ann Intern Med 1978;89:888-92 Risk Of Developing Lymphoma Study Type Zufferrey et al Scand J Rheumatol 1995;24:342-345 Retrospective Primary Sjogren‟s N 55 Average follow up in years 12 (8 to 18) NHL 5 (9%) Time to diagnosis of lymphoma 4 to 12 years Hernandez et al Scand J Rheumatol 1996;25:396-7 Kruize A et al Rheum 1996;39:297 Sutcliffe et al Sem Arthr and Rheum 1998;28(2):80-87 Primary Sjogren‟s per EC KCS, PSS, SSS referred to optho 30 with PSS Retrospective Primary Sjogren‟s per EC Community based chart review, no biopsy required Multicenter, retrospective 39 3.2 (0.5 to 12.5) 10 to 12 4 (10%) 3 (4%) 5 (7%) All MALT 2 (3%) Mean 1.8 years (0.7 to 2.7 years) 2 mos to 3 years 72 72 10 2 to 26 years Martens et al J Rheumatol 1999;261:1296 74 7.2 7.6 and 9.5 years Voulgarelis et al Arthr and Rheum 1999;42(8):1765-17772 765 6.33 (1 month to 8.6) 33 (4%) Average 7.5 yrs (1-36 years) Lymphoma And Other Malignancies In Primary Sjogren‟s Syndrome.A Cohort Study On Cancer Incidence And Lymphoma Predictors. Theander E et al.Ann Rheum Dis 2005 Nov 10 [epub ahead of print]  Prospective cohort of primary Sjogren‟s patients to analyze risk of general malignancy and lymphoma Mean follow up 8 years (range 1 month to 19 years), total observation 2464 years in AECC SS group 507 patients with pSS as per Copenhagen, European or AECC   Lymphoma And Other Malignancies In Primary Sjogren‟s Syndrome. A Cohort Study On Cancer Incidence And Lymphoma Predictors. Theander E et al.Ann Rheum Dis 2005 Nov 10 [epub ahead of print]  In patients with primary Sjogren‟s, there is a 16 fold increased risk of lymphoma No significant increased risk of developing malignancy in patients with primary Sjogren‟s   No increased risk for patients with sicca symptoms alone to develop lymphoma Sjogren‟s Associated With Increased Risk Of Non-Hodgkin‟s Lymphoma Comparison for All Malignancies AECC Sjogren‟s syndrome (n=286) Non-AECC Sicca Syndrome (n=221) N 33 13 SIR 1.42 0.77 95% CI 0.98 – 2.00 0.41 – 1.32 Comparison for NHL AECC Sjogren‟s syndrome (n=286) Non-AECC Sicca Syndrome (n=221) N 11 0 SIR 95% CI 7.77 – 27.85 15.57 Theander et al. Ann Rheum Dis 2005 Nov 10 Elevated Incidence Of Hematologic Malignancies In Patients With Sjogren‟s Compared With Rheumatoid Arthritis National Finish Registry, cohort of  676 patients with Primary Sjogren‟s disease  709 patients with Secondary Sjogren‟s disease  9469 patients with Rheumatoid Arthritis Kauppi M et al. Cancer Causes Control 1997;8:201-204 Time to Diagnosis of Lymphoma  Conflicting results Some studies suggest increased risk over time Lymphoproliferative disease probability 2.6% at 5 years and 3.9% at 10 years   Ioannidis JP et al. Arthritis and Rheum 2002;46(3):741-747 Risk Of Lymphoma Increased With Time After Diagnosis Of Primary Sjogren‟s (mean 8 yrs) SIR 0 – 5 years 6 – 10 years 10 – 15 years 6.4 11.1 20.8 95% CI 1.3 – 18.7 3.0 - 28.5 6.8 – 48.6 Theander et al. Ann Rheum Dis 2005 Nov 10 Malignant Non-Hodgkin‟s Lymphoma Types Variable  follicle center, lymphoplasmacytoid, DLBC, MALT Mostly low grade B cell  46-56% are MALT Mostly high grade DLBC Lymphoma Types 26/27 were NHL (B cell origin in 24, T cell origin in 2) 8 low grade  6 mucosa associated lymphoid tissue type (MALT)  2 follicular mixed type 18 intermediate type  10 diffuse medium, 4 diffuse large  2 angioimmunoblastic T cell  1 follicular medium type, 1 T cell rich B cell type 1/27 was Hodgkin‟s lymphoma 14/27 had stage I and II localized disease Mean age of onset of Sjogren‟s 51.3 yrs, disease duration 3.4 yrs JCAT 2003 Jul-Aug;27(4):517-24 Clinical Signs Associated With Lymphoma Development          Salivary gland enlargement Lymphadenopathy Splenomegaly Palpable purpura* Cutaneous vasculitis Low grade fever Leg ulcers Peripheral neuropathy History of cytotoxic therapy/parotid irradiation Laboratory Predictors Of Lymphoma Development       Anemia Lymphopenia Low CD4+ T lymphocytes, low CD4+/CD8+ ratio Mixed cryoglobulinemia* Low C3 Low C4* Ramos-Casals M et al. Rheumatology 2005;44(1):89-94 Hypocomplementemia Is Associated With Systemic Manifestations, Lymphoma And Death  Hypocomplimentemia detected in 24% of 336 patients with primary Sjogren‟s as per ECE criteria, prospective follow up since 1994 of 218 patients  Low C4 levels:  associated with higher prevalence of peripheral neuropathy, cutaneous vasculitis, RF, cryoglobulins compared with normal C4 levels  Are an independent predictor of lymphoma in new and prevalent cases Ramos-Casals M et al. Rheumatology 2005;44(1):89-94 Ioannidis JP et al. Arthr and Rheum 2002;46:741-7 Theander E et al. Arthr and Rheum 2004;50:1262-9 Tzioufas AG et al. Arthr and Rheum 1996;39:767-72 Hypocomplementemia Is Associated With Systemic Manifestations, Lymphoma And Death  Lower survival in patients with lower complements (c3 or c4 or CH50) at baseline  Patients with low C4 levels had increased cause-specific standardized mortality ratio for lymphoproliferative disease compared with patients with normal C4 levels Recommend to check complements at diagnosis and follow up of primary Sjogren‟s to serve as predictor for outcomes Ramos-Casals M et al. Rheumatology 2005;44(1):89-94  CD 4+ T Lymphocytopenia Is Associated With Development Of Lymphoma Theander et al. Ann Rheum Dis 2005 Nov 10 Lymphocytopenia Mandl Tet al. J Rheumatol. 2004;31(4):726-8 Idiopathic CD 4+ T lymphocyte counts lower among anti-SSA antibody seropositive SS patients compared to correlating seronegatives and primary Sjogren’s sundrome. Low Complement And Low CD4+ Theander et al. Ann Rheum Dis 2005 Nov 10 Independent predictors of developing lymphoproliferative disease: 1) 2) 3) parotid enlargement (HR 5.21, CI 1.76-15.4, p=0.003) palpable purpura (HR 4.16, CI 1.65-10.5, p=0.002) low C4 (HR 2.4, CI .99-5.83, p=0.052) if one of 3 of the above (n=367) at onset then 9.08 higher risk of LPD development than those who did not Ioannidis JP et al. Arthritis and Rheum 2002;46(3):741-747 Ioannidis JP et al. Arthritis and Rheum 2002;46(3):741-747 Mortality And Lymphoma In PSS Standardized mortality ratio 1.15 (CI 0.86-1.73) Over 700 patients with primary SS Follow up: max 18 years (mean 6 years) 39 deaths (7 due to lymphoma) close to 20% of deaths due to lymphoma ALL cases of lymphoma that resulted in death occurred in patients who presented with low C4 or palpable purpura at their FIRST study visit Ioannidis JP et al. Arthritis and Rheum 2002;46(3):741-747 Mortality And Lymphoma In PSS Mixed results given diversity of patient population & follow up Tumour grade predicts mortality Median survival 3.3 yr for high grade Ioannidis JP et al. Arthritis and Rheum 2002;46(3):741-747 Median survival low grade 6.33 yrs, intermediate or high grade 1.833 yrs Worse overall survival if    B symptoms (RR 9.2, p 0.017) tumour size >7 cm (RR7.7, p0.046) histo class int-high (RR4.1 p 0.067) Voulgarelis et al Arthritis Rheum 1999;42:1765-72 Mortality Patients with secondary Sjogren‟s had increased mortality compared with those with primary Sjogren‟s (p= 0.04) Patients with primary Sjogren‟s had no increased mortality to general population Martens PB. Survivorship in a Population Based Cohort of Patients with Sjogren‟s Syndrome, 1976-1992 J Rheumatol 1999;26:1296-300 Summary Increased risk of non-Hodgkin‟s lymphoma  previously thought to be 44 fold  now thought to be 16 fold Clinical predictors include:  salivary gland swelling  lymphadenopathy  cutaneous vasculitis  low grade fever  peripheral neuropathy Laboratory predictors include:  low complements  lymphopenia  low CD4+, low CD4+/CD8+  cryoglobulinemia Recommendations for Screening for Lymphoma No formal guidelines Consider  Confirming diagnosis of primary Sjogren‟s syndrome  Role of labial salivary gland biopsy  Measuring complements, lymphocytes, CD4+ at diagnosis & f/u Low threshold for imaging and biopsy (FNA, excisional) in patients with clinical features of salivary gland enlargement, lymphadenopathy, cutaneous vasculitis, low grade fevers  Future Directions Future Directions  Understanding concepts in Sjogren‟s etiology and pathogenesis What is the extent of shared etiology of cryoglobulinemia, hypocomplementemia, B cell activation and CD4 T cell depletion? Ramos-Casals et al. Triple association between Hepatitis C Virus infection, systemic autoimmune diseases, B cell lymphoma. J Rheum 2004;31:495-9   B Cell Activating Factor (BAFF(Blys)) regulates B lymphocyte proliferation and survival, associated with B cell hyperactivity, BAFF levels correlated with circulating Ab (IgG, RF, anti-Ro and anti-La), found in T cells infiltrating labial salivary glands in SS Ramos-Casals M, Font J, Primary Sjogren’s syndrome: current and emergent aetiopathogenic concepts. Rheumatology 2005;44:1354-1367 Lavie F et al. Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjogren's syndrome . J Path 2004;202(4):496-502 Mariette X et al. Ann Rheum Dis 2003;62:168-71 Thank you