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Lymphoma Studies in Patients with Sjögren's Syndrome

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Lymphoma Studies in Patients with Sjögren's Syndrome Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1331 Lymphoma studies in patients with Sjögren's syndrome LILIAN VASAITIS ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-9912-9 UPPSALA urn:nbn:se:uu:diva-320220 2017 Dissertation presented at Uppsala University to be publicly examined in Enghoffsalen, Ingång 50 bv, Akademiska sjukhuset, Uppsala, Wednesday, 7 June 2017 at 13:00 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in Swedish. Faculty examiner: Associate Professor Thomas Mandl (Department of Clinical Sciences Malmö, Lund University). Abstract Vasaitis, L. 2017. Lymphoma studies in patients with Sjögren's syndrome. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1331. 94 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9912-9. Patients with primary Sjögren’s syndrome (pSS) are at increased risk of developing malignant lymphoma. The studies in this thesis aim at broadening our understanding of the association between these two conditions. Germinal centre (GC)-like structures were found in minor salivary gland biopsies taken at the time of pSS diagnosis in 25% of 175 studied patients. Lymphoma development was observed in 86% of the GC-positive pSS patients and 14% of the GC-negative patients. GC-like structures in salivary gland biopsies at pSS diagnosis might identify pSS patients at high risk for later lymphoma development. We used the National Patient Register and the Cancer Register to identify pSS patients with lymphoid malignancy for the following studies. The lymphoma tissues were reviewed and classified according to the WHO classification. In a study of 79 patients with available lymphoma tissues, we identified histopathological and clinical features compatible with IgG4-related disease (IgG4-RD) in one patient (1.3%). Histological features of IgG4-RD in lymphoma tissue in patients with an initial pSS diagnosis seem to be rare but, if present, may indicate underlying IgG4-RD. We identified and compared pSS patients with (n=18/17%) and without (n=87) pre-existing lymphoma at pSS diagnosis and found similar pSS characteristics in both groups. Mucosa- associated lymphoid tissue (MALT) lymphoma in salivary glands was more common in patients with pre-existing lymphoma. The findings support the removal of pre-existing lymphoma as a general exclusion criterion for a pSS diagnosis in classification criteria. Further, the findings suggest an investigation for pSS in patients presenting with MALT lymphoma in salivary glands. We compared the distribution of lymphoma subtypes with a general population reference. Both diffuse large B-cell lymphoma (DLBCL) (32%) and marginal zone lymphoma (MZL) (31%) were common, but only MZL (MALT lymphomas) occurred at an increased relative frequency compared to the general population. Men constituted 15% of 105 pSS patients with lymphoma. Men had a shorter time between the pSS and lymphoma diagnoses and more often had lymphoma in the salivary glands compared with women. Increased awareness of signs of lymphoma in salivary glands already during the first years after pSS diagnosis is justified in men with pSS. Keywords: Sjögren's syndrome, primary Sjögren's syndrome, lymphoma, IgG4-related disease Lilian Vasaitis, Department of Medical Sciences, Akademiska sjukhuset, Uppsala University, SE-75185 Uppsala, Sweden. © Lilian Vasaitis 2017 ISSN 1651-6206 ISBN 978-91-554-9912-9 urn:nbn:se:uu:diva-320220 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-320220) To Indra and Paulius List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Theander E, Vasaitis L, Baecklund E, Nordmark G, Warfvinge G, Liedholm R, Brokstad K, Jonsson R, Jonsson MV. (2011) Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren's syndrome. Annals of the Rheumatic Diseases, 70(8):1363-8 II Vasaitis L, Sundström C, Backlin C, Nordmark G, Baecklund E. (2016) Sporadic occurrence of non–diagnosed IgG4-related disease in lymphoma patients with a previous Sjögren’s syndrome diagnosis. Acta oncologica, 55(9-10):1139-44 III Vasaitis L, Nordmark G, Theander E, Backlin C, Smedby K E, Ask- ling J, Rönnblom L, Sundström C, Baecklund E. Support for remov- al of lymphoma as an exclusion criterion in classification criteria for primary Sjögren’s syndrome. Manuscript IV Vasaitis L, Nordmark G, Theander E, Backlin C, Smedby K E, Ask- ling J, Rönnblom L, Sundström C, Baecklund E. Population-based study of primary Sjögren’s syndrome and lymphoma: gender differ- ences, clinical characteristics, and lymphoma subtypes. Manuscript Reprints were made with permission from the respective publishers. Related Papers Vasaitis L (former Vasiliauskiene L), Wiik A, Høier-Madsen M. (2001) Prevalence and clinical significance of antikeratin antibodies and other sero- logical markers in Lithuanian patients with rheumatoid arthritis. Annals of the Rheumatic Diseases, 60(5):459-66 Nordmark G, Kristjansdottir G, Theander E, Appel S, Eriksson P, Vasaitis L, Kvarnström M, Delaleu N, Lundmark P, Lundmark A, Sjöwall C, Brun JG, Jonsson MV, Harboe E, Gøransson LG, Johnsen SJ, Söderkvist P, Elor- anta ML, Alm G, Baecklund E, Wahren-Herlenius M, Omdal R, Rönnblom L, Jonsson R, Syvänen AC. (2011) Association of EBF1, FAM167A (C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syn- drome. Genes & Immunity, 12(2):100-9 Bolstad AI, Le Hellard S, Kristjansdottir G, Vasaitis L, Kvarnström M, SjöwallC, Johnsen SJ, Eriksson P, Omdal R, Brun JG, Wahren-Herlenius M, Theander E, Syvänen AC, Rönnblom L, Nordmark G, Jonsson R. (2012) Association between genetic variants in the tumour necrosis fac- tor/lymphotoxin α/lymphotoxin β locus and primary Sjögren's syndrome in Scandinavian samples. Annals of the Rheumatic Diseases, 71(6):981-8 Nordmark G, Wang C, Vasaitis L, Eriksson P, Theander E, Kvarnström M, Forsblad-d'Elia H, Jazebi H, Sjöwall C, Reksten TR, Brun JG, Jonsson MV, Johnsen SJ, Wahren-Herlenius M, Omdal R, Jonsson R, Bowman S, Ng WF, Eloranta ML, Syvänen AC; UK Primary Sjögren’s Syndrome Registry. (2013) Association of genes in the NF-κB pathway with antibody-positive primary Sjögren's syndrome. Scandinavian Journal of Immunology, 78(5):447-54 Vasaitis L. (2016) IgG4-related disease: A relatively new concept for clini- cians. European Journal of Internal Medicine, 27:1-9 Vasaitis L. (2016) Metal dust as a possible inducer of immunoglobulin G4- related skin nodules. British Journal of Dermatology, 175(5):871 Contents Introduction ................................................................................................... 11 Sjögren’s syndrome .................................................................................. 12 Primary Sjögren’s syndrome .................................................................... 13 Classification criteria ........................................................................... 13 ESSDAI ................................................................................................ 17 ESSPRI ................................................................................................ 18 Epidemiology ....................................................................................... 18 Etiology and pathogenesis ................................................................... 19 Haematological disturbances ............................................................... 24 Autoantibodies ..................................................................................... 25 Cellular infiltration in salivary glands ................................................. 25 Germinal centre-like structures in minor salivary glands .................... 26 Glandular manifestations ..................................................................... 27 Extraglandular manifestations ............................................................. 27 Constitutional features ......................................................................... 29 Co-morbidity ........................................................................................ 29 Risk factors and causes of mortality in pSS ......................................... 29 Sex differences ..................................................................................... 29 Diagnosis of pSS in clinical practice ................................................... 29 Treatment ............................................................................................. 30 Lymphoma ................................................................................................ 31 Risk and predictors for lymphoma in pSS ........................................... 31 Possible mechanisms of lymphoma development in pSS .................... 34 Lymphoma subtypes in pSS and lymphoma diagnosis ........................ 36 Outcome and treatment of lymphoma in pSS ...................................... 37 IgG4-related disease ................................................................................. 37 Pathogenesis of IgG4-RD .................................................................... 38 Similarities and differences with pSS .................................................. 38 Diagnosis of IgG4-RD ......................................................................... 40 Lymphoma in IgG4-related disease ....................................................
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