€ gren Syndrome-associated lymphomas: an update on Sjo pathogenesis and management Gaetane Nocturne1 and Xavier Mariette1,2 1

INSERM U1012, Paris-Sud University, and 2Department of Rheumatology, Hopitaux Universitaires Paris-Sud, Paris-Sud University, Assistance Publique des Hopitaux de Paris, Le Kremlin-Bic^etre, France

Summary Primary Sj€ ogren Syndrome (pSS) is an autoimmune disease associated with an increased risk of lymphoma. Lymphomas complicating pSS are mostly low-grade B cell non-Hodgkin lymphomas, predominantly of marginal zone histological type. Mucosal localization is predominant, notably mucosaassociated lymphoid tissue lymphomas. Lymphomas often develop in organs where pSS is active, such as salivary glands. Germinal centre (GC)-like structures, high TNFSF13B (BAFF) and Flt3-ligand (FLT3LG) levels and genetic impairment of TNFAIP3 are new predictors of lymphoma development. These new findings allow a better understanding of the pathogenic mechanisms leading to lymphoma. We propose the following scenario: auto-immune B cells with rheumatoid factor (RF) activity are continuously stimulated by immune complexes containing antibodies against more specific autoantigens, such as SSA/Ro, SSB/La or others. Germline abnormality of TNFAIP3 leads to a decreased control of the NF-kB pathway and thus promotes survival of B cells and oncogenic mutations especially in GC structure. Moreover, B cells are stimulated by a positive loop of activation induced by BAFF secretion. Thus, lymphomagenesis associated with pSS exemplifies the development of antigen-driven B-cell lymphoma. The control of disease activity by a well-targeted immunosuppressor is the primary objective of the management of the patient in order to repress chronic B cell stimulation. Keywords: lymphomagenesis, mucosa-associated lymphoid tissue lymphoma, Sj€ ogren syndrome, auto-immunity, NF-kB. Sj€ ogren syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltrates of salivary and tears glands, leading to oral and ocular dryness and by autoantibody secretion. It can be encountered either alone (primary Sj€ ogren syndrome, pSS) or in the presence of other systemic

Correspondence: Professor Xavier Mariette, INSERM U1012, H^ opitaux Universitaires Paris-Sud, Universite Paris-Sud, 78 rue du General Leclerc, 94270 Le Kremlin Bic^etre, France. E-mail: [email protected]

ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

autoimmune diseases (secondary Sj€ ogren syndrome), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory myositis or systemic sclerosis. Its estimated prevalence ranges from 06 to 6 per 1000 inhabitants (Tomsic et al, 1999; Bowman et al, 2004; Alamanos et al, 2006; Qin et al, 2014), which means that pSS is the second most common systemic autoimmune disease, with only RA estimated to be more prevalent. The clinical picture combines sicca symptoms, fatigue and arthralgia in almost all patients. In addition, a third of pSS patients develop several systemic complications. Occurrence of lymphoma is known to be one of the most severe complications of pSS (Lichtenfeld et al, 1976). Investigation of the pathophysiology of lymphomagenesis is a key line of research. First, it might give us tools for an earlier and better detection of high-risk patients. Second, it might give clues for a better understanding of the pathophysiology of both mechanisms of autoimmunity and of lymphomagenesis outside the context of auto-immunity. Third, it might lead to the identification of new treatment targets in autoimmune diseases. This review will propose an update concerning the pathogenesis of pSS-associated lymphoma focusing on the new pathogenic pathways that have been shown to be involved in lymphomagenesis.

Epidemiology The three most common systemic autoimmune diseases, RA, pSS and SLE, are associated with an increased risk of lymphoma (Zintzaras et al, 2005) (Table I). Of these diseases, the highest risk of lymphoma is associated with pSS, with two studies calculating the relative risk (RR) to be between 15 and 20, compared with the general population (Zintzaras et al, 2005; Theander et al, 2006). However, more recent studies have estimated a lower RR of lymphoma in pSS. First, a Danish and Swedish survey assessed the history of autoimmune diseases and chronic inflammatory disorders in 3055 patients with lymphoma and 3187 matched controls (Smedby et al, 2006). Risks of all non-Hodgkin lymphomas (NHLs) were increased in pSS patients compared to controls [Odds ratio (OR) = 61, 95% confidence interval (CI) = 14– 27]. As already described (Smedby et al, 2005; Zintzaras et al, 2005), an increased risk of lymphoma was also observed in doi: 10.1111/bjh.13192

Review Table I. Prevalence and standard index ratio of lymphomas complicating primary Sjogren syndrome.


pSS patients (n)

Cases of lymphoma [n (%)]

SIR (95% CI)


1978 1997 1997 2001 2006 2012 2012 2014

142 295 676 110 286 6911 443 14570

7 9 11 3 11 23 7 143

444 333 87 13 1557 71 90 49

Kassan et al (1978) Valesini et al (1997) Kauppi et al (1997) Pertovaara et al (2001) Theander et al (2006) Weng et al (2012) Johnsen et al (2012) Fallah et al (2014)

(5) (3) (16) (27) (38) (03) (16) (098)

(167–1184) (173–64) (43–155) (27–38) (777–2785) (425–103) (71–253) (42–58)

pSS: primary Sjogren syndrome; SIR: standard index ratio; 95% CI: 95% confidence interval.

RA patients (OR = 15, 95% CI = 11–19), SLE patients (OR = 46, 95% CI = 10–22) and patients with coeliac disease (OR = 21, 95% CI = 10–48). More recently, a large Taiwanese study using National Health Insurance claims data found that, in a nationwide population cohort of 7852 patients suffering from pSS, the RR of developing NHL in women affected by pSS was estimated at 7 (Weng et al, 2012). A Norwegian study assessed 443 pSS patients among 896 840 inhabitants (Johnsen et al, 2012). Seven cases of NHL (16%) were found during a total follow-up of 3813 person-years, resulting in a standardized incidence ratio (SIR) of 90 (95% confidence interval 71–263) for NHL in pSS patients. Last, Fallah et al (2014) assessed 14 570 pSS patients diagnosed between 1968 and 2010; 143 lymphomas were identified, leading to a SIR of 49 (42–58). It has been described that the risk of lymphoma development increases with disease duration, with a cumulative risk at 5 years of 34% and 98% at 15 years from diagnosis (Solans-Laque et al, 2011). However, the date when pSS symptoms started and thus, the disease duration are frequently difficult to determine. Moreover, sometimes, even if the symptoms began earlier, the diagnosis of pSS is made at the same time as the diagnosis of lymphoma. pSS mainly affects women with a sex ratio of one male for nine female. Male gender has been suspected to be predictive of lymphoma risk but results are conflicting. In a recent metaanalysis including 18 articles, male gender was not associated with lymphoma occurrence (Nishishinya et al, 2014).

Clinical aspects, histopathology and therapeutic approach The latest World Health Organization (WHO) classification distinguishes three subtypes of B-cell marginal zone lymphoma (MZL) according to the sites involved: extranodal marginal zone of mucosa-associated lymphoid tissue (MALT) lymphoma, splenic MZL (SMZL) and nodal MZL (Swerdlow et al, 2008). MZL, particularly MALT lymphoma, is the most common histological type of lymphoma encountered in the setting of pSS. Among the other lymphoma sub-types which have been found increased, lympho-plasmacytoid lymphomas 2

are probably MZL with plasma-cell differentiation and diffuse large B-cell lymphoma (DLBCL) may be, at least in some cases, the transformation of previous low grade lymphomas (Royer et al, 1997; Voulgarelis et al, 1999; Ekstrom Smedby et al, 2008). Salivary glands (parotid and submandibular), the target organ of the disease, is the most frequent localization of MALT lymphomas in pSS but other mucosal sites could be affected, such as orbits, naso-pharynx, stomach, thyroid and lung. In the large majority of cases, they present as parotid gland enlargement. In this situation, clinically differentiating a lymphoma from a benign polyclonal parotid hyperplasia is not so easy. Hyperplasia is frequently bilateral, goes up and down. Lymphoma is more often unilateral; tumefaction is fixed and sometimes hard. Complementary examinations may help. Parotid gland magnetic resonance imaging (MRI) may be helpful to differentiate gland hypertrophy from lymphoma (Makula et al, 2000). In the hands of trained investigators, salivary gland ultrasound with Doppler enables differentiation between normal or atrophic tissue, focal salivary gland inflammation or lymph nodes/suspected lymphoma and gives the possibility of directing biopsy during the same procedure (Theander & Mandl, 2014). Lymph nodes may also be involved. The most frequent histological sub-groups are MZL (monocytoid) or DLBCL. Non-Hodgkin lymphomas complicating pSS are characterized by an indolent course, small tumour burden, normal lactate dehydrogenase (LDH) and b2-microglobulin levels and an excellent performance status. B symptoms are absent and bone marrow involvement is rare. In 10% of patients, low-grade lymphomas might transform to high grade lymphoma, mainly of DLBCL type, which has been convincingly seen to arise from the same clone as the low-grade lymphomas. The event-free survival (EFS) rate of nodal MZL has been shown to be worse that that of MALT lymphoma (Voulgarelis et al, 2012). The therapeutic approach must be personalized. In patients with localized low-grade lymphoma affecting the exocrine glands, a watchful policy can be a justified option (Pollard et al, 2011). Conversely, it was shown that patients with disseminated MALT lymphoma or with MALT ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

Review lymphoma and high disease activity were exposed to an increased risk of progression and might benefit from early treatment in order to avoid transformation into more aggressive lymphomas (Pollard et al, 2011). The best treatment regimen is a combination of rituximab with either alkylating agents (cyclophosphamide/chlorambucil) fludarabine or bendamustine (Rummel et al, 2013; Saadoun et al, 2013; Zucca et al, 2013). The latter combination of rituximab and bendamustine has shown favourable effectiveness and safety in recent studies concerning MZ and MALT lymphomas (Rummel et al, 2013). Treatment in DLBCL patients should be adapted to the histological grade and has been based on the CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) regimen combined with rituximab (Voulgarelis et al, 2006). NHL in pSS patients is associated with good prognosis. A recent retrospective study analysing 53 cases of NHL in pSS patients reported a 3-year overall survival and EFS of 97% and 78% respectively, in patients with MALT lymphomas (Voulgarelis et al, 2012). The histological pattern of MALT lymphomas is relatively homogenous. It displays diffuse lymphoid infiltrates that included small lymphocytes with round nuclei or with plasma-cell differentiation and/or centrocyte-like cells with indented nuclei. These cells invade the epithelial lining from the marginal zone of the lymphoid follicle, destroying the architecture of the gland and giving rise to classical important lympho-epithelial lesions. MALT lymphoma needs to be differentiated from so-called myo-epithelial sialadenitis (MESA) or lympho-epithelial sialadenitis (LESA), characterized by fusion of the different foci which become coalescent; some minor lympho-epithelial lesions are oligoclonal but in many cases, they remain polyclonal. MESA could be a transitional stage before MALT. MALT lymphoma is characterized by immunoglobulin light chain restriction and monoclonality, assessed by molecular biology. Classical characteristics of MALT lymphomas are present (Ferreri & Zucca, 2007): B phenotype of MALT lymphomas is confirmed by panB markers, such as CD19, MS4A1 (CD20), CD22, CD79A and CD79B. Monotypic immunoglobulin (Ig) of IgM isotype is often found at the membrane with a predominance of the j light chain (Royer et al, 1997). pSS-asociated lymphomas are not associated with viral infection: no association was found with Epstein-Barr virus (EBV), human herpes virus 8 (HHV-8), hepatitis C virus (HCV) or human T-cell lymphocytotropic virus 1 (HTLV-1) (Royer et al, 1997) and classical oncogenic events are not likely to promote lymphomagenesis in the context of pSS. Translocations involving MALT1 gene have been shown to play a role in MALT lymphoma development in general (t(11;18) (q21;21) and t(14;18) (q32;q21), involving BIRC3-MALT1 and IGH-MALT1 genes respectively). In comparison, these translocations are rather infrequent in MALT lymphoma-complicated pSS (prevalence of 27% and 15% respectively) (Streubel et al, 2004). Two studies in the 1990’s found mutations of common oncogenes in pSS-associated lymphomas but were never confirmed. The translocation ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

t(14;18) that leads to deregulation of the pro-oncogene BCL2 was found in 5/7 MALT lymphomas complicating pSS (Pisa et al, 1991), but not in the pre-lymphoma biopsies from these seven patients. One single study found mutations of TP53 in four patients with pSS and lymphoma (Tapinos et al, 1999).

Classical predictive factors The classical predictive factors of lymphoma are summarized in Table II. The main clinical predictors are permanent swelling of salivary glands, lymphadenopathies, skin involvement and especially palpable purpura, the latter being very suggestive of cryoglobulinaemia. The main biological predictors are cryoglobulinaemia, lymphopenia (especially CD4 cells), low complement levels and a monoclonal component in serum or urine. Of note, all these predisposing factors are easy to check in daily practice. Thus, they should be included in the management of every pSS patient in order to customize the followup. There is no consensus on the frequency of monitoring these predictive factors. It has to be adapted to the patient and their disease activity. In case of inactive disease, an annual or biannual follow-up is sufficient. In case of active disease or in the presence of several risk factors, this should be shortened to every 6 months. These patients with predictive factors of lymphoma occurrence could be the best population for testing new agents targeting B cells. It is striking that these factors could be linked to two major disease features that may promote lymphomagenesis:

Table II. Main classical clinical and paraclinical predictive factors of lymphoma development. Predictive factors Clinical Permanent swelling of salivary glands Adenopathy Purpura Paraclinical Cryoglobulinaemia Lymphopenia Low C4

Monoclonal component GC-like structures within salivary glands


Anaya et al (1996); Ioannidis et al (2002); Nishishinya et al (2014) Anaya et al (1996); Nishishinya et al (2014) Ioannidis et al (2002); Nishishinya et al (2014); Theander et al (2006) Nishishinya et al (2014); Tzioufas et al (1996) Solans-Laque et al (2011); Theander et al (2006) Ioannidis et al (2002); Nishishinya et al (2014); Solans-Laque et al (2011); Theander et al (2006) Anaya et al (1996) Theander et al (2011)


Review chronic antigenic stimulation and high disease activity. In the last few years, several studies have focused on these two major axes and witnessed major advances in pathogenesis of pSS-associated lymphomas.

Advances in pathogenesis: from new predictors to new pathways In the past ten years, significant advances have been made in the understanding of the mechanisms conducting polyclonal autoimmune B cells to monoclonality conferring a low grade B cell lymphoma comportment on these cells.

Rheumatoid factor reactivity and chronic auto-antigenic stimulation As mentioned above, mixed-cryoglobulinaemia, which is a cold-precipitable rheumatoid factor (RF), is a well-established predictive factor of lymphoma development in pSS. Very interestingly, it has been demonstrated that IgM-j produced by lymphomatous B cells from 2 pSS patients with salivary gland lymphoma had RF activity (Martin et al, 2000). Similarly, Bende et al (2005) studied the complementarity determining region (CDR3) repertoire from different mature B-NHLs. They demonstrated that 41% of MALT lymphomas occurring in salivary glands (with no information regarding an underlying diagnosis of pSS, but it should be present in the majority of them, as previously demonstrated (Dunn et al, 2004)) expressed B cell antigen receptors (BCR) with strong CDR3 homology to RF. Conversely, this percentage was only 18% in MALT lymphoma occurring in stomach and homology with RF was never found in pulmonary MALT lymphomas. The mechanism stimulating these RF+ B cells is probably a key for understanding the lymphomagenesis process in autoimmunity. Leadbetter et al (2002), demonstrated that immune complexes (IC) rather than IgG alone are required to effectively activate RF+ B cells in two mouse models of lupus. Anti-nucleosome antibodies are produced in the lymph node germinal centre (GC) and form IC, which secondarily stimulate RF+ B cells localized within the marginal zone (Sang et al, 2014). If this model is valid in pSS, a key question is the nature of the first auto-antigen inducing chronic B-cell stimulation and then formation of IC. Given that anti-Ro/SSA and/or anti-La/SSB are characteristic of pSS, Ro/SSA and La/SSB are the first candidates. Anti-Ro/SSA are detected in serum from two thirds of pSS patients and GC-like structures developed within salivary glands at the site of inflammation may promote their production (Bombardieri et al, 2012). Interestingly EBV infection of these auto-immune B cells might play a role in their persistence in salivary ectopic GC (Croia et al, 2014). In lupus, it has been demonstrated that anti-Ro/SSA antibodies are more prone to form IC than anti-DNA antibodies (Ahlin et al, 2012) and thus activate RF-B cells. 4

Other auto-antigens have been described in pSS, such as carbonic anhydrase isoenzyme II (Ono et al, 1999) and muscarinic type 3 receptor (Waterman et al, 2000) and could play a role in initial chronic auto-antigenic stimulation. Identification of novel auto-antigens might allow better understanding of the process leading from antigenic stimulation to lymphomatous escape. Last, auto-antigens like Ro or La might directly stimulate lymphomatous B cells in the salivary glands without an intermediate formation of IC. However, converse to RF activity, an auto-reactivity of some pSS-associated lymphoma against Ro or La has never been described.

Germinal centre structures as a new predictive factor Demonstration of ectopic GC-like structures in chronically inflamed tissues in patients with autoimmune disorders is a relatively common finding. They not only share morphological features with secondary lymphoid organs, such as a dark and a light zone within the normal epithelium, but also mechanisms controlling their induction and maintenance. The cross talk between lymphoid tissue inducer (LTi) and lymphoid tissue organizer cells promotes their induction. Lymphotoxin plays a major role in this process. Expression of CXCL13 and IL7 also promotes the recruitment of LTi cells that express CXCR5 (the receptor of CXCL13) and IL7 receptor (IL7R; also known as CD127) (Pitzalis et al, 2014). It is worthy of note that polymorphisms located on CXCR5 gene are associated with pSS (Lessard et al, 2013) but also with NHL independently of auto-immunity (Song et al, 2012). Interestingly, GC-like structures have been identified in the salivary glands of pSS patients (Amft et al, 2001). In a novel murine model of salivary gland inflammation, the formation of GC-like structures was associated with development of anti-nuclear antibodies (Bombardieri et al, 2012). Actually, B cells in these structures undergo somatic hypermutations and antigen-driven selection of the variable region genes of immunoglobulins. GC-like structures are likely to promote chronic activation of auto-immune B cells (Salomonsson et al, 2003). Bombardieri et al (2007) demonstrated that activationinduced cytidine deaminase (AICDA) was expressed in follicular dendritic cells within GC-like structures in pSS patients and that the association between AICDA and GC-like structures was also found in MALT lymphomas complicating pSS. The latter result supports the functional key role of these structures in the process of lymphomagenesis. GC-like structures have been shown to be predictive of an increased risk of lymphoma in pSS patients (Theander et al, 2011). Theander et al (2011) studied 175 minor salivary gland biopsy performed at diagnosis in pSS patients. GC-like structures were found in 86% of the patients who will later developed NHL versus 22% of the patients without subsequent NHL (P = 0001). Interestingly, these structures were detectable more than 7 years before lymphoma occurrence. ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

Review To sum up, there are epidemiological, genetic and pathogenic arguments supporting the role of GC structures in the occurrence of pSS-associated lymphoma. Therefore, avoiding their formation could be a promising therapeutic approach [lymphotoxin-a/lymphotoxin-b, ICOS/ICOSLG, MBTPS1 (S1P)]. Finally, routine histopathological patients findings have been shown to detect patients at high risk of lymphoma occurrence. Lymphocytic infiltration of minor salivary glands is assessed by the focus score (i.e. the number of lymphocyte foci per 4 mm2 glandular tissue). A Dutch study has recently demonstrated that a focus score ≥3 was an independent risk factor of lymphoma occurrence in pSS patients (Risselada et al, 2014). Given that, in most of cases, the presence of GC is not routinely assessed, a high focus score (≥3) could be a useful intermediate biomarker associated with a more important B-cell activation and the presence of GC.

B cell cytokines: TNFSF13B (BAFF), Fms-like tyrosine kinase 3 ligand (FLT3LG) and TXLNA (IL14) TNFSF13B (also termed BAFF) promotes B cell maturation, proliferation and survival. Mice transgenic (Tg) for this cytokine are characterized by an over-expression of TNFSF13B (BAFF) and develop features of SLE and later clinical characteristics of pSS, such as sialadenitis (Mackay et al, 1999); 3% of these mice develop lymphoma when old. In the last few years, several studies have focused on the role of TNFSF13B (BAFF) in pSS. It was first demonstrated that serum TNFSF13B (BAFF) levels were enhanced and correlated with levels of anti-SSA/Ro, anti-SSB/La and RF in pSS patients (Mariette et al, 2003). Second, enhanced levels of TNFSF13B (BAFF) have been found in the salivary glands. Very interestingly, it has been shown that TNFSF13B (BAFF) was secreted not only by usual professional TNFSF13B (BAFF)-producing cells, such as monocytes-macrophages and dendritic cells (DC), but also by T and B cells and by the target cells of auto-immunity in pSS: salivary epithelial cells (Daridon et al, 2007; Lavie et al, 2008). This finding strongly supports the hypothesis that the epithelial cell is not only the passive victim in pSS but also an active culprit that might promote the over-activation of immune system. TNFSF13B (BAFF) release is mainly induced by type 1 and 2 IFN (Litinskiy et al, 2002; Ittah et al, 2006; Brkic et al, 2012) and by viral infections (Ittah et al, 2008, 2011). Thus TNFSF13B (BAFF), the secretion of which results from the innate immune system, may be a link between innate immunity and autoimmunity. Two recent studies have demonstrated that TNFSF13B (BAFF) might also be involved in the occurrence of lymphoma in pSS patients. By studying 76 pSS patients, Quartuccio et al (2012) demonstrated that TNFSF13B (BAFF) serum levels were increased in patients with lymphoproliferative disorders. Actually, TNFSF13B (BAFF) levels increased in parallel with the importance of the B-cell-activation from ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

low to high in the following subsets of patients: patients without lymphoproliferation, patients with cryoglobulinaemia, patients with MESA, patients with lymphoma. In the French prospective ASSESS (Assessment of Systemic Signs and Evolution of Sj€ ogren Syndrome) cohort, TNFSF13B (BAFF) level was increased among pSS patients with current or previous lymphoma compared with patients without lymphoma (Gottenberg et al, 2013). Moreover, TNFSF13B (BAFF) level correlated to disease activity assessed by the ESSDAI [European League Against Rheumatism (EULAR) Sj€ ogren Syndrome Disease Activity Index] and significantly correlated with serum beta2-microglobulin. Thus, TNFSF13B (BAFF) is likely to promote B-cell transformation in the lymphomagenesis process complicating pSS. Interestingly, in these two studies, increased serum TNFSF13B (BAFF) level was found in patients with previous lymphoma, in most cases in complete remission. Thus, this increase in serum TNFSF13B (BAFF) level could be, at least in part, not related to the activity of the lymphoma, but could be constitutional and persist after the lymphoma was cured. It could be linked to genetics as a polymorphism in the TNFSF13B (BAFF) promoter is associated with a higher TNFSF13B (BAFF) level. The data about a possible association between this SNP and pSS are still controversial (Gottenberg et al, 2006; Nossent et al, 2008; Nezos et al, 2014). Screening of TNFSF13B (BAFF) levels in pSS patients could facilitate the selection of patients who may benefit from anti-TNFSF13B (BAFF) targeted therapy (belimumab). Future studies will help to determine if this target therapy would be also able to decrease the risk of lymphoma. FLT3LG is a cytokine involved in the differentiation and proliferation of early B cell progenitors (Ray et al, 1996). It is produced by stromal cells in the bone marrow and other haematopoietic cells and, notably, T cells. Its receptor, FLT3, is expressed by immature haematopoietic progenitor cells (Drexler & Quentmeier, 2004). FLT3LG is increased in the majority of leukemias (Drexler, 1996). Given its implication in malignancies and in B cell development, Tobon et al (2010) assessed FLT3LG in pSS patients. First FLT3LG serum levels were increased in pSS patients compared to controls. Second, FLT3LG level was associated with disease activity, as assessed by ESSDAI (Seror et al, 2010), and high levels of FLT3LG were found in two patients who subsequently developed lymphoma. TXLNA (IL14) was initially designated as high molecular weight B cell growth factor. It promotes B cell proliferation, especially of B cells within the GC (Ambrus & Fauci, 1985). Mice Tg for IL14a present both clinical and biological characteristics of pSS (Shen et al, 2006). They first present increased serum levels of IgM and IgG at age 3–9 months. Then, they develop auto-antibodies, sialadenitis and immune complex-mediated nephritis at age 9–17 months. At 14– 18 months, 95% of IL14a Tg mice develop B cell lymphomas in the liver and gastrointestinal tract or lung with histological features of a large B cell lymphoma. Thus, these mice offer a 5

Review very robust murine model for pSS and highlight the role of chronic B cell activation in the disease. Interestingly, Shen et al (2009) showed that IL14a serum levels were increased in pSS patients compared to controls. To date, no study has assessed the role of this cytokine in lymphomagenesis.

TNFAIP3 (A20) and control of B-cell activation Lymphomagenesis in pSS could be considered as a multiple step process where the first event is the chronic stimulation at the site of the disease of polyclonal B cells, especially, as stated before, B cells with a RF activity. A consequence of this polyclonal activation of autoimmune B cells might be the increased frequency of oncogenic mutations. In this context of chronic stimulation, a dysfunction of any check-point of auto-immune B-cell activation could precipitate autoimmune B cells into a malignant transformation. Our group has tested this hypothesis by studying the role of tumour necrosis factor alpha-induced protein 3 (TNFAIP3, also termed A20) abnormalities in lymphomas complicating pSS. The TNFAIP3 gene encodes the TNFAIP3 (A20) protein, which is a central gatekeeper of NF-kB activation. TNFAIP3 was found to be down-regulated in salivary glands from pSS patients in comparison with controls, and the cells with down-regulated TNFAIP3 expression exhibited enhanced NFkB activities (Sisto et al, 2011). Germinal abnormalities in TNFAIP3 have been associated with different auto-immune diseases (Musone et al, 2011) and somatic mutations of the gene have been observed in several lymphoma subtypes, particularly MALT lymphoma, the lymphoma subtype most frequently associated with pSS. Chanudet et al (2009) demonstrated that deletion of 6q23 including TNFAIP3 was present in 18% of ocular adnexal MALT lymphomas and was exclusively found in cases without any characteristic translocation involving MALT1, BCL10 or FOXP1 (Chanudet et al, 2009). This result was confirmed in 105 cases of ocular adnexal MALT lymphoma (Bi et al, 2011). In addition, this study demonstrated that TNFAIP3 mutation/deletion was associated with increased expression of NF-jB target genes, such as CCR2, TLR6 and BCL2. Interestingly, all these studies demonstrated that TNFAIP3 gene inactivation was exclusive with classical translocation. This is understandable given the link between TNFAIP3 and MALT1. MALT1 with BCL10 couple antigen-receptor signals to the canonical NF-jB pathway. As mentioned above, translocations associated with MALT lymphomas leads to the over-expression of these two proteins. MALT1 possesses a caspase-like domain. It has been demonstrated that this domain was functional and was able to cleave TNFAIP3 and to impair its capacity of control of NF-jB activation (Coornaert et al, 2008). The same group demonstrated that MALT1 deficiency protects mice from experimental autoimmune encephalomyelitis partly thanks the prevention of the disappearance of TNFAIP3 (Mc Guire et al, 2013). Kato et al (2009) confirmed that somatic mutation/deletion of TNFAIP3 was frequent in MALT lymphomas (218% of this series) but 6

also in Hodgkin lymphomas (333%). Moreover, this study gives clues to the functional consequences of this genetic inactivation. It was demonstrated that a TNFAIP3-deficient lymphoma cell stably generated tumours in immunodeficient mice. Interestingly, the re-expression of wild type TNFAIP3 lead to tumour control. We have recently demonstrated that rs2230926, a coding SNP located in exon 3 of TNFAIP3, which leads to the replacement of a phenylalanine by a cysteine, was not associated with pSS alone but with the phenotype pSS complicated by lymphoma (Nocturne et al, 2013). Moreover, we had the opportunity to study both germinal and somatic sequences of TNFAIP3 in 20 pSS patients with lymphoma. We demonstrated that functional abnormalities of the TNFAIP3 gene were present in one third of germinal DNA and in another third of lymphoma DNA. Overall, 60% of these patients presented a potential coding abnormality of TNFAIP3, either germinal or somatic. When focusing on patients with MALT lymphoma, this percentage increased to 77%. Last, we confirmed that two of these abnormalities (rs2230926 and an insertion of two guanines in exon 3) lead to less effective control of the NF-kB pathway. The very new result of this study is that, in the context of auto-immunity with a continuous stimulation of auto-immune B cells, a subtle germinal abnormality of genes controlling NF-kB activation present in all cells since genetically-mediated, may have specific consequences in B cells because they are continuously stimulated by the autoimmune process.

Other genes and pathways involved in control of B-cell activation Other lines of research involved in the control of B cell activation may be promising in the future. Reksten et al (2014) recently investigated which genetic polymorphisms were associated with GC-like structures. Among the 107 genes assessed, the only association was found with CCL11, a chemokine recruiting eosinophils and involved in the allergic response. However, no data is available concerning the role of this chemokine in pSS-associated lymphomas.

Analogies between pSS-associated lymphoma and lymphoma occurring in chronic HCV infection Despite conflicting results, epidemiological studies have reported a higher risk of NHL occurrence in patients chronically infected by HCV compared to controls with ORs ranging from 2 to 4 (Negri et al, 2004; Schollkopf et al, 2008). A meta-analysis including seven studies from the International Epidemiology Consortium confirms this association because HCV was detected in 36% of NHL cases and in 27% of controls [OR = 178, 95% CI (14–225)] (de Sanjose et al, 2008). HCV infection is the prototype of chronic infection with a high level of blood circulating IC: it is characterized by ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

Review the long course of the symptom-free disease, the high level of viral antigen and the high anti-HCV humoral response without any curative effect. Thus, it fulfils the conditions for an antigen-driven over-stimulation of cells bearing a membrane immunoglobulin with RF activity. Interestingly pSS- and HCV-associated lymphomas share several clinical features: predominance of B cell low grade and marginal zone subtype, the frequency of mucosal localization (Bachy et al, 2010), the association with cryoglobulinaemia (De Re et al, 2000) and localization in the target organ. It has been proposed that chronic B cell stimulation plays the central role in lymphomagenesis occurring in HCV-infected patients (Mariette, 2001). The first event of lymphomagenesis may be the chronic stimulation of polyclonal B cells with RF activity at the site of the disease. In the case of HCV, viral antigen complexes with anti-HCV IgG may be recognized by RF-expressing B cells. This over-activation of auto-reactive B cells may promote the occurrence of chromosomal abnormalities, leading to monoclonal transformation. Interestingly, in HCVassociated lymphoma, antiviral therapy alone may induce remission of the lymphoma (Hermine et al, 2002). Given the similarities between pSS- and HCV-associated lymphoma, it is tempting to speculate that in pSS, as proposed in HCVassociated lymphoma, chronic antigenic stimulation is the key event of lymphomatous escape and that an efficient control of the auto-immune process by a well-targeted immunosuppressor could decrease the risk of lymphoma in pSS.

The 2014 proposed scenario for the pathophysiology of primary € gren Syndrome-associated lymphoma Sjo The past ten years have allowed better understanding of the pathogenic mechanisms leading to the transformation of an auto-reactive B cell clone to lymphoma. This transformation is a multi-step process (Fig 1). The first event of lymphomagenesis is a succession of chronic stimulations by auto-antigens. Analogous with a recent study in lupus (Sang et al, 2014), we suggest that a first stimulation against still unknown auto-antigens (Ro and La could be some of them) may occur in ectopic salivary GC, leading to formation of IC, which secondarily stimulate marginal zone RF+ B cells that are prone to become lymphomatous. Thus, the chronic stimulation by immune complexes (with Ro/La or an unknown antigen) at the site of the disease (mucosa salivary and lachrymal gland tissue) of polyclonal RF+ B cells would be a key event involved in lymphomagenesis. In addition, secretion of TNFSF13B (BAFF) and other cytokines by the environment (epithelial cells, T cells and even B cells themselves) may promote the increased survival of these RF+ clones through both paracrine and autocrine mechanisms. Given their ongoing stimulation by IC, auto-reactive RF-B cells have to be perfectly controlled. The fact that this activation occurs in MALT tissue and not in spleen, lymph nodes or bone marrow could ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

Ectopic GC

Autoreacve B cells

B cell activation: - Ectopic GC - Chronic inflammation - viral infection Auto-Ab: - anti Ro/SSA - anti La/SSB - other specificities?

Marginal zone

IC: IgG/auto-Ag


Polyclonal B cells



TNFSF13B (BAFF) Other cytokines Mutations of oncogenes Activation of NF- B

Monoclonal ± lymphomatous B cells

- Mutations of TNFAIP3 - Other genes controlling NF- B activation

Fig 1. The 2014 scenario for the pathophysiology of primary Sj€ ogren syndrome-associated lymphoma. The lymphomagenesis of primary Sj€ ogren syndrome is a multi-step process. Chronic antigenic stimulation plays a key role. The first stimulation against still unknown auto-antigens (Ro and La?) may occur in ectopic salivary GC, leading to formation of IC. These IC can stimulate polyclonal RF+ B cells within the marginal zone. In addition, several factors may amplify this phenomenon: paracrine and/or autocrine TNFSF13B (BAFF) production, mutations of oncogenes and over-activation of the NF-kB pathway. Moreover, innate or acquired defects impacting proteins involved in the control of NF-kB activation, such as TNFAIP3 abnormalities, may accentuate B cell over-activation. The accumulation of the events might precipitate marginal zone RF+ B cells to monoclonal  lymphomatous escape. IC: immune complexes, IgG immunoglobulin G, GC: germinal centre, RF: rheumatoid factor, Auto-AB: auto-antibody, auto-Ag: auto-antigen.

be important, as the mechanisms of control of B-cell activation could be less efficient in this tissue. In this context, none of the mechanisms of control of activation of the B cells might support impairment. Thus, the acquisition of mutations or deletions in TNFAIP3, which controls NF-kB activation, gives a survival advantage to these B cells harbouring these acquired somatic mutations or deletions. More interestingly, some subtle germline genetic mutations of TNFAIP3 or of other genes controlling NF-kB activation and leading to a slight dysfunction of TNFAIP3 could have consequences only in these B cells continuously stimulated by the IC and favour their escape as lymphoma B cells. For undetermined reasons (genetic predisposition such as CXCR5 polymorphism, environmental triggers), some patients develop GC-like structures that might be considered as an ineffective attempt to clear auto-antigens. Conversely, these structures might promote stimulation of auto-reactive 7

Review B cells. Moreover, dysregulated NF-kB signalling is a known feature of the oncogenic mutations in B cells located within the GC. Failure to eliminate these B cells could also lead to prolonged AICDA (also termed (AID) activity and increased numbers of somatic mutations, including oncogenic mutations, which would confer to these cells a low grade B cell lymphoma comportment.

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Sjögren Syndrome-associated lymphomas: an update on pathogenesis and management.

Primary Sjögren Syndrome (pSS) is an autoimmune disease associated with an increased risk of lymphoma. Lymphomas complicating pSS are mostly low-grade...
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