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Lymphoma development in patients with autoimmune and inflammatory disorders – What are the driving forces?

Seminars in Cancer Biology, pages 61 - 70

Abstract

For decades, it has been known that patients with certain autoimmune and inflammatory disorders, such as rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS), have an increased risk of developing malignant lymphoma. Although the clinico-biological reasons for this association remain largely unknown, our knowledge has improved and new insights have been obtained. First, the direct link between autoimmunity and lymphomagenesis has been strengthened by large epidemiological studies showing a consistent risk increase of lymphoma associated with certain autoimmune/inflammatory conditions in independent cohorts from different countries. Second, a number of local and systemic disease-related risk factors in these diseases have been repeatedly linked to lymphoma development, with the prime examples being disease severity and the degree of inflammatory activity. Considering the key role of B- and T-cell activation in the pathogenesis of both autoimmunity and lymphoma, it is perhaps not surprising that longstanding chronic inflammation and/or antigen stimulation have emerged as major predisposing factors of lymphoma in patients with active autoimmune disease. Finally, increasing evidence suggests that lymphomas associated with autoimmunity constitute a different spectrum of entities compared to lymphomas arising in patients without any known autoimmune or inflammatory conditions, pointing to a different pathobiology. In this review, we summarize the recent literature that supports a direct or indirect link between immune-mediated disease and lymphoma and describe the characteristics of lymphomas developing in the different diseases. We also discuss molecular, genetic and microenvironmental factors that may come into play in the pathobiology of these disorders.

Keywords: Lymphoma, Autoimmune disease, Risk factors, Chronic inflammation, Antigen stimulation, Genetic events.

1. Introduction

The longstanding recognition of increased lymphoma risk in patients with some of the most common autoimmune and inflammatory conditions has been the strongest argument for a direct association between these diseases and lymphoma development [1], [2], and [3]. Today, it is well established that the risk of developing lymphoma is increased in patients with autoimmune or inflammatory conditions such as rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE), celiac disease, dermatitis herpetiformis, and Hashimoto's thyroiditis. However, for other autoimmune/inflammatory diseases the data is either (i) conflicting (e.g. as in psoriasis, Crohn's disease and sarcoidosis), (ii) associations with lymphoma have been poorly studied (e.g. in psoriatic arthritis and rare vasculitides), or (iii) no overall increased risk has convincingly been identified (e.g. ulcerative colitis, ankylosing spondylitis and polymyalgia rheumatica) [1], [2], and [3].

That said, when studying these associations one must bear in mind the large heterogeneity not only within and between the various autoimmune/inflammatory diseases, but also within and between different subtypes of malignant lymphomas. Therefore, an overall lack of association with an inflammatory disease does not preclude an increased risk of lymphoma among subgroups of patients. Indeed, with larger and more detailed studies, data is now emerging which supports the idea that the increased lymphoma risk may be confined to one or two specific lymphoma subtypes and also to subgroups of patients displaying particular features of the immune-mediated disease. The prime example is the strong association between disease intensity in RA and one of the most aggressive lymphoma subtypes, namely diffuse large B-cell lymphoma (DLBCL) [4] .

Furthermore, it is apparent that the magnitude of the risk estimates varies considerably between studies. One of the reasons behind this diversity is that earlier and smaller studies on selected patients typically reported higher risk estimates compared to more recent, larger and population-based studies [1], [2], and [3]. Nevertheless, a recurrent finding in rheumatic diseases is that the highest relative risk for lymphoma is associated with pSS, followed by SLE and RA, thus indicating a disease-specific risk profile. Recent estimates of the relative risks in unselected populations appear to be more consistent across studies from Western countries, ranging from about 2 in RA, 3–7 in SLE to 9–16 in pSS compared to a general population (more recent and seminal studies of lymphoma risk in selected autoimmune/inflammatory conditions are summarized in Table 1 ). In addition, despite improved disease control, it is noteworthy that in Swedish RA patients the average risk for lymphoma (approximately double that of the general population) has remained relatively stable over the last decades [5] .

Table 1 Studies of lymphoma risks in patients with RA, SLE, Sjögren's syndrome and celiac disease published since 2009. a

Disease Country Study period RR of lymphoma/SIR (95% confidence interval) Reference author, year
RA
  US 1993–2002 OR NHL 1.2 (1.1–1.3) Anderson, 2009 [120]
  Sweden 1999–2006 RR lymphoma 2.7 (1.8–4.1) Askling, 2009 [121]
  California, US 1991–2002 RR NHL

Men 2.1 (1.7–2.5)

Women 1.4 (1.2–1.6)
Parikh-Patel, 2009 [122]
  Sweden 1997–2006 HR lymphoma, first 10 years of RA disease: 1.8 (1.0–3.0) Hellgren, 2010 [5]
  UK 2002–2009 SIR NHL 3.1(1.8–5.1) Mercer, 2013 [123]
  Denmark 2000–2008 SIR NHL 2.3 (0.9–5.4) Dreyer, 2013 [124]
 
Sjögren
  US 1993–2002 OR NHL 1.9 (1.5–2.3) Anderson, 2009 [120]
  China 1990–2005 SIR NHL 48.1 (20.7–94.8) Zhang, 2010 [125]
  Spain 1988–2008 SIR NHL 15.6 (8.7–28.2) Solans-Laqué, 2011 [21]
  Taiwan 2000–2008 SIR NHL

Men 3.1 (0.6–9.0)

Women 7.1 (4.2–10.3)
Weng, 2012 [126]
  Norway 1980–2009 SIR NHL 9.0 (7.1–26.3) Johnsen, 2013 [127]
  Meta-analysis 11studies 1954–2009 Pooled RR 13.8 (8.5–19.0) Liang, 2013 [128]
 
SLE
  US 1993–2002 OR NHL 1.5 (1.2–1.9) Anderson, 2009 [120]
  Korea 1997–2007 SIR NHL 15.4 (2.9–37.7) Kang, 2010 [129]
  Taiwan 1996–2007 SIR lymphoma 7.3 (7.0–7.6) Chen, 2010 [130]
  Denmark 1951–2006 SIR NHL 5.0 (1.9–13.3) Dreyer, 2011 [131]
  International (US, Canada, Europe, Korea) 1958–2009 SIR lymphoma 4.1 (3.2–5.0)

SIR NHL 4.4 (3.5–5.5)

SIR HL 2.3 (0.9–4.7)
Bernatsky, 2013 [132]
 
Celiac disease
  Sweden 1965–2004 OR NHL 5.4 (3.6–8.1) Gao, 2009 [30]
  1975–1984 OR NHL 13.2 (3.6–48.0)
  1985–1994 OR NHL 7.9 (3.4–18.5)
  1995–2004 OR NHL 3.8 (2.3–6.4)
  US 1993–2002 OR NHL 1.5 (0.9–2.5)

OR T-cell lymphoma 5.9 (2.4–14)
Anderson, 2009 [120]
  Sweden 1969–2008 SIR NHL 2.8 (2.4–3.4)

SIR T-cell NHL 48.0 (15.8–145)

SIR B-cell NHL 1.9 (1.3–2.7)
Elfström, 2011 [133]
  Scotland, UK 1970–2004 SIR NHL 5.2 (1.4–13.2) Grainge, 2012 [134]
  Meta-analysis 8 studies (NHL) OR NHL 2.6 (2.0–3.3) Tio, 2012 [33]
  5 studies (T-cell NHL) 1993–2008 OR T-cell NHL 15.8 (7.8–31.9)
  US 1981–2010 SIR NHL 6.9 (4.2–8.2)

SIR DLBCL 5.4 (1.9–10.5)

SIR T-cell NHL 22.4 (7.1–46.4)
Leslie, 2012 [135]
  Sweden 1969–2009 SIR NHL 2.8 (2.1–3.7) Lebwohl, 2013 [26]

a Studies before 2009 reviewed in [1] and [2].

DLBCL = diffuse large B cell lymphoma, HL = Hodgkin lymphoma, HR = hazard ratio, NHL = non-Hodgkin lymphoma, OR = odds ratio, RA = rheumatoid arthritis, RR = relative risk, SIR = standardized incidence ratio, SLE = systemic lupus erythematosus.

Although strong evidence for an increased risk of lymphoma in certain autoimmune/inflammatory conditions has existed for many years, it was only more recently that we began to identify factors that may act as the driving forces behind lymphomagenesis within this particular setting. In this review, we summarize the disease-related, environmental and genetic risk factors that have been proposed as the potential “drivers” ultimately leading to lymphoma development in patients with autoimmune diseases. In light of the crucial role of B- and T-cell activation in the pathogenesis of both autoimmunity and lymphomas, chronic inflammation and antigen stimulation are especially relevant to discuss as potential determinants for lymphoma development within this setting. Finally, we also review potential leads to the pathobiology provided by studies of clinical and molecular characteristics of the specific lymphoma subtypes that have been associated with each autoimmune/inflammatory condition.

2. Risk factors for lymphoma development in autoimmune conditions – where do we stand?

2.1. Disease activity and severity

Studies of risk factors for lymphoma development in autoimmune conditions have indicated a strong association between disease severity and/or disease activity and increased lymphoma risk in some of the most common immune-mediated diseases. For example, in RA, a clear correlation has been demonstrated between lymphoma risk and features linked to disease severity, such as the presence of Felty's syndrome [6] , secondary Sjögren syndrome [7] , high erythrocyte-sedimentation rate (ESR) values [8] and erosive joint disease [4] and [9]. The strongest support for an association between disease activity in RA and risk for lymphoma comes from a Swedish case–control study of 373 RA cases with lymphoma and 373 RA controls without lymphoma [4] . The cumulated disease activity based on a score that includes the number of swollen and tender joints, ESR values and the treating physician's global assessment was estimated for the entire RA disease period up until lymphoma diagnosis. A 70-fold increased lymphoma risk was observed in RA patients with the highest cumulative disease activity compared to those with low disease activity. Furthermore, a striking association was observed between high RA disease activity (90-fold increased risk) and DLBCL, whereas all other lymphoma subtypes showed less strong association (up to a 5-fold increased risk).

In SLE, disease activity has not been as clearly linked to lymphoma risk as in RA, although some studies indicate correlations with severe disease manifestations, such as hematological manifestations, pulmonary involvement and sicca symptoms [10] and [11], and with a high SLE damage score [12] . However, in a recent study of 75 SLE-lymphoma patients together with 4961 cancer-free SLE controls, disease activity, as measured by the SLE disease activity index, was not associated with lymphoma risk, although the authors acknowledged that some aspects of disease severity may not have been well-captured by their approach [13] . Nevertheless, lymphoma characteristics in SLE are similar to those found in RA, with both diseases displaying an increased risk of developing DLBCL [10], [11], [14], [15], and [16].

In pSS, which is characterized by lymphocytic infiltrations and polyclonal B-cell activation in exocrine glands, at least 30% of patients also suffer from extra-glandular, systemic manifestations. A number of risk factors for lymphoma development in pSS have been recognized, all of which are linked to more severe and active pSS. Established risk factors include swelling of major salivary glands [17] , lymphadenopathy, splenomegaly, peripheral neuropathy, skin vasculitis or palpable purpura, as well as laboratory findings of cryoglobulinemia, low complement levels of C4 and C3, lymphopenia, CD4 lymphopenia, and M-components in serum or urine [18], [19], [20], [21], and [22]. Recently, severe salivary gland dysfunction by parotid scintigraphy at pSS diagnosis [23] , and ectopic germinal center-like structures in minor salivary gland biopsies at diagnosis of pSS were also linked to increased lymphoma risk [24] . Hence both local and systemic disease-related factors may contribute to lymphomagenesis in pSS. The majority of lymphomas occurring in pSS are extranodal marginal zone lymphomas of mucosa-associated tissue (MALT lymphomas) localized to the salivary glands, although there have also been reports suggesting an increased risk of DLBCL [15], [16], [19], [20], and [25].

In celiac disease, it has been hypothesized that the increased lymphoma risk is associated with the intestinal inflammation caused by ingested gluten. Strong support for this reasoning is provided by the finding that patients with celiac disease and persistent villous atrophy at follow-up biopsies have a higher risk for lymphoproliferative disease than patients whose follow-up biopsy shows mucosal healing [26] . Indeed, in this study the lymphoma risk was not significantly increased in celiac patients with mucosal healing compared to the general population. Some smaller studies also support the notion that non-adherence to a gluten-free diet is linked to lymphoma risk [27] and [28]. Indirectly, the gradual decline in the relative risk of developing lymphoma in patients with celiac disease over the last decades underscores the beneficial effects of new diagnostic tools (serological markers and human leukocyte antigen (HLA)-typing) [29], [30], and [31], which ultimately lead to earlier detection and treatment (gluten-free diet). Admittedly, as alluded to earlier, secular trends in risks are difficult to evaluate when the awareness and diagnostic intensity for the underlying disease (here: celiac disease) have increased over time. Although lymphomas occurring in the presence of celiac disease are typically enteropathy-associated T-cell lymphoma localized to the intestine, we note that there are also reports suggesting an association with DLBCL [15], [16], [32], and [33].

2.2. Immunosuppressive drugs

Over the years, a major concern has been whether the actual immunosuppressive drugs used to treat inflammatory diseases, could carry an inherent and consequently increased risk of lymphoma. Although some studies in RA have suggested an increased risk with a few of the traditional disease modifying drugs (i.e. azathioprine [4] and methotrexate [34] ), most larger studies have failed to show direct associations with disease modifying therapy overall or with specific drugs belonging to this group [35] . For azathioprine, increased relative risks of lymphoma have also been reported in patients with inflammatory bowel disease [36] , although the authors of this meta-analysis acknowledged that they could not determine whether the associations resulted from the medication, the activity of the underlying disease, or a combination of factors.

When biological drugs were first introduced (the tumor necrosis factor inhibitors (TNFi) were introduced in the late 1990s), some studies in RA reported an increased lymphoma risk associated with the use of these drugs. However, most subsequent studies involving larger numbers of patients and a longer follow-up have failed to show a clinically significant increased lymphoma risk in patients treated with TNFi compared with non-TNFi-exposed RA patients [37] . On the other hand, in inflammatory bowel disease, an association has been described between patients treated with TNFi in combination with thiopurines (azathioprine or 6-mercaptopurine) and the occurrence of a rare T-cell lymphoma, hepatosplenic T-cell lymphoma [38] . Thus far, the mechanisms behind this rare event remain poorly understood.

It is finally noteworthy that some of the immune-mediated conditions linked to increased lymphoma risk have not typically been treated with strong immunosuppressive agents (e.g. pSS, celiac disease and Hashimoto's thyroiditis), and thus immunosuppressive treatment cannot explain the increased lymphoma risk in these diseases. Hence, although we cannot fully exclude the possibility that immunosuppressive drugs may play a role in lymphomagenesis, there is currently no strong evidence alluding to immunosuppressive therapy as a principal determinant of lymphoma development in patients with autoimmune/inflammatory conditions.

2.3. ‘Cell-intrinsic’ and ‘cell-extrinsic’ factors

Other proposed risk determinants for lymphoma include genetic susceptibility or environmental factors common to both the autoimmune disease and the lymphoma. For example, the HLA class II region determines susceptibility to a range of autoimmune disorders, and has also recently been shown to harbor risk loci for both Hodgkin [39] as well as non-Hodgkin lymphomas, most notably for the follicular lymphoma subtype [40] and [41]. These findings are strongly indicative of a role of adaptive immunity not only in immune-mediated diseases such as RA but also in lymphomagenesis. However, studies in patients with autoimmune diseases have not been able to show a significantly increased lymphoma risk among relatives [42] and [43]. It is therefore likely that shared genetic susceptibility is not of major importance within this context.

There are few known environmental risk factors shared by lymphoma and autoimmune/inflammatory diseases. Smoking has emerged as an important risk factor for anti-citrullinated protein antibody-positive RA [44] , however, tobacco use has not explicitly been investigated as a risk factor for RA-associated lymphomas. In SLE, there is a modest association with smoking and the risk of SLE [45] , but no significant associations have been found in other investigated diseases (e.g. pSS, celiac disease, and Hashimoto's thyroiditis) [46], [47], and [48]. In lymphoma, smoking has in some studies been linked to an increased risk of follicular lymphoma, T-cell lymphoma and a modest increase in risk for Hodgkin lymphoma, but in most studies not with an increased lymphoma risk overall [49] and [50]. Currently, there is little to suggest that smoking is a shared, common risk factor for lymphomas in autoimmune diseases.

Among infectious agents, the Epstein–Barr virus (EBV) is of particular interest since it is a ubiquitous virus that persists in B cells, and displays growth transforming and oncogenic capacity linked to lymphoma development, in particular in the context of various types of immune-suppression. That notwithstanding, EBV appears to be of limited importance in patients with autoimmune/inflammatory diseases since the proportion of EBV-positive lymphomas and the distribution of positivity among lymphoma subtypes (present in about 40% of Hodgkin lymphoma, and in up to 10% of DLBCL) seems to be similar when investigated in RA [4] and [51], SLE [10], [11], and [14], pSS [52], [53], and [54], celiac disease [55] and [56], Hashimoto's thyroiditis [57] as well as in lymphomas occurring within the general population [58] .

Nevertheless, a potential role for EBV in lymphoma development within the framework of autoimmunity cannot be excluded since case reports have described the occurrence of EBV-positive lymphoproliferative lesions during immune-suppressive treatment in patients with autoimmune disease, with spontaneous lymphoma regression occurring once immunosuppressive drugs have been discontinued [59] . Notably, several of these reports originate from Asian countries where EBV-associated lymphomas in general are more common than in Western populations [60] . Another example stems from reports on EBV-positive lymphomas in patients with inflammatory bowel disease treated with thiopurines [61] .

3. How can local or systemic inflammation lead to lymphoma?

Despite the emerging data linking autoimmune/inflammatory conditions with lymphoma development, we still do not understand the exact pathways and biological mechanisms by which these lymphomas occur. Sifting through B-cell lymphoma tumor characteristics in patients without autoimmune disease, it is evident that exposure to various types of antigens (e.g. autoantigens, viral and microbial antigens) and/or activation of the B-cell receptor (BcR) signaling pathway play essential roles in lymphomagenesis [62], [63], and [64]. In this context, it is also important to remember that the B cell itself undergoes several potentially dangerous genetic events during B-cell maturation, such as IGHVIGHDIGHJ recombination, somatic hypermutation (SHM) and class-switch recombination (CSR), all of which involve double-strand breaks and increase the risk of introducing genetic aberrations [65] and [66] (T-cells similarly undergo V(D)J recombination at the T-cell receptor loci but neither SHM nor CSR occur). Indeed, chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus as well as off-target somatic mutations introduced by the activation induced deaminase (AID) enzyme are common findings in many lymphoma entities.

Nevertheless, several studies have provided both indirect and direct evidence for antigen involvement in lymphomagenesis. The former mainly concern immunogenetic data, such as biased IGHV gene usage, ongoing SHM, ‘stereotyped’ or quasi-identical BcRs, while the latter relate to e.g. associations with infections by EBV, CMV, HCV, Helicobacter pylori, Chlamydia psittaci or the identification of BcR specificity toward various types of auto-antigens. Furthermore, these studies also pointed to a strong association between chronic active BcR signaling (not only through antigen activation but also due to mutations within the BcR signaling pathway [see below]) and lymphoma cell survival [63], [67], [68], and [69]. This has become even more apparent recently by the significant clinical effect of BcR inhibitors (i.e. ibrutinib) in several lymphoma entities [64], [70], and [71].

Hence, considering the strong connection between disease activity and lymphoma development in autoimmune/inflammatory conditions and the essential role of B cells (and T cells) in the pathogenesis of autoimmunity, it is highly likely that a similar scenario occurs in lymphomas developing within these diseases, whereby B cells (or T cells) are exposed to and get activated by a range of antigens, leading to proliferation and clonal expansion, which in turn increases the risk of accumulating genetic events and ultimately results in development of an overt lymphoma. Whilst this course of events is highly plausible, currently there is limited data to support (nor to refute) this hypothesis.

3.1. From local inflammation to lymphoma

There is indisputable evidence that local inflammatory processes and antigenic drive can promote lymphoma development at the site of inflammation/immune-activation. In this regard, the best examples are pSS, celiac disease and Hashimoto's thyroiditis.

In pSS, the highly increased relative risk (up to 1000-fold) of developing MALT lymphoma of the parotid gland [16] and [18], and the fact that the target site of inflammation, namely, the salivary glands, are easily accessible for sequential biopsies have prompted a number of studies investigating the multistep process which eventually leads to tumor expansion. Early events include persistent chronic antigenic stimulation, B-cell activity, clonal expansions of B cells and the acquisition of genetic aberrations ( Fig. 1 ) [72], [73], and [74]. Clonal expansions are commonly observed in both the blood and salivary gland tissue in pSS [75] , however this is not a reliable predictor of lymphoma development. More recently, the expansion of a unique, autoreactive and anergic CD21-/low B-cell population was observed in the peripheral blood of patients with pSS [76] and it was postulated that other immune reactions, such as those involving Toll-like receptors, may eventually activate this cell population, potentially leading to lymphoproliferation and culminating in lymphoma development.

gr1

Fig. 1 Local inflammation and lymphoma development.

A role for (auto)antigen-drive in pSS-associated lymphomas arose from numerous observations such as ongoing SHM within the tumor cells [77] , isotype switching during the lymphoma disease [78] , and restricted IGH and kappa (IGK) gene repertoires. In addition, antigen reactivity studies have shown that these lymphoma B cells may display RF activity [79] and [80], thereby indicating that lymphoma in pSS frequently develops from rheumatoid factor-expressing B cells. Although other tumor cell IG specificities have also been described, taken collectively these studies imply that auto(antigen)-reactivity plays a role in the pathogenesis of pSS-associated lymphomas [81] . Importantly, studies have also described progressive clonal expansion during the course of the pSS disease, whereby the same subclone from the initial salivary gland tissue eventually evolves into MALT or B cell lymphoma [74], [82], [83], [84], and [85].

Numerous factors essential for B-cell hyperactivity and lymphoproliferation in pSS have been identified within both the salivary gland microenvironment and in the blood of pSS patients (recently reviewed in [86] ); findings which indirectly support the association between pSS activity and lymphoma development. One such factor is B-lymphocyte stimulator (BlyS) (also known as B-cell activating factor, BAFF), a key player in B-cell maturation and survival, which has been implicated in the formation of tertiary lymphoid centers in pSS. High BlyS levels have been found in serum, saliva and in the salivary glands of pSS patients and, recently, increased serum BlyS was observed in pSS patients with lymphoma compared to those without a lymphoproliferative disorder [87] . Levels were also significantly correlated with high pSS disease activity measured by ESSDAI (European League Against Rheumatism SS disease activity index). Another factor, FMS-like tyrosine kinase 3 ligand (Flt3-L), a cytokine which stimulates the growth of progenitor cells in the bone marrow and blood, was also recently associated with high ESSDAI scores, some previously described markers for lymphoma development in pSS (purpura, low levels of C4, lymphocytopenia) and the development of parotid MALT lymphoma [88] . Flt3-L expression was also detected in the lymphoma cells from parotid gland biopsies taken at MALT lymphoma diagnosis.

In MALT lymphomas, three types of chromosomal translocations (i.e. t(11;18)(q21;q21)/API2-MALT1, t(14;18)(q32;q21)/IGH-MALT1 and t(1;14)(p22;q32)/IGH-BCL10) have been demonstrated, all of which lead to constitutive activation of the NF-?B pathway [67] (Ferreri et al. Sem Cancer Biology 2013). Interestingly, a role for the TNFAIP3 gene, encoding for the A20 protein in the NF-?B pathway, was recently implicated in the transformation of pSS to lymphoma [89] and [90].

In celiac disease, T-cell mediated inflammation of the small intestinal mucosa is triggered by gluten exposure. Failure to respond to a gluten-free diet has been associated with the presence in the mucosa of abnormal intraepithelial lymphocytes (IEL) characterized by an aberrant phenotype and clonal TcR rearrangements [91] . In recent years, refractory celiac disease with mucosal infiltration of abnormal IELs has been divided into two distinct subtypes (RCD I and RCD II). The second type is now considered an intraepithelial lymphoma characterized by clonal T-cell infiltration, carrying a high risk of progression into aggressive enteropathy-type T-cell lymphoma [92] and [93]. Importantly, it was recently demonstrated that the clone giving rise to enteropathy-associated T-cell lymphoma was present years before in an oligoclonal intestinal T-cell infiltrate [94] ( Fig. 1 ).

Patients with Hashimoto's thyroiditis have been estimated to exhibit a 60-fold increased risk of thyroid lymphoma, although the absolute number of patients developing this rare lymphoma entity is low. Most of the thyroid lymphomas are of the MALT type or DLBCL, and most cases (60–90%) arise against a background of thyroiditis. The working hypothesis for this association is that chronic antigenic stimulation leads to malignant transformation (reviewed in [95] ) and this reasoning is supported by several lines of evidence; (i) clonal IGHVIGHDIGHJ gene rearrangements expressed by thyroid lymphoma cells have been detected among oligoclonal rearrangements in the preceding thyroiditis phase in the same patients [96] ; and (ii) a fraction of thyroid lymphomas utilize the same IGHV genes expressed by anti-thyroid antibodies [97] .

3.2. DLBCL associated with non-autoimmune chronic inflammation – a separate lymphoma entity

A new lymphoma entity associated with local inflammation was added to the 2008 World Health Organization (WHO) lymphoma classification [58] . This entity “DLBCL associated with chronic inflammation” is defined as DLBCL occurring in the context of long-standing chronic inflammation and demonstrating an association with EBV, and is thought to be distinct from lymphomas that arise in parallel to chronic autoimmune diseases. Such cases typically involve body cavities or narrow spaces and the “prototypic form” is DLBCL developing in the pleural cavity of patients with long-standing (often more than 10 years) pyothorax. Other settings include chronic inflammation or suppuration in chronic osteomyelitis, metallic implant or chronic skin ulcer [98] and [99] and it has been postulated that a local immunosuppressive effect builds up within the enclosed compartment. Cytokines released by the chronic inflammatory cells, such as IL-10 which inhibits T-cell proliferation, may contribute to the proliferation of EBV-infected B cells which subsequently accumulate genetic alterations, undergo clonal selection and eventually evolve into lymphoma [99] and [100].

It is difficult to envisage that the DLBCL evolving in the salivary glands of patients with long-standing pSS and in the thyroid gland due to many years of Hashimoto's thyroiditis, and the occasional DLBCL localized to joints in severe RA, are completely distinct from “DLBCL associated with non-autoimmune chronic inflammation” or that they do not share some features and pathogenetic mechanisms. Although much work remains to be done in order to fill in the gaps in our knowledge, EBV analysis of such cases may be an appropriate starting point, given that, by definition, this disease is EBV-positive.

3.3. From systemic inflammation to lymphoma

The mechanisms involved in lymphomagenesis in situations where there appears to be a strong association between systemic inflammation and the development of lymphoma are also not well understood. As the basis for further understanding of these events, and to direct further studies in this field, we can focus on RA.

As mentioned above, a strong association between systemic RA disease activity and the development of a particular lymphoma entity, namely DLBCL, typically presenting with disseminated lymphoma in a high proportion of patients, has been identified [4] . More detailed characterization of these RA-related DLBCL has revealed that the vast majority are of the non-germinal center (GC)/activated B-cell (ABC) subtype [101] and [102]. This finding clearly indicates a role for activated peripheral B cells in the development of lymphomas in RA patients ( Fig. 2 ). The essential role played by B cells in RA inflammation is well established and forms the basis for the successful treatment of RA with rituximab, an anti-CD20 monoclonal antibody [103] . Additional support for the role of B cells in RA-DLBCL derives from a study investigating the proliferation-inducing ligand, APRIL, a cytokine essential for B-cell proliferation and development [104] . In this study, the expression of APRIL was investigated in DLBCL tissue obtained from both RA and SLE patients (also at increased risk of DLBCL of the non-GC/ABC subtype) and compared to DLBCL cases that have arisen in the absence of inflammatory disease. Results indicated that APRIL-positive cells were specific to DLBCL, being almost non-existent in other lymphoma subtypes such as follicular and small lymphocytic lymphomas; subtypes with no increased frequency in RA or SLE and not linked to RA disease activity. Furthermore, higher APRIL expression was detected in DLBCL tissue from a subset of RA patients with high cumulative RA disease activity compared to RA patients with low disease activity, and also in the SLE patients when compared with DLBCL patients without inflammatory disease.

gr2

Fig. 2 B-cell lymphomas developing in autoimmune disease and their potential cellular origin.

In non-autoimmune DLBCL, it is evident that the ABC-type is highly dependent on chronic active BcR signaling and recurrent activating mutations within several key components of the BcR pathway have been identified (e.g. CARD11, CD79a, CD79b) [105], [106], and [107] and these mutations often lead to constitutive activation of the NF-?B pathway. Interestingly, it is this dependence on NF-?B activity for survival and proliferation that has spurred studies to investigate therapeutics that could target this pathway. In keeping with this line of thinking, preliminary data exists that supports the role of BcR inhibitors in the treatment of the ABC-type of DLBCL [64] and [108]. Constitutive NF-?B activation can also result from mutations within the Toll-like receptor pathway (e.g. MYD88) and the NF-?B pathway itself (e.g. TNFAIP3) [109] and [110]. It would thus be logical to assume that the aforementioned pathways are also important in DLBCL developing in immune-mediated disease; however there is currently no data available to support this line of thinking.

In RA, where the clinical signs of inflammation and hence the lymphocytic activity and proliferation are typically localized in the joints, it could be speculated that the early events in lymphoma development occur in tertiary lymphoid structures located within the synovia. However, one observation strongly arguing against joints as a common starting point for the lymphoma process in RA is the extreme rarity of RA-related lymphomas in joints [111] . For example, in a population-based study of lymphomas in RA patients, none of the 343 lymphomas were localized to a joint [4] . Interestingly, recent support for an explicit role for lymph nodes in the immune events in RA has emerged, thus implying that early immune events in RA-DLBCL occur within a similar environment to that of general DLBCL. In this study, there was increased immune cell activation in lymph nodes in patients with early arthritis and even in autoantibody-positive individuals (at risk of RA, but without arthritis) with an increase in activated CD69+ CD8+ T cells and CD19+ B cells compared to healthy individuals [112] .

Taken together, it appears that RA-DLBCL develops from activated B cells that have become “over-stimulated” in the context of a chronic auto-immune/inflammatory disease. Future efforts must now include detailed molecular characterization of such lymphomas to understand if similar or different genetic events are accumulated compared to non-immune-mediated DLBCL.

4. Therapeutic implications

In RA, given the strong association between disease activity and lymphoma risk, the observation of an unchanged and rather static lymphoma incidence during the last decade, despite the presumably improved RA therapy may seem surprising [5] . However, this finding may instead favor the idea that improved inflammatory control is not sufficient for prevention of lymphomagenesis and that the particular steps critical to lymphoma development must also be targeted. In theory, it may also be that potent immune-modulating therapies reduce the disease-associated lymphoma risk at the expense of inducing lymphomas primarily through their immune-suppressive effect. To ascertain what is indeed occurring, it will be of utmost importance to monitor the distribution of lymphoma subtypes in patients with chronic inflammatory diseases who have been exposed to recent and more potent immune-modulatory therapies.

A number of new drugs or drug candidates are regarded as promising for the treatment of both autoimmune diseases and lymphoma. Several of them are targeting B cells through different approaches or are directed against certain pathways, e.g. tyrosine kinase inhibitors [103], [113], and [114].

Some relevant experience already exists from two drugs that are used in both inflammatory diseases and in lymphoma regimens i.e. corticosteroids and the anti-CD20 antibody, rituximab, which targets B cells. The risk of developing lymphoma following steroid treatment has been evaluated in a number of inflammatory conditions and the results have varied. However, some of these studies are hampered by the underlying condition treated with steroids. In one study investigating lymphoma risk in RA patients in comparison with non-lymphoma RA controls, steroid treatment, both oral (for more than two years) and intra-articular, was associated with a decreased lymphoma risk [4] and [115]. In this study, which primarily concerned historical patients with a high accumulated burden of disease and minimal treatment with disease-modifying drugs, the risk reduction associated with steroids was particularly pronounced for DLBCL. For intra-articular steroids, the strong inverse association with lymphoma was restricted to cases consistently receiving this treatment for the management of flares. A lymphoma-protective role of corticosteroids is theoretically possible. Explanations could include both the potent anti-inflammatory effect but also other mechanisms as e.g. apoptosis of lymphoid cells, of importance when steroids are part of lymphoma regimens, albeit at doses far higher than those typically used to curb inflammation.

Rituximab, part of the treatment of most B-cell lymphomas, is licensed for the use in RA, but is commonly used off-label also in other inflammatory diseases, e.g. SLE and pSS [116] and [117]. The individual response in rheumatic diseases is highly variable even in patients with seemingly the same clinical picture, suggesting diversity in underlying immune activity. Larger number of rituximab-treated patients and longer follow-up is needed to evaluate if this treatment in inflammatory diseases may decrease a future (B-cell) lymphoma risk or even increase the risk of other lymphomas. Occasional T-cell lymphomas have been reported after rituximab treatment [118] . Although there is so far nothing to suggest that rituximab as lymphoma therapy generally works differently in patients with an underlying inflammatory disease than in general lymphoma patients, there are some observations of pSS-associated MALT lymphoma in the salivary glands not responding to rituximab [119] .

5. Concluding remarks

Whilst there is currently insufficient evidence to support a role for immune-suppressive drugs and environmental and/or genetic risk factors in the development of lymphomas in immune-mediated disease, a link between the level of inflammation and disease severity and increased lymphoma risk has been established, particularly in certain conditions such as RA, pSS and celiac disease. In these conditions, there are reasons to believe that chronic activation and/or stimulation of B cells or T cells are major predisposing factors for lymphoma development, which is also in line with current understanding of the pathogenesis in lymphomas not associated with autoimmune/inflammatory diseases. Although we still do not appreciate the exact molecular and cellular events important in this process and the fact that several parallel or independent pathways likely are involved, chronic immune stimulation is probably caused by one or several of the following mechanisms; (i) direct antigen stimulation by microbial or auto-antigens, (ii) indirect immune stimulation due to longstanding chronic inflammation, and (iii) molecular events targeting key pathways leading to constitutive B-cell/T-cell activation. Considering that different autoimmune/inflammatory conditions display different spectra of lymphomas, the type of immune dysfunction involved in lymphoma pathogenesis is probably disease-specific. For instance, in RA and SLE, aggressive systemic inflammation will lead to chronic activation of peripheral B cells which increases the likelihood of clonal B-cell populations and ultimately the ABC-type of DLBCL; in Sjögren's syndrome patients develop local lymphoproliferative lesions in salivary glands with an increased risk of MALT lymphomas; finally, T-cell expansions at the site of inflammation in celiac disease may predispose for enteropathy-associated T-cell lymphoma.

It will now be important to systematically collect and perform in-depth molecular studies in material obtained both retrospectively and prospectively from autoimmune patients developing lymphomas in order to characterize key pathogenetic events. In light of the new era of tyrosine kinase inhibitors that target specific pathways, e.g. BcR inhibitors in several lymphoma entities, this is also a new promising avenue that perhaps should be considered in autoimmune patients with high disease activity.

Conflict of interest

The authors have no conflict of interest to declare.

Acknowledgements

Supported by Swedish Cancer Society and the Swedish Research Council.

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Footnotes

a Unit of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden

b Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden

c Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

d Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden

? Corresponding author at: Department of Rheumatology, Entrance 30, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel.: +46 18 6110000; fax: +46 18 558432.