Symposium

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doi: 10.1111/j.1365-2796.2008.02029.x

Autoimmune and inammatory disorders and risk of malignant lymphomas an update

K. E. Smedby1, J. Askling2, X. Mariette3 & E. Baecklund4
From the 1Department of Medicine, Clinical Epidemiology Unit; and 2Rheumatology Unit, Karolinska University Hospital; Stockholm, Sweden; 3Department of Rheumatology, Hopital Bicetre, Assistance Publique-Hopitaux de Paris, Le Kremlin Bicetre, France; and 4Department of Rheumatology, Akademiska University Hospital, Uppsala, Sweden

Abstract. Smedby KE, Askling J, Mariette X, Baecklund E (Karolinska University Hospital, Stockholm, Sweden; Hopital Bicetre, Assistance Publique-Hopitaux de Paris, Universite Paris-Sud 11, Le Kremlin-Bicetre, France; and Akademiska University Hospital, Uppsala, Sweden). Autoimmune and inammatory disorders and risk of malignant lymphomas an update (Review). J Intern Med 2008; 264: 514527. As specic autoimmune disorders now constitute established risk factors for malignant lymphomas, we describe this association. We review reported risk levels, risk determinants, lymphoma subtypes and biological mechanisms in autoimmunity/inammation, emphasizing on recent ndings.

Whilst numerous reports describe average lymphoma risks in large patient groups, theres a recent shift of focus to risk determinants and the role of inammatory activity. Studies highlight associations with diffuse large B-cell lymphoma, apart from lymphoma development in target organs of inammation. Future studies of high-risk patient subsets using detailed assessments of autoimmunity inammation and lymphoma may give important clues to lymphomagenesis. Keywords: autoimmunity, chronic inammation, immune stimulation, malignant lymphoma.

Introduction
Several autoimmune and chronic inammatory conditions have been consistently linked with an increased risk of malignant lymphomas, although the reported risk levels have typically varied. The conditions include rheumatoid arthritis (RA) [18], Sjogrens syndrome [9, 10], systemic lupus erythematosus (SLE) [1114], coeliac disease [1518], dermatitis herpetiformis [15, 19, 20] and chronic thyroiditis [13, 21, 22]. Other disorders inconsistently associated with an increased occurrence of lymphomas mainly include inammatory bowel disorders, psoriasis and systemic sclerosis [13, 2328]. In recent years, there has been a shift of focus from studies describing average risks of malignant lymphomas in large groups of patients with autoimmune

and inammatory conditions, to studies investigating how lymphoma risks may vary amongst patients with different phenotypic or treatment-related characteristics of the same disorder. Studies of patients with RA or Sjogrens syndrome now strongly indi cate that the risk of lymphoma is highly correlated with disease severity [4, 29]. However, lower but still increased risks in association with use of some traditional disease-modifying drugs, e.g. azathioprine, may also be present [29, 30]. Intense research efforts regarding the potential lymphomagenicity of TNF-blockers have not substantiated any short-term increases in risk for this group of drugs taking disease activity into account [31, 32]. Further investigations of determinants of lymphoma development in autoimmunity and inammation may help us identify individuals at the greatest risk of lymphoma already at diagnosis of the inammatory con-

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dition and could provide guidance to optimal interventions. Malignant lymphomas constitute a vastly heterogeneous group of malignancies in terms not only of morphological and clinical characteristics [33] but also of aetiological factors [34]. With regard to lymphoma development in primarily affected organs, such as mucosa-associated lymphoid tissue (MALT) lymphoma in the parotid gland in Sjogrens syndrome or enteropathy-type T-cell lymphoma in coeliac disease, a critical role for local chronic antigen stimulation is well documented [35, 36]. However, less is known about lymphomagenic mechanisms leading to more common lymphoma subtypes in distant sites. Although clinically overt autoimmune and inammatory disorders appear to explain only a small proportion of all malignant lymphomas [6], knowledge of mechanisms of lymphomagenesis in this setting may give clues to lymphoma development in a larger group of patients. In the present review, we summarize the current knowledge about risk levels, lymphoma subtypes and clinical and biological risk determinants in autoimmunity inammation and suggest directions for future research in this rapidly evolving eld.

logical characteristics: largest study samples for the condition in question, population-based design, recent publication or novel nding. Validity was further evaluated on the basis of a well-dened study base, especially for case series.

Risk levels and lymphoma subtypes Autoimmune inammatory disorders consistently associated with risk of lymphoma RA, Sjogrens syndrome, SLE, coeliac disease, dermatitis herpetiformis, Hashimoto thyroiditis.
In RA, Sjogrens syndrome, SLE, coeliac disease, der matitis herpetiformis and Hashimoto thyroiditis, an increase in risk of malignant lymphomas overall or of non-Hodgkin lymphoma (NHL) has been observed in a large number of studies in different populations and with different design. Interestingly, the magnitude of the associations varies several-fold amongst these disorders. Reported average relative risks from the largest studies range from about twofold in RA [18], to 9- to 18-fold increase in Sjogrens syndrome [9, 10]. In between these two, the risk of lymphoma is increased from 3- to 6-fold in SLE [1114], coeliac disease [1518] and Hashimoto thyroiditis [13, 21, 22], and 2- to 10-fold in dermatitis herpetiformis [15, 19, 20]. Risk estimates are often derived from cohorts of patients hospitalized with the disorder in question [2, 3, 5, 8, 9, 11, 13, 15, 19], possibly characterized by more severe disease. However, reassuringly, risks based on well-dened population-based cohorts of incident patients in RA [4, 5], Sjogrens syndrome [10] and SLE [12] do not deviate from the overall pattern described above. Investigations of specic associations with Hodgkin lymphoma (HL) in autoimmunity inammation are fewer and reported risk estimates are typically more pronounced, but less precise than for NHL. A 3- to 5-fold increased risk of HL has been observed in RA [2, 3, 37] and SLE [38]. However, these registrybased cohort studies span over early calendar periods when some misclassication of NHL cases as HL may have inated observed risk estimates [2, 3, 37, 38].

Methods
We previously identied epidemiological studies of cohort or case-control design or case series in the area of autoimmunity and chronic inammation and risk of malignant lymphomas published up until 2005 through Medline searches [6]. We have now extended and updated our previous search to also encompass the years 2006 to 2008. Medline searches were performed using combinations of the following key words: (the disease in question), lymphoma, cancer or malignancy, and risk, cohort or case-control. We have chosen to summarize the results of the most important studies with a focus on recent advances. Because of the large number of inammatory conditions and studies identied through our search, papers were prioritized for citation based on the following methodo-

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With regard to risk of specic NHL subtypes, Sjo grens syndrome, Hashimoto thyroiditis and coeliac disease are strongly linked with lymphoma development in the respective target organs. Hence, Sjo grens syndrome is strongly associated with MALT lymphoma in the parotid gland [39, 40], Hashimoto thyroiditis with MALT lymphomas in the thyroid gland (occasionally transforming to diffuse large B-cell lymphoma) [21, 41] and coeliac disease with enteropathy-type T-cell lymphoma in the small intestine [33, 35]. In patients with Hashimoto thyroiditis, theres a recent indication of an association with MALT lymphomas localized also outside of the thyroid gland [42]. Importantly, recent studies also highlight associations between several autoimmune disorders and the common NHL subtype diffuse large B-cell lymphoma. Theander et al. [10] reported seven out of 12 Sjogren-associated NHLs (58%) to be of the diffuse large B-cell type, whereas a proportion of 30% could have been expected [33]. In a large pooled analysis of casecontrol study data within the InterLymph consortium [14], Sjogren was associated with a ninefold risk increase of diffuse large B-cell lymphoma and a 30-fold increase of MALT lymphomas, but the former association was more important in absolute terms. Amongst close to 400 patients with RA and lymphoma in the study by Baecklund et al. [29], about 50% of the lymphomas were of the diffuse large B-cell type and they were further characterized as predominantly of the nongerminal centre type [43, 44]. Additionally, in SLE, an overrepresentation of diffuse large B-cell lymphomas has also been reported [6, 14, 45, 46]. In a Swedish re-evaluation study of 10 SLE-associated diffuse large B-cell lymphomas, the majority (80%) were of the aggressive nongerminal centre type [46]. In coeliac disease, there is mounting evidence of an increase of B-cell lymphomas apart from the strong link with enteropathy-type T-cell lymphoma [16, 47].

to risk of NHL overall are mixed [13, 14, 4851], whereas there are consistent ndings of an increased risk of T-cell NHL across studies analysing risk of NHL subtypes [7, 13, 14, 25]. An increase in risk of the cutaneous T-cell NHL form mycosis fungoides has been noted [25], which could be because of early lymphoma being mistaken for psoriasis [52]. However, two recent large case-control studies, the InterLymph pooled analysis [14] and a registry-based Scandinavian study [13], observed instead an increased risk of the specic T-cell NHL type anaplastic large-cell lymphoma. In patients with Crohns disease, study results of lymphoma risk have varied. The two largest investigations including a Scandinavian cohort study of 20 000 patients [23] and a meta-analysis of a total of 60 000 patients [24], both reported a moderate increase of NHL of 3040%. However, in the Scandinavian study, no association was apparent after 5 years of follow-up, and in the meta-analysis, latency was not evaluated. Hence, the risk level may have been overestimated because of some short-term misclassication of incipient lymphomas as Crohns disease, but a true positive association cannot be excluded. In systemic sclerosis, patients were at an average twofold increase in risk of NHL in a large Scandinavian registry-based case-control study [13]. However, the risk was not signicantly increased beyond 4 years of follow-up. Otherwise, studies of cancer risk in systemic sclerosis have generally lacked the power to determine potential associations with malignant lymphomas [27, 53, 54]. Sarcoidosis is a chronic granulomatous disorder displaying some autoimmune features [55] where case reports have highlighted a possible association with HL [56]. In two large Scandinavian registry-based case-control studies, one of the risks of HL [37] and the other of NHL [13] increased risks were noted, but became less pronounced after 4 years of follow-up. In a registrybased cohort study partly based on the same data [28], increased risks of HL as well as NHL were likewise conned to the rst years of follow-up. Hence, these reports probably largely reect the presence of a

Autoimmune inammatory disorders possibly associated with risk of lymphoma Psoriasis, Crohns disease, Systemic sclerosis, Sarcoidosis. In psoriasis, study results with regard
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paramalignant sarcoidosislymphoma syndrome [57], although a small persistent increase in risk of lymphoma cannot be excluded.

Autoimmune inammatory disorders not convincingly associated with lymphoma Ulcerative colitis, multiple sclerosis, ankylosing spondylitis, systemic vasculitides, type-1 diabetes. Patients with ulcerative colitis have been extensively studied with regard to risk of cancer including risk of malignant lymphomas and theres no convincing evidence of an average increased risk of the latter [23, 58]. Elevated risk estimates of lymphoma have been reported from subpopulations of ulcerative colitis patients treated with thiopurines or methotrexate, but the studies were based on small numbers of lymphoma cases thus limiting inference [59, 60]. Larger studies will be needed to determine if subpopulations of ulcerative colitis patients at high risk of lymphoma exist and if so, if they are best characterized in terms of disease severity or specic treatments [61]. In multiple sclerosis, the largest study so far, a Danish cohort study based on hospital discharge diagnoses (n = 11 800) showed no association with risk of NHL or HL [62], which is consistent with a few smaller studies [6365]. In ankylosing spondylitis [66], systemic vasculitides [67, 68] or type-1 or autoimmune diabetes [14, 69, 70], theres no convincing evidence of an increase in risk of malignant lymphomas.

namely inammatory myositis and autoimmune haemolytic anaemia. Not only dermatomyositis but also polymyositis have been associated with a 2- to 4-fold increased risk of NHL [72, 73]. In the largest of these studies, a pooled analysis of 1500 myositis patients [73], there was, however, no statistically signicant increase in risk of NHL beyond the rst year of follow-up. Similarly, there are ample observations of an increased occurrence of cancer overall in myositis, but all cancers typically cluster around the time of the myositis diagnosis [73, 74]. Autoimmune haemolytic anaemia is a rare but wellknown complication of NHL and of specied treatment regimens in chronic lymphocytic leukaemia [75]. However, several recent reports also describe a possible association with history of haemolytic anaemia and risk of developing NHL or chronic lymphocytic leukaemia (CLL). Two Scandinavian case-control studies [13, 76] observed a 5- to 12-fold increased risk of NHL in association with inpatient records of autoimmune haemolytic anaemia, although the magnitude of the association decreased with longer latency to the malignancy. However, in the recent pooled InterLymph analysis, a history of selfreported haemolytic anaemia was associated with a 2- to 3-fold increased risk of NHL that persisted with more than 10 years of disease [14]. The latter study also indicated a possible association between haemolytic anaemia and diffuse large B-cell lymphoma in particular [14].

Autoimmune inammatory disorders as paramalignant phenomena in lymphoma Inammatory myositis, autoimmune haemolytic anaemia. A problematic issue in the study of autoimmune and inammatory disorders as risk factors for lymphoma development is the tendency of incipient hematolymphoproliferative malignancies to occasionally manifest with paraneoplastic autoimmune phenomena [71], which could lead to misclassication of yet undiagnosed lymphomas as autoimmune disorders. Such misclassication could in theory inuence shortterm risk estimates for practically all disorders included in the present review. However, the phenomenon is especially important in at least two disorders,

Risk determinants Clinical risk determinants Disease severity disease-related factors. Disease
severity or other factors related to the underlying disease per se have repeatedly been hypothesized as potential risk factors for lymphoma development in patients with chronic inammatory diseases. Despite such suggestions, few studies have actually addressed or been able to address this issue. Obstacles have included small numbers of lymphoma cases, lack of consistent measures of disease activity and use of less suitable control populations without the inammatory

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disease in question. The last years, however, increasing support has emerged for disease-related factors as important determinants behind lymphoma development in several diseases. In RA, early support for a link between RA disease severity and lymphoma came from a study of patients with Feltys syndrome [77], a complication of severe RA, where a 13-fold increased risk for NHL was seen in patients with Feltys syndrome compared to the general population, i.e. a much higher than approximately twofold increased risk reported amongst RA patients in general. No association was noted with specic treatments in Feltys syndrome [77]. In the study by Baecklund et al. [29], a number of potential risk factors for lymphoma were assessed in a population-based Swedish case-control study of 378 RA patients with lymphoma and 378 lymphoma-free RA controls. A strong association was observed between risk of lymphoma and cumulative disease activity based on number of swollen and tender joints, erythrocyte sedimentation rates and doctors global assessments of disease activity as recorded at all visits from onset of RA until lymphoma diagnosis. Patients with the highest cumulative disease activity had a 60-fold increased risk of lymphoma compared to those with the lowest cumulative disease activity (Fig. 1) and the

association was even more pronounced for diffuse large B-cell lymphoma (mainly of the nongerminal centre type). These ndings indicate a role for activated peripheral B cells in many RA-related lymphomas. In Sjogrens syndrome, a number of studies have shown that manifestations of severe disease such as palpable purpura, parotid enlargement and hypocomplementemia are predictive of lymphoma development [10, 40, 7881]. Associations with lymphoma risk in Sjogren patients were also reported for concomitant mixed monoclonal cryoglobulinemia [10, 79] and CD4+ T-lymphocytopenia [10]. Importantly, in the study by Theander et al. [10], the increased lymphoma risk was conned to patients fullling the diagnostic American-European Consensus Criteria for Sjogrens syndrome, whereas other sicca patients had no increase in risk. However, it is not known whether specic risk factors predict the development of specic lymphoma subtypes in Sjogrens syndrome, e.g. who is at risk for aggressive DLBCL or indolent MALT lymphoma respectively. In SLE, only a few studies have investigated putative risk determinants for lymphoma. Although existing studies are hampered by small numbers of lymphoma

* Odds ratio (OR) and 95% confidence interval (CI)

Fig. 1 Relative risk* of lymphoma in relation to cumulative disease activity assessed in 378 case patients with rheumatoid arthritis (RA) and lymphoma and matched RA controls [29].

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cases, results suggest a role for disease severity rather than treatment also in this condition. In one case-control study, nested within a national Swedish SLE cohort, longstanding haematological SLE aberrations were present in most of the 16 NHL cases (88%), and lymphoma risk was also linked to sicca symptoms and pulmonary involvement [46]. However, treatment with cyclophosphamide or azatioprine was unrelated to risk [46]. A high proportion (62%) of haematological SLE manifestations was also described in a large US cohort of SLE patients where 11 NHL-patients were identied [82], whereas renal SLE involvement and use of immunosuppressive treatment were rare. A possible association between the SLICC damage index that reects cumulative disease activity and clinical severity in SLE, and the risk for haematological malignancy in SLE was recently reported in a multi-site international case-cohort study [83]; however, there was also an indication of an increase in risk with persistent use of immunosuppressive medications. Further studies are in progress to investigate SLE determinants in more detail [83]. In coeliac disease, the hypothesis that gluten-free diet may protect against lymphoma is highly interesting, but most of the supportive evidence available at present stems from indirect observations [15] or from studies based on small numbers of lymphoma cases [18, 84, 85]. In a Finnish study, ve patients with coeliac disease and lymphoma all reported poor compliance to gluten-free diet [85]. Similarly, in a recent study including nine coeliac patients with enteropathy-type T-cell lymphoma, seven reported noncompliance to strict gluten-free diet [18]. Very few studies have been devoted to possible determinants of T-cell NHL risk in psoriasis. A large US study noted a more pronounced increase in risk of lymphoma in patients with severe psoriasis based on insurance les compared with patients with milder psoriasis forms [26]. In a cohort study from the UK, long-term use of methotrexate gave a fourfold increase in NHL overall [51]. Hence, more studies are needed to disentangle potential lymphoma predictors in psoriasis.

patients with inammatory diseases is complex. The increased lymphoma incidence associated with the underlying disease and differences in subgroups of patients depending on, e.g. activity and severity of the disease must be taken into account. As patients selected for immunomodulating therapy are likely to have active disease, studies comparing individuals requiring treatment with untreated individuals may falsely exaggerate the risk associated with treatment. Within the group of nonbiologic disease modifying anti-rheumatic drugs (DMARDs), two drugs, namely methotrexate (MTX) and azathioprine, have repeatedly been suggested to increase lymphoma risk [29, 33]. Although there are numerous case-reports of EBV-positive lymphoproliferative lesions arising in patients treated with MTX [33, 86, 87], a number of large, population-based studies have not been able to substantiate an increase in risk of lymphoma associated with MTX per se [29, 88, 89]. Corticosteroids have been used as an effective treatment in inammatory diseases since its introduction in the 1950s. Its role for lymphoma development has been explored in several studies with mixed results. Hence, no association as well as increased or decreased risks of lymphoma have been reported [7, 29, 90, 91]. Compelling evidence that steroids do not increase lymphoma risk comes from a study of patients with giant cell arthritis and polymyalgia rheumatica, disorders that require therapy with steroids for years [92]. In this large registry-based study, both conditions were associated with a reduced rather than an increased risk of NHL [92]. Similarly, results from studies of use of nonsteroidal antiinammatory drugs (NSAIDs) and risk of lymphoma are inconsistent [7, 29, 93]. In addition, a recent meta-analysis of data from nine case-control studies and one cohort study found little evidence that corticosteroids or NSAIDs are independent risk factors for NHL [94]. Instead, reports linking these drugs to NHL may rather reect an increased baseline risk of lymphoma in exposed patient populations (patients with, e.g. RA). Since the approval of the rst biologics, i.e. drugs designed to block specic steps in propagation of inammation, there has been concern about their

Treatment-related determinants.

The assessment of lymphoma risk in association with treatments in

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potential effect on lymphoma development. The experience of the rst biologics, the tumour necrosis factor (TNF) antagonists now extends up to 10 years with a range of approved indications [RA, psoriasis, psoriatic arthritis, ankylosing spondylitis (adalimumab, etanercept and iniximab), Crohns disease (adalimumab and iniximab), ulcerative colitis (infliximab) and juvenile chronic arthritis (etanercept)]. Safety-data are currently available both from randomized clinical trials and from observational studies. In two recent meta-analyses of 9 [95] vs. 18 [96] separate trials of TNF-antagonists in RA, conclusions differed somewhat. In the rst study encompassing 3493 patients treated only with adalimumab and infliximab, and 1512 controls [95], four lymphomas were observed in the treatment group and none amongst the controls suggesting an increased lymphoma risk with these drugs. Moreover, in extended phases of the included studies, an additional six lymphomas occurred in the treated groups and none in the controls. In the other meta-analysis based on over 8800 RA patients [96], no increased risk was observed for lymphoma for any of the three currently licensed TNF-antagonists, although condence intervals were wide. Most observational cohort studies have not detected any signicant increase in lymphoma risk with TNF-antagonists compared with classical DMARDs to date [5, 32, 97]. In a recent study from the Swedish Biologics Register (ARTIS), an increased lymphoma risk was observed in RA patients starting anti-TNF therapy 19982001, but not amongst those starting later [31]. An explanation for this and other early ndings [98] may be a channelling bias, that is, that the rst patients selected for treatment with anti-TNF had a more severe disease and a higher lymphoma risk than RA patients selected for treatment in later periods. However, we have to stay cautious as the number of lymphoma cases in the different European registries of biologics use is small. Also, it should be noted that safety-data for long-term use (>10 years) is still not available. There are, so far, no reports of increased lymphoma risks with TNF-antagonist treatment for other indications than RA, with one exception. Amongst young adults with inammatory bowel disease treated with 520

iniximab or adalimumab in combination with other immunosuppressive drugs, several cases of the rare hepatosplenic T cell lymphoma have been reported [99]. The same type of lymphoma was recently described also in a patient treated with adalimumab for Feltys syndrome. In conclusion, it is still premature to rule out any increase in lymphoma occurrence with anti-TNF therapy, or alternatively, to conclude that prolonged therapy may reduce the elevated lymphoma risk by suppressing inammation. Other newer drugs belonging to the biologics group and currently licensed for use in RA include rituximab, a monoclonal anti-CD20 antibody, abatacept, a selective T cell costimulation inhibitor and anakinra, an interleukin 1 receptor antagonist. For these drugs, safety data regarding lymphoma occurrence is still scarce [100, 101]. However, no increase in lymphoma risk has so far been observed with rituximab [100]. Instead, a possible benet on both the inammatory disease and the lymphoma have been highlighted in case-reports of patients with RA, SLE or Sjogrens syndrome and B-cell lymphoma treated with lymphoma regimens including rituximab [100].

Other determinants.

Alternative explanations for the increased lymphoma risk in patients with autoimmune inammatory diseases include genetic factors common to both disorders, and viral infections, particularly Epstein-Barr virus (EBV). However, none of these factors seem to be able to explain more than a fraction of the excess risks. Three studies using Scandinavian registers examined risk of lymphoma in relatives of patients with RA [102] and relatives of patients with a large number of different autoimmune disorders respectively [13, 37]. In the rst study, there was no increase in risk of lymphoma amongst rstdegree relatives of RA patients [102]. In the second, family histories of sarcoidosis and ulcerative colitis were associated with a small increase in risk of HL [37], and in the third, a family history of systemic autoimmune disease was associated with a small and nonsignicantly increased risk of NHL [13]. Thus, altogether these studies suggest that shared susceptibility is of limited importance. EBV is involved in lymphomagenesis in conditions characterized by

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severe immune dysfunction, e.g. up to 90% of lymphomas in organ transplanted patients are EBV-positive [103]. In autoimmune inammatory diseases, the proportion of EBV-positive lymphomas appears to be much lower in population-based materials. In the study by Baecklund et al. [29], 12% of the RA-associated lymphomas were EBV-positive. Similarly, in a study of NHL in patients with SLE, two out of 15 (13%) examined lymphomas were EBV-positive [46]. However, theres still evidence that EBV is indeed involved in the occasional development of lymphoproliferative disease during immunosuppressive treatment for underlying autoimmune disease, typically with spontaneous remission of the lymphomatous lesion after treatment discontinuation [86, 87].

increase in risk of diffuse large B-cell lymphoma in Sjogrens syndrome [10] could imply a role for a sys temic inammatory component in Sjogren as well. However, we should keep in mind that some diffuse large B-cell lymphomas may represent transformations of a previous low-grade lymphoma of the MALT type. For distinguishing between these two mechanisms, it will be important to set up prospective cohorts of patients with incident RA, SLE or Sjogrens syn drome, and assess the ability of systemic inammatory markers as well as markers of autoreactive B cells to predict occurrence of lymphoma.

Antigen selection.

Biological risk determinants Notions of inammatory activity. In autoimmune

disorders, the broad term inammatory activity encompasses at least two different notions; persistent inammation and persistent activation of autoimmune B cells. In RA, there are frequently signs of both activation of autoimmune B cells (presence of rheumatoid factor, anti-cyclic citrullinated peptide, anti-CCP, antibodies and free light chains) and of systemic inammation (swollen joints, increase in erythrocyte sedimentation rate and in C-reactive protein). In Sjo grens syndrome, however, activation of autoimmune B cells is evident, but in most cases, clinical signs of systemic inammation are lacking [104]. It is possible that these two driving mechanisms lead to different kinds of lymphoma. Long-standing systemic inammatory activity could lead to the development of nonlocalized lymphoma, as in RA and the observed increased occurrence of diffuse large B-cell lymphoma [29], the most frequent lymphoma in the general population. In contrast, long-term stimulation of auto-reactive B cells could be more relevant for lymphomagenesis in organ-specic autoimmune disorders. For example, in Sjogrens syndrome, marginal zone autoimmune B cells are activated within salivary glands and other mucosal sites specically affected by the autoimmune process leading to an increased occurrence of MALT lymphoma and other marginal-zone B-cell lymphomas [39, 40]. The recently noted

A recent promising avenue of research is that of antigen receptors of membrane immunoglobulins of lymphomatous B cells in the context of autoimmunity. In a large series of salivary gland lymphomas in Sjogrens syndrome, homology of the CDR3 region of membrane immunoglobulins was noted with CDR3 used by rheumatoid factor in more than 40% of cases [105]. This suggests that IgG could be responsible for the B-cell stimulation, possibly through immune complexes, and highlights analogies with lymphomas complicating hepatitis C virus infection and cryoglobulinemia [106] (Fig. 2).

The role of BAFF (BLyS) and other chemokines.

Increased expression of B-cell activating factor (BAFF), a cytokine also called B-lymphocyte stimulator (BLyS) [107], may explain pathogenic B-cell activation in several systemic autoimmune diseases and in lymphomas. BAFF plays a crucial role in B-cell maturation, plasma cell survival, antibody response

Hepatitis C

HCV pc RF B mc RF B B B B

Lymphoma
B B B

Sjgren

Virus ? Auto-Ag ?

Chromosomic abnormalities

Fig. 2 Outline of analogies in the development of hepatitis C virus (HCV)-associated lymphomas and lymphomas arising in Sjogrens syndrome [104]. B k, B lymphocyte; pc, polyclonal; mc, monoclonal; RF, rheumatoid factor.

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promotion and immunoglobulin-class switch recombination [108]. In humans, patients with SLE and primary Sjogrens syndrome have elevated serum levels of BAFF [109, 110] that may be correlated with the autoantibody levels [110]. Elevated BAFF levels are also found in the target organs of autoimmunity and can be secreted by resident cells (salivary epithelial cells in SS [111] and synoviocytes in RA [112]. In addition, BAFF levels are increased in patients with lymphoma irrespective of autoimmunity [113]. BAFF is secreted by the lymphomatous B cells, which leads to autocrine activation of B cells [113]. Mechanism related to BAFF levels and or function could thus represent a common link between autoimmunity and lymphoma. In hepatitis C virus-associated cryoglobulinemia, BAFF levels were reported in one study to be higher in patients with vasculitis or associated lymphoma than in patients with asymptomatic cryoglobulinemia [114]. It is also possible that the presence of some chemokines within the target organs of autoimmunity could attract B cells and create a milieu favourable to lymphomagenesis. In one study of patients with Sjogrens syndrome, expression of the chemokines CXCL13 and CCL21 in the salivary glands were associated with the formation of ectopic salivary lymphoid follicles, and the expression of CXCL12 was directly linked with occurrence of lymphomas [115].

tion whether the heterogeneous pattern of lymphoma risk across different autoimmune inammatory conditions reects a dose-dependency of an otherwise general association between inammation and lymphoma risk. With this view, the observed lack of an overall increase in risk of lymphoma in some conditions (e.g. ulcerative colitis, giant cell arteritis, ankylosing spondylitis) may be because of a too low inammatory burden or a too short duration of inammation. Alternatively, different phenotypes of inammation may entail different lymphoma risks, such that e.g. chronic relapsing small-joint inammation with moderately elevated ESR could entail a higher risk than a similar amount of large-joint inammation with highly elevated ESR. We may also ask whether the standard measure of association in observational studies, i.e. the relative risk (such as the relative risk of around 2 for lymphoma in RA), is an optimal measure, as an average relative estimate might conceal subsets of individuals with more clinically relevant risks. A correct understanding of this issue is not only important from an etiological point of view but also from a drug safety point of view; failure to understand the expected background risk of lymphoma in a treated population might lead to incorrect safety assessments. For instance, the typical relative risk of around 1.21.5 for lymphoma in Crohns disease could at least in theory harbour a several-fold increased risk for 10% of patients with the most severe inammation. A doubled lymphoma risk (compared with the background population) in a high-risk subset of patients after treatment with a new drug, might easily be mistaken for a safety concern when it would actually signal a lymphoma-protective effect had a proper comparator been used. Recent advances from large-scale studies of genetic susceptibility in combination with phenotype information [116] suggest profound differences in the aetiology between subsets of patients with seemingly the same condition clinically adding to the uncertainty of who is at risk and at what level. Whereas it is also becoming clear that these aetiological differences may be reected in differences in the occurrence of comorbidities, it is yet unclear whether this also reects variations in lymphoma risk. Indeed, we

Conclusions and directions for future research

Overall, autoimmunity inammation describes an association with malignant lymphomas. Currently, we can safely conclude that this can be described as an association between one aetiologically and clinically heterogeneous set of conditions with another. This conclusion, in turn, outlines some important directions for future research. From the inammatory perspective, autoimmune inammatory conditions display marked variations with respect to inammatory phenotype, intensity and accumulated amount of inammation and with respect to aetiology. Findings such as the strong association between cumulative inammatory activity in RA and risk of lymphoma raise the ques522

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have reached a point where we no longer need largescale cohorts to indicate the average relative risk of lymphoma versus the general population, but instead studies combining genotypic and phenotypic information about the autoimmune disease and its treatment, with detailed data on lymphoma occurrence and with the ultimate aim of identifying heterogeneities in risk rather than the average. Clearly, this raises demands in terms of study-size and points to the need for collaborative efforts, nationally and or internationally. Interestingly, but based on only a few studies, there appears to be neither little familial clustering of inammation autoimmunity and lymphomas suggesting only a minor role for shared aetiology nor is there any strong evidence that standard anti-inammatory therapy would markedly increase lymphoma risk, with the possible exception of azathioprine. The long-term safety of newer therapies including biologics is yet to be determined. From the lymphoma perspective, diffuse large B-cell lymphomas seem to display the most pronounced and general association with autoimmunity inammation, although certain specic T-cell lymphomas have been linked to distinct autoimmune conditions (e.g. enteropathy-type T-cell lymphoma to coeliac disease). From a mechanistic perspective, in vitro and in vivo studies have generated a series of interesting hints of potential biological steps linking inammation autoimmunity to lymphoma development. Again, this raises the question of commonalities versus specicity and calls for comparative studies assessing whether the mechanisms at play in a specic autoimmune disorder may be relevant for the development of only one or several specic lymphoma subtypes. Finally, we need to ask ourselves whether the association between autoimmunity inammation and lymphoma might tell us something about lymphomas outside the setting of autoimmune inammation. Is diffuse B-cell lymphoma a disease of sustained immune activation, regardless of autoimmunity? Does a certain amount of any type of inammation sufce? In times when autoimmunity inammation remains one of the best characterized risk factors for malignant lymphomas, questions like the above urgently need to be addressed.

Conict of interest statement

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