Lymphocyte transformation and autoimmune disorders

Autoimmunity Reviews 12 (2013) 802–813

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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

Review

Lymphocyte transformation and autoimmune disorders C. Tarella a, b, c,⁎, A. Gueli a, b, c, M. Ruella a, b, c, A. Cignetti a, b, c a b c

Haematology and Cell Therapy Division, Mauriziano Hospital, Turin, Italy Dept. of Medicina & Oncologia Sperimentale, University of Turin, Turin, Italy Molecular Biotechnology Center (M.B.C.), University of Turin, Turin, Italy

a r t i c l e

i n f o

Available online 4 December 2012 Keywords: Autoimmune disorders Non-Hodgkin's lymphoma Epidemiology Lymphomagenesis Rituximab Autologous stem cell transplantation

a b s t r a c t The many features that link autoimmune disorders (AD) and lymphoma are reviewed herein. Firstly, the epidemiology indicates the increased risk of non-Hodgkin's lymphoma (NHL) development in many AD, and especially in Sjögren's syndrome, rheumatoid arthritis and systemic lupus erythematosus. In these AD, the relative risk of NHL occurrence varies between 2 and 4 up to 40 fold higher than in the general population, according to various surveys. Factors favouring or predicting NHL have been reported in detail. B-cell activation and proliferation are part of AD and are essential factors for the onset of malignant cell clones in a deregulated immunological environment. Targeting deregulated or malignant B-cells is the goal of some newly developed treatments. The prototype is anti-CD20 rituximab that has substantially modified the prognosis of B-cell NHL and is also an effective new treatment opportunity for some AD. Similarly, intensified treatments with autologous haematopoietic stem cell transplant (ASCT) that were developed for high-risk lymphoma are now under advanced investigation for use in some refractory AD. Thus, the successful use of rituximab and ASCT in both AD and NHL further emphasizes the close link between these two entities. This review provides details on the main epidemiological features regarding NHL incidence in AD, the pathogenetic factors that favour lymphoma onset and some recent advances in therapeutic approaches that are effective in both autoimmune and malignant lymphoproliferative disorders. © 2012 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Lymphoma in autoimmune disorders: main epidemiological aspects 2.1. Lymphoma in Sjögren's syndrome . . . . . . . . . . . . 2.2. Lymphoma in rheumatoid arthritis . . . . . . . . . . . . 2.3. Lymphoma in systemic lupus erythematosus . . . . . . . 2.4. Lymphoma in gastrointestinal autoimmune disorders . . . Lymphomagenesis in autoimmune disorders . . . . . . . . . . . 3.1. Role of chronic B-cell stimulation . . . . . . . . . . . . . 3.2. Role of inherited genetic factors . . . . . . . . . . . . . 3.3. Pathogenesis in Sjögren's syndrome . . . . . . . . . . . 3.4. Pathogenesis in rheumatoid arthritis . . . . . . . . . . . 3.4.1. Possible association with EBV activation . . . . . 3.4.2. Pathogenetic role of immunosuppressive treatment

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Abbreviations: AD, autoimmune disorders; SS, Sjögren's syndrome; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; NHL, non-Hodgkin's lymphoma; HL, Hodgkin's lymphoma; RR, relative risk; SIR, standardized incidence ratio; MALT, mucosa-associated lymphoid tissue; DLBCL, diffuse large B-cell lymphomas; FL, follicular lymphoma; EATL, enteropathy associated T-cell lymphoma; SLICC, Systemic Lupus International Collaborating Clinics; EBV, Epstein–Barr virus; TNF, tumour necrosis factor; MTX, methotrexate; APRIL, cytokine A proliferating-inducing ligand; ASCT, autologous stem cell transplantation; MS, multiple sclerosis; SSc, systemic sclerosis; PML, progressive multifocal leukoencephalopathy; EBMT, European Group for Blood and Marrow Transplantation. ⁎ Corresponding author at: SCDU Ematologia e Terapie Cellulari, AO Ordine Mauriziano — Umberto I, University of Torino, L.go Turati 62, 10128, Torino, Italy. Tel.: +39 011 508 2949, +39 011 508 2175 (hosp), +39 011 670.6444 (lab), +39 347 4315493 (portable); fax: +39 011 508 2446. E-mail address: [email protected] (C. Tarella). 1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autrev.2012.11.004

C. Tarella et al. / Autoimmunity Reviews 12 (2013) 802–813

3.5.

Pathogenesis in systemic lupus erythematosus . . . . . . . . . . . . . . 3.5.1. Animal models of SLE . . . . . . . . . . . . . . . . . . . . . 3.5.2. A proliferating-inducing ligand (APRIL) . . . . . . . . . . . . . 3.5.3. Pathogenetic role of immunosuppressive treatment . . . . . . . 4. Lymphoma and autoimmunity: clinical aspects and shared treatments . . . . . . . 4.1. Main clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Rituximab in lymphoma and in autoimmune disease . . . . . . . . . . . 4.2.1. General aspects . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Rituximab in Sjögren's syndrome, rheumatoid arthritis and systemic 4.2.3. Safety of rituximab in patients with autoimmune disorders . . . . 4.3. Autologous haemopoietic stem cell transplantation in autoimmune disease . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The term non-Hodgkin's lymphoma (NHL) identifies a heterogeneous group of malignancies, including at least 40 different subtypes, displaying quite variable clinical behaviour [1]. In the last six decades, the worldwide incidence of malignant lymphomas has increased dramatically and NHL is now the fifth most common malignancy in the United States [2]. The reasons for this remarkable and progressive increase of NHL remains mostly unknown, although several risk factors favouring the onset of lymphoma have been identified and are still under investigation. In particular, the increased risk of NHL development associated with immune-suppressed conditions, such as HIV-associated or post-transplant drug-induced immunodeficiency, has been viewed with interest for possible correlations with the rise of NHL incidence observed in the last decades. Among the illnesses characterized by immune-deregulation, autoimmune disorders (AD) represent the most frequently occurring diseases. AD are a family of more than 100 heterogeneous conditions that affect 5 to 8% of the world's population, and like NHL, autoimmune diseases have also displayed a continuously increasing incidence. The diseases are characterized by aberrant activation of the immune system with failure of immune regulation to maintain adapted tolerance. Several recent observations have demonstrated the increased risk of developing lymphomas in patients suffering from AD. A strong association with lymphoma has been clearly demonstrated in certain autoimmune and chronic inflammatory diseases, including Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, coeliac disease, dermatitis herpetiformis, and chronic thyroiditis. New insights into the pathogenesis of AD along with the development of innovative treatments have reinforced the concept that close connections exist between autoimmunity and lymphoma. This review will illustrate the many aspects that correlate most AD with NHL, including the main epidemiological features, the pathogenetic factors that favour lymphoma onset in patients with AD and some recent advances in therapeutic approaches that are effective in both autoimmune and malignant lymphoproliferative disorders.

2. Lymphoma in autoimmune disorders: main epidemiological aspects The association between lymphoma and autoimmunity has been known for several years. [3,4]. Studies performed recently have produced additional information on the incidence of lymphoma in patients with AD, however disparate estimates have been reported [5–7]. In 2008, the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues acknowledged a new diagnostic entity termed “other iatrogenic immunodeficiency-associated lymphoproliferative disorders”, including lymphomas arising in patients treated with

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immunosuppressive agents for AD [8,9]. Basically, the risk of lymphoma is increased in patients with AD compared to the normal population, on the other hand a higher incidence of autoimmunity is also recorded among patients with lymphoma [10–13]. In general, the combined prevalence of AD is higher among women than men but the overall association with NHL is stronger in men than in women [14]. Moreover, advanced age, prolonged disease course and increased disease severity, but not family history of autoimmune conditions, seem to be associated with an increased risk of non-Hodgkin's lymphoma [15]. A typical correlation with B-cell lymphomas has been documented in AD that are mainly characterized by chronic inflammation, such as Sjögren syndrome, rheumatoid arthritis and systemic lupus erythematosus [16–19]. By contrast, gastrointestinal autoimmune conditions, such as Crohn's disease and coeliac disease are more frequently linked to T-cell lymphomas [20]. In fact, both the incidence and the histological lymphoma subtypes are quite variable depending on the specific form of AD [17]. The forms of AD which are most commonly associated with lymphoma development, i.e., Sjögren's syndrome (SS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and gastrointestinal AD will be discussed herein. The overall standardized incidence ratio (SIR) and the main risk factors for NHL development are summarized in Table 1.

2.1. Lymphoma in Sjögren's syndrome Among AD, the highest incidence of lymphomas is recorded in SS, with an estimated relative risk (RR) of 4 to 40 fold higher than in the general population [3,21,22]. In a large cohort of patients, Kauppi et al. reported that the RR of developing NHL was 8.7 for primary SS (pSS), compared to 4.5 for the secondary form of the disease [23,24]. Masaki and Sugai observed monoclonal B cell proliferation in about 25% of SS. In this study, 5% of their patients developed NHL in mucosa-associated lymphoid tissues (MALT) [25]. A recent Hungarian single centre experience confirmed that among 231 NHL patients, 20 patients also had an AD and the highest prevalence was SS [26]. As shown in Table 1, the SIR for lymphoma in SS is highly heterogeneous among various studies, and is approximately 18 [27,28]. In a cohort of 584 SS patients followed up from 1980 to 2010, 53 consecutive NHL cases were recorded. MALT lymphomas made up the majority (59%) of NHL subtypes, followed by nodal marginal zone lymphomas (MZL) (15%) and diffuse large B-cell lymphomas (DLBCL) (15%) [29]. A recent Chinese retrospective analysis of 1320 SS patients followed up for an average of 4.4 years revealed that 2.2% developed malignancies (SIR= 3.25) with an SIR for lymphoma of 48.1. [30]. Several clinical factors, in particular those associated with disease severity such as lymphadenopathy, vasculitis, including purpura, parotid gland enlargement and inflammatory neuropathy, have frequently been

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Table 1 Incidence and risk factors for lymphoma development in the main autoimmune disorders. Autoimmune disorder

SIR

Sjögren syndrome

3.1–48.1 MALT

Prevalent lymphoma subtype Risk factors

Rheumatoid arthritis

1.6–24

Non-GC DLBCL

Systemic lupus erythematosus 2.9–44.4 DLBCL Coeliac disease Crohn's disease

3.2–12 1.3–2.5

EATL Hepato-splenic TL

Reference

Primary SS, cryoglobulinaemia, low C4, low CD4/CD8 ratio, monoclonal gammopathy, cytopenia, vasculitis and purpura, adenomegaly, parotid enlargement, neuropathy High inflammatory activity, disease severity, splenomegaly, granulocytopenia, Immunosuppression (?) Disease severity, haematological aberrations, sicca symptoms and pulmonary involvement, immunosuppression (?) Poor compliance to gluten-free diet Immunosuppression (?)

[3,6,7,11,14,21–40]

[3,6,7,18,43–62] [3,6,7,17,63–76] [6,83,84,87–98] [6,81,99–116]

SIR = standardized incidence risk; EATL = enteropathy-associated T cell lymphoma; DLCBL = diffuse large B-cell lymphoma, GC = germinal centre-like; MALT = mucosa associated lymphoid tissue; TL= T-cell lymphoma.

observed in SS patients who developed NHL [31]. Moreover, some laboratory findings, such as mixed monoclonal (type II) cryoglobulinaemia, low serum complement (C4) levels and the presence of monoclonal gammopathy in the serum or free light chain in the urine have been associated with NHL development [11,24,32–35]. Other studies have shown that low CD4+ (HR=8.14) and a low CD4+/CD8+ ratio (HR=10.92) are strong indicators of risk for lymphomas [36]. A recent Italian study confirmed that salivary gland enlargement, low C3 and/or C4 levels and disease duration are independent risk factors for B cell NHL in primary SS [37]. Solans-Laqué et al. reported that purpura, parotidomegaly, anaemia, leukopenia, lymphocytopenia, hypergammaglobulinaemia, low C3, and low C4 levels at SS diagnosis were significant predictors of NHL development, though only hypocomplementaemia and lymphocytopenia were independent risk factors. In particular, hypocomplementaemia was related to earlier development of NHL and higher mortality. In this study, the cumulative risk of developing lymphoma ranged from 3.4% in the first 5 years to 9.8% at 15 years. The SIR for NHL development was 15.6 [38]. A retrospective study of 536 consecutive patients showed that the presence of neutropenia, cryoglobulinaemia, splenomegaly, lymphadenopathy, and low C4 levels at diagnosis predicts a more than 5-fold risk of MZL compared to patients with no risk factors. The presence of lymphocytopenia (p=0.044) at diagnosis is a risk factor for the development of DLBCL [39]. Lastly, onset of SS at a young age has also been associated with a greater risk of developing NHL [40]. Most NHLs diagnosed in SS patients belong to the B-cell subtype, and in particular MALT is the most common form [25]. The other common subtypes, i.e., DLBCL, follicle centre lymphoma (FL) and lymphoplasmocytoid cell lymphoma account for approximately 30% of NHLs occurring in SS [11,32,41]. NHL has an extranodal presentation in approximately 80–85% of cases, with peculiar involvement of the disease target organs. Indeed, the parotid gland is the most frequent site of lymphoma development [42]. 2.2. Lymphoma in rheumatoid arthritis The RR of lymphoma in rheumatoid arthritis is about 2 fold, with a very heterogeneous SIR (Table 1) [18,43–48]. Men with RA exhibit a higher SIR for the development of both NHL and Hodgkin's lymphoma (HL) than their female counterparts [49,50]. The French registry collected 38 cases of lymphoma, 31 NHLs and 7 Hodgkin's or Hodgkin's-like lymphomas, and it was found that as compared with the general population, the SIR of lymphoma was 2.4 [51]. The increased risk of lymphoma seems to be mainly related to the severity of the disease [52,53]. Indeed, patients with Felty's syndrome, characterized by splenomegaly and granulocytopenia, have a higher risk of lymphoma development compared to the general population of RA patients [54]. Moreover, patients with high inflammatory activity as shown by joint destruction, high erythrocyte sedimentation rate, and a high number of affected joints have a high RR for NHL development [55]. In the French registry, the incidence of lymphoma was

higher in patients treated with anti-TNF monoclonal antibodies (moAb) than with soluble-receptor anti-TNF therapy (etanercept). Patients receiving adalimumab or infliximab had a higher risk of lymphoma than those treated with etanercept, with an SIR of 4.1 and 3.6 vs. 0.9, respectively. The 2- to 3-fold increased risk of lymphoma observed in patients receiving anti-TNF therapy was similar to what was expected for such patients with severe inflammatory diseases [51]. A meta-analysis showed an increased incidence of malignancy in patients with rheumatoid arthritis treated with anti-TNF antibodies, with a disproportionate number of lymphomas [56]. A recent metaanalysis showed a tendency for increased B-NHL in the anti-TNF treated group. However, according to the authors, since the overall incidence of lymphoma is rare, it does not reach statistical significance [57]. Diffuse large B-cell lymphoma, with a predominant non-germinal centre subtype, was the most common form of NHL (50%) observed among 400 patients with RA [52,58]. Moreover, a 3- to 5-fold increased risk of HL and a higher RR for multiple myeloma were also observed in RA [59–62]. 2.3. Lymphoma in systemic lupus erythematosus Several studies have demonstrated that patients with SLE have an increased risk of haematologic cancer. In particular, SLE patients have a 3- to 6-fold RR of lymphoma, with some studies reporting a risk of lymphoma of up to 40-fold [17,63–73]. The meta-analysis by Zintzaras et al. reported an SIR of 7.4 [3]. Bernatsky et al. examined about 9500 patients for an average follow-up of 8 years and found that the SIR for NHL was 3.64 [74]. Moreover, a 3- to 5-fold increased risk of HL was observed in SLE [68]. In a Danish cohort of 576 SLE patients with a median follow-up of 13.2 years, the SIR for cancer was 1.6, with an SIR for NHL of 5.0 [75]. In a nationwide cohort study in Taiwan that included 11,763 patients with SLE without a history of malignancies, a total of 259 cancers were observed (SIR 1.76), and in particular, the SIR was higher for haematologic malignancies (SIR 4.96), with an SIR for NHL of 7.27. As shown in Table 1, the SIR ranged from 2.9 to 44.4. Younger patients had a greater risk ratio of cancer and the risk ratio decreased with age. The risk ratio of cancer decreased with time, yet remained elevated compared with that of the general population [76]. As is the case for other AD, disease severity has also been identified as a risk determinant for lymphoma development in SLE. In one study, haematological SLE aberrations, sicca symptoms and pulmonary involvement were the main risk factors for NHL, while treatment with cyclophosphamide or azathioprine was unrelated to risk [77]. In SLE, the cumulative disease activity and the clinical severity, as assessed by the Systemic Lupus International Collaborating Clinics (SLICC) damage index, are known to be possible risk factors for haematological malignancy. Moreover, the prolonged use of immunosuppressive medications has been viewed as a lymphoma risk factor. A large multi-centre SLE study found that the RR of cancer in SLE is higher in early than in late SLE, suggesting that immunosuppressive

C. Tarella et al. / Autoimmunity Reviews 12 (2013) 802–813

drugs may play a minor role in the increased risk of cancer [74]. On the contrary, a nested case cohort study suggested an increased risk of haematological cancer for all immunosuppressive agents combined, especially after 5 years of drug exposure [78]. With regard to NHL subtype, the most commonly occurring form in SLE is the DLBCL [17,63]. In a Swedish study of 10 SLE-associated DLBCL, the majority (80%) were of the aggressive, non-germinal centre type [77]. 2.4. Lymphoma in gastrointestinal autoimmune disorders Besides the main diseases that are most commonly associated with NHL, other AD have also been shown to carry an increased risk of lymphoma, with an RR of 3- to 6-fold in coeliac disease, while the risk in inflammatory bowel disease (IBD) remains unclear [73,79–86]. Studies have proven beyond a doubt that patients with diagnosed coeliac disease have an increased risk of malignancy and in particular of NHL [83,87–97]. A recent study showed that coeliac patients had a significantly increased risk of malignancy compared with the general population, (SIR = 1.41) with an SIR for NHL of 12. Similarly, patients with dermatitis herpetiformis have a significantly raised risk of NHL (SIR = 5.14). In coeliac disease, the role of the gluten-free diet as protection against NHL is of interest but it is based on indirect observations or studies with small numbers of cases [84,88,93,96]. A Finnish study highlighted that five coeliac patients who developed NHL reported poor compliance to the gluten-free diet before the onset of lymphoma [96]. Another Italian study reported non-compliance to a strict gluten-free diet in coeliac patients with enteropathyassociated T-cell lymphoma (EATL) [84]. In coeliac disease, besides the strong link with EATL, there is mounting evidence of an increase in B-cell lymphomas as well [82,98]. Finally, coeliac disease, like SS and Hashimoto thyroiditis, shows a peculiar occurrence of lymphoma in the gut, which is the target organ of the underlying autoimmune diseases. In IBD, the real risk of NHL is a matter of debate, with some studies suggesting a moderate risk and others affirming no increased risk of NHL at all [99]. Loftus et al. reported an SIR of lymphoma of 2.4 among 216 patients with Crohn's disease (CD) [100]. A Canadian study involving 2857 CD patients demonstrated an increased risk of lymphoma (RR, 2.4) especially in men (RR, 3.6) [101]. In a large Swedish study on 20,120 patients with CD, the SIR for haematopoietic cancers was 1.3, with an increased risk of NHL in the first 5 years of follow-up from the time of CD diagnosis, although no significant differences in the RR were observed [81,99]. Hemminki et al. reported that the SIR of NHL was 2.5 in more than 20,000 hospitalized CD patients [102]. In contrast to these studies, a large UK retrospective cohort study revealed no increased risk of lymphoma (RR, 1.4) [103]. The non-correlation to lymphoma for CD is confirmed by other population-based cohort studies [104–108]. A meta-analysis analysed seven population-based studies with a total of 18,000 patients and estimated that the RR of lymphoma in CD was 1.5. In conclusion, on the basis of currently available data, it would appear that the risk of NHL in IBD patients is similar to, or just slightly higher than in the general population [105,109]. Finally, immunosuppressive treatments employed in both IBD and RA, may play a role in the possible risk of NHL. The TREAT registry and a recent meta-analysis showed that the incidence of lymphoma in patients treated with infliximab was similar to the incidence in patients not treated with infliximab [110–112]. Whether the combined use of TNF antagonists with immunosuppressants is associated with an increased risk of NHL is unclear [113]. A meta-analysis of 26 randomized controlled trials, case–control and cohort studies did not show any association between an increased risk of NHL and combination therapy with azathioprine and TNF antagonists [114]. Several cases of the rare hepatosplenic T cell lymphoma have been reported in young adults with inflammatory bowel disease treated with infliximab or adalimumab in combination with other immunosuppressive drugs [115,116].

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In summary, the association between autoimmune disorders and risk of NHL is not general but rather mediated through specific NHL subtypes. Positive associations are most evident for some specific NHL subtypes, including primarily: i. diffuse large B-cell lymphoma, which is increased in association with RA, SS, SLE, and coeliac disease; ii. marginal zone lymphoma, distinctly associated with SS; iii. lymphoplasmocytoid lymphoma, associated with RA; and iv. T-cell lymphoma, associated with coeliac disease. Coeliac disease and psoriasis are both associated with T-cell NHL of the anaplastic large cell type, in addition to the well-known close link between coeliac disease and EATL. Increased risks have been generally observed for both nodal and extranodal NHL. 3. Lymphomagenesis in autoimmune disorders NHLs usually arise through a multistep accumulation of genetic aberrations that lead to a selective growth advantage of the malignant clone. Such multistep process likely involves somatic mutations of genes in relevant molecular pathways. Recurrent translocations, which occur during various steps of B-cell differentiation, are often an initial step in the malignant transformation. Translocations lead to the deregulated expression of oncogenes that often control cell proliferation, survival, and differentiation. These translocations alone are often insufficient to cause lymphoma development. Accordingly, secondary genetic alterations are required for the full malignant transformation [117]. To date, the sequence of specific molecular events leading to transformation of an autoimmune lymphocyte into a neoplastic cell is unclear. Putative molecular targets, such as cytokine A proliferating-inducing ligand (APRIL), B-cell activating factor of the TNF family (BAFF), and TNF-AIP3 have been investigated but a specific role in the setting of transformation of autoimmune disorders has not been clearly established [118–121]. For instance, recent genome-wide association studies have demonstrated a strong link between TNF-AIP3 polymorphisms and a range of chronic inflammatory disorders including SLE and RA [122]. Both SLE and RA are associated with a significantly increased risk of lymphoma, particularly MALT lymphoma. Although it is tempting to hypothesize that TNF-AIP3 inactivation may be preferentially associated with MALT lymphoma arising in an autoimmune environment, a recent analysis of MALT lymphomas in patients with clinical presentation of AD showed that the incidence of TNF-AIP3 and TNF genetic abnormalities was not especially high compared to what was observed in unselected MALT lymphomas in other studies [123–125]. Despite the lack of distinctive molecular pathways, there are several possible mechanisms through which autoimmunity is related to the risk of developing lymphoma [126]. Both autoimmune and lymphoproliferative diseases are the result of the progressive elimination of the checkpoints that inhibit uncontrolled B-cell growth, including both autoimmune and malignant lymphocytes [127]. Possible mechanisms for the progression of autoimmune diseases into lymphomas include deregulation and hyperactivity of B cells related to chronic antigenic stimulation, as well as impaired T-cell function. It is also possible that autoimmune disease therapy plays a role in the development of a subsequent lymphoma. However, studies on lymphoma risk following autoimmune therapies (such as methotrexate and TNF antagonist agents) have not yet produced conclusive results [127]. 3.1. Role of chronic B-cell stimulation Autoimmunity results in overstimulation and defective apoptosis of B cells. RA, primary SS, SLE, and coeliac disease are all characterized by B-cell proliferation and auto-antibody production [128–131]. The development of mature B-cell neoplasms tends to mimic stages of normal B-cell differentiation, as illustrated in Fig. 1 [117]. DLBCL, MZL, and lymphoplasmacytic lymphomas all arise from B cells that have somatic hypermutations in the variable region immunoglobulin

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Fig. 1. Proposed model of lymphomagenesis in autoimmune disorders.

genes. These mutations occur during the germinal centre (GC) stage, after T-cell-dependent antigen exposure. Although NHL subtypes lacking somatic hypermutation may be antigen stimulated, such antigen stimulation is thought to occur through a T-cell-independent mechanism outside of the germinal centres [132]. Thus, the observed NHL subtype pattern in these four conditions is consistent with the hypothesis that both chronic B-cell stimulation and antigenic drive, either during or after the germinal centre stage, play a role in autoimmunity-related lymphomagenesis [133]. The relevance of similar mechanisms is biologically well established in some settings. Both the development of parotid marginal zone (i.e., MALT) lymphoma in patients with SS and small intestinal T-cell lymphoma in patients with coeliac disease are thought to represent endpoints of a multistep process of local antigen-driven chronic inflammation that is characterized by organ-specific B- or T-cell proliferation, polyclonality, and, ultimately, monoclonality [131,134]. Systemic autoimmune features, such as increased resistance to apoptosis, may further enhance the carcinogenic effects of sustained B-cell proliferation. For instance, BAFF enhances the survival of B cells, and is found to be over-expressed in SS, RA, SLE, and in lymphomas as well [118,119,121]. Secondary inflammation due to autoimmune stimulation can also promote these processes which are evident in the continuum of histological changes associated with SS (see Section 3.3) [16]. Finally, several infections have been associated with the development of lymphoproliferative disease and are likely to operate through some of the same pathways [135–137].

3.3. Pathogenesis in Sjögren's syndrome Marginal-zone B-cell lymphoma of the MALT type is the most frequently observed subtype in primary SS. The sequence linking mechanisms of autoimmunity, lymphoproliferation, and the development of lymphoma in the target tissues of patients with primary SS is one of the most thoroughly investigated models and one of the strongest proven associations between autoimmunity and lymphomagenesis [138]. Oligoclonal or monoclonal B-cell expansions are a key feature of primary SS. Clonal B-cell expansions can often be detected in the biopsies of inflamed glands from patients with primary SS by polymerase chain reaction (PCR)-based technologies. However, the detected cells are not necessarily malignant [139]. A focal periductal lymphoid infiltrate of the lacrimal and salivary glands is one of the histopathological hallmarks of SS [140]. During disease progression, ectopic lymphoid organization progressively increases and forms ectopic ‘tertiary’ germinal centre-like structures of inflamed tissues, which resemble the GCs of secondary lymphoid organs [141]. Extranodal MZL in primary SS might originate in this newly formed ‘tertiary’ lymphoid tissue, with a tendency to spread to other mucosal or nodal sites as well [138]. The transition from benign chronic lymphoepithelial sialadenitis to indolent extranodal low-grade MZL of the MALT-type is a multistep, autoantigen-driven process. It has been speculated that chronic autoantigenic B-cell stimulation, mediated by the B-cell surface Ig receptors, increases the risk of monoclonality and, finally, leads to malignant transformation by a subsequent oncogenic event [139,142]. 3.4. Pathogenesis in rheumatoid arthritis

3.2. Role of inherited genetic factors In addition to various types of extrinsic factors, genetic factors likely play a role in lymphomagenesis and autoimmunity. It has been suggested that there could be some inherited mutations causing susceptibility to both autoimmune diseases and lymphomas. One way to test for this hypothesis would be to look for familial aggregation of both autoimmune diseases and lymphomas. However, previous large, population-based, case–control studies found that family history of autoimmune disease was generally not a predictor of lymphoma risk [73]. Similarly, a prior study of relatives of RA patients did not show an increased risk of lymphoma [53].

3.4.1. Possible association with EBV activation An association between disease severity and NHL risk has been reported in RA, but whether this association is related to high inflammatory activity, treatment, and/or Epstein–Barr virus (EBV) activation is unclear because few studies have tried to separate these inter-related factors [55,143,144]. One proposed explanation in immunosuppressed patients in general is that a dormant EBV becomes active and facilitates lymphoma development. The EBV is an oncogenic virus that has been implicated in certain types of lymphoma. Impaired T-cell function is the main risk factor for NHL [145,146]. Such T-cell impairment might facilitate EBV replication. EBV is not

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usually detected in NHL cells in patients with normal immune systems. However, EBV-positive lymphoma is frequently found in immunosuppressed patients. Only 3 studies have investigated the role of EBV, as detected by in situ hybridization, in RA-related lymphomas, and most had few lymphoma cases to analyse. Baecklund et al. found that only 12% of the RA-related lymphomas were EBV positive, and they were most frequently HL rather than NHL [52]. Askling et al. found that 1 of 12 (8%) lymphomas in their study was EBV positive [46]. Mariette et al. found that only 2 of 25 (8%) lymphomas they identified were EBV positive [147]. In a further analysis of the literature, two studies found no difference between EBV positive rates in RA versus non-RA tumours, while two other studies identified a slightly higher rate than in non-RA lymphomas [52,143,148,149]. These data suggest that EBV might not be a strong etiologic factor in RA-related lymphomas. 3.4.2. Pathogenetic role of immunosuppressive treatment There is an on-going debate among rheumatologists about the possible correlation between the use of potentially toxic medications, that are effectively employed in RA patients, and the increased risk of lymphoma. Most studies revealed no statistically significant increased risk of lymphoma with methotrexate or azathioprine [133,150]. An increased incidence of lymphoma in patients treated with TNF inhibitors was suggested. However, follow-up in the studies that were taken into consideration was too short to definitively determine increased risk [46,56,151,152]. Most lymphomas in RA patients, in fact, develop ≥5 years after treatment initiation; however, most studies evaluating TNF inhibitor risk lasted only 1–4 years. Therefore, the increased incidence of lymphoma in the first few years of treatment cannot necessarily be attributed to TNF inhibitor use. In addition, a confounding factor might be disease severity, since patients with the most severe forms of disease are treated with the strongest medications. Thus, in most studies it is difficult to distinguish whether lymphoma risk derives from medications or disease severity or both. Recent works suggest that it is the disease itself, not its treatment that is associated with increased risk of lymphoma in patients with RA [153,154]. To date, the standard of care is to continue aggressive treatment to reduce disease activity in patients with RA because the association of lymphoma with medications appears to be small in most large studies and high disease activity appears to confer a higher risk of lymphoma. 3.5. Pathogenesis in systemic lupus erythematosus 3.5.1. Animal models of SLE Studies in animal models have revealed some common risk factors for the development of SLE in humans and in certain mouse strains, including female gender, increased serum levels of type I IFNs, and induced expression of “IFN signature” genes in immune cells [155–157]. Thus, it has been hypothesized that female sex hormones (for instance, oestrogens) and type I IFNs might also play a role in the increased risk of B cell malignancies among SLE patients. Indeed, increased nuclear levels of oestrogens and of IFN-inducible p202 protein are associated with increased lupus susceptibility in certain female strains of mice, which in turn might increase the risk of developing B cell malignancies [158]. In humans, the p202 functional homologue IFI16 might be implicated as well [159]. A complete understanding of the molecular mechanisms through which the p200-family proteins regulate B cell homeostasis is needed to identify SLE patients with an increased risk of developing B cell malignancies. 3.5.2. A proliferating-inducing ligand (APRIL) A report by Lofstrom B et al. has elucidated some molecular features of DLBC lymphomas arising in SLE and in RA in humans. The authors undertook their analyses focusing on the cytokine A proliferating-inducing ligand (APRIL), which is strongly expressed in DLBC lymphomas in the general population, and is detected in high concentrations in the sera

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of some RA and SLE patients. A very high odds ratio (OR) was found for elevated APRIL expression in the SLE lymphoma tissues (OR: 23.6, 95% CI 2.4–231.2), but not in the RA DLBCL (OR 0.8, 95% CI 0.3–2.0). The authors note that the high expression of APRIL in DLBC lymphomas in some SLE patients might indicate that APRIL mediates lymphoma development in these subsets of AD. However, it cannot yet be ruled out that the findings could simply reflect a deregulation of APRIL per se in these patient groups [120]. 3.5.3. Pathogenetic role of immunosuppressive treatment There are ongoing concerns that much of the excess cancer risk in SLE is due to the use of immunosuppressive drugs. This is largely based on data showing increased cancer risk in solid organ transplant, where patients are similarly treated with immunosuppressant agents. However, several studies have found that many of the SLE patients diagnosed with malignancies had not been exposed to immunosuppressive drugs [65,77,160,161]. Data are available from some case– control analyses performed in an SLE sample from Sweden. This study, with only 16 cases of NHL arising in SLE, was unable to produce precise estimates of the effects of azathioprine or cyclophosphamide exposure and did not focus on other drug exposures. Additionally, they were not able to produce estimates adjusted for disease activity [77]. Likewise, data from earlier analyses, based on the Lupus Erythematosus International Collaborating Clinics multi-centre international cohort, showed that the relative risk of lymphoma was the highest very early in the SLE disease course, which puts the role of drugs into question [74]. Because of the lack of precise results, further attempts to differentiate the effects of lupus activity versus treatment are on-going in a case–cohort study of lymphoma risk in SLE, endorsed by the SLICC research group. Indeed, the possible role of immunosuppressive treatments in the development of lymphoma remains an open issue in both RA and SLE [162]. 4. Lymphoma and autoimmunity: clinical aspects and shared treatments 4.1. Main clinical features To date, the clinical behaviour of lymphomas complicating AD has not been extensively investigated. Apparently, both clinical presentation and outcome are not markedly different compared to lymphomas arising de-novo in the general population. Most of the information regarding diagnosis and outcome of lymphoma in AD has been obtained by studies on SS. Indeed, as already discussed in the epidemiology chapter (Section 2.1), the association between SS and NHL is well established and extensively characterized. Although these signs can be found in SS patients with no evidence of lymphoma, patients displaying these features need careful follow-up due to the high likelihood of NHL development. Indeed, regular assessment of serum immunoelectrophoresis, cryoglobulinaemia assay, urinary free light chain assay and physical and instrumental examinations of the exocrine and lymphatic glands are recommended in SS patients in order to identify the presence of possible NHL at an early stage. Moreover, the presence of typical symptoms such as fever, night sweating, weight loss and gastric involvement should be carefully considered as possible early manifestations of lymphoma. With regard to RA, a main issue concerns the possible prognostic differences between de-novo vs. RA-associated NHL. In a study on 33 RA-associated NHLs, predominantly of DLBCL subtype, the median survival time from lymphoma diagnosis was 6 months [148] indicating a worse outcome compared to de-novo DLBCL [163]. A recent study reported additional and somewhat different results based on the analysis of a series of 65 RA-associated lymphomas and 1500 non-RA lymphoma controls [164]. RA was inversely associated with death from lymphoma, although it was positively associated with death by other causes. At present, the impact of the underlying

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immune disorders on the clinical outcome of lymphoma arising in AD remains to be defined and further investigations are needed. Particular attention should be paid to identifying NHL in patients with SLE. The diagnostic procedure may be challenging, since both diseases share some clinical features, such as lymphadenopathy/ lymphadenomegaly, fever, weight loss, hepato-splenomegaly, and cytopenia. Thus, careful monitoring, including physical and instrumental examination of the spleen, liver and lymph nodes and regular assessment of cell blood count and serum immunoelectrophoresis is also recommended for SLE. Aggressive NHL subtypes, namely the DLBCL form, frequently occur in SLE, whereas indolent lymphoma is the most common occurrence in SS [165,166]. Based on the mortality data generated by the SLICC, the standardized mortality ratio due to NHL is 2.8 in SLE compared to the general population. Lastly, as is the case for RA, no conclusive data are available regarding possible distinct features in the clinical outcome of NHL in SLE [162,167]. 4.2. Rituximab in lymphoma and in autoimmune disease 4.2.1. General aspects Monoclonal antibody therapy with the anti-CD20 rituximab represents one of the most important advances in the treatment of lymphoproliferative disorders in the last 30 years. The use of rituximab was approved for the treatment of low-grade NHL in 1997. Since its introduction, the management of patients with B-cell NHL has improved considerably, mostly by combining rituximab with various chemotherapy/radiotherapy regimens. Several randomized trials have demonstrated significant improvements in the clinical outcome of patients receiving rituximab plus chemotherapy compared to chemotherapy alone. This has been shown in most B-cell lymphomas, particularly in DLBCL and in FL subtypes [168–171]. The current indications for rituximab in NHL are: i. first line treatment for follicular NHL combined with chemotherapy; ii. monotherapy treatment of relapsed/refractory follicular NHL; iii. maintenance therapy for relapsed/refractory follicular NHL responding to induction chemotherapy; iv. first line treatment for diffuse large B-cell NHL combined with the CHOP (cyclophosphamide–doxorubicin–vincristine– prednisone) regimen; v. first line treatment for chronic lymphocytic leukaemia (CLL) and treatment for relapsed/refractory CLL. Moreover, rituximab is effectively added to high-dose treatments with autograft for high-risk B-cell lymphoma [172]. The overall efficacy and tolerability of rituximab therapy in B-cell malignancies has stimulated the interest in rituximab for the treatment of B-cell related autoimmune diseases. In fact, successfully employed treatments in B-cell malignancies have frequently been exploited to manage severe auto-immune diseases, without co-incident NHL. The use of rituximab in AD is in line with this concept. However, the actual mechanism whereby B cell depletion by rituximab may improve the disease remains to be formally elucidated. It is well-established that AD occur when the normal mechanisms of immune tolerance to self-antigens fail or are bypassed. This brings about the generation of abnormal self-reactive B cells. Thus, B cell depletion was initially conceived in AD to simply eliminate the abnormal auto-antibodies [173]. As recently proposed, the auto-antibody decline per se is not sufficient to explain the clinical benefit of B-cell depletion therapy [174]. While it is likely that the decrease in at least some auto-antibodies may be responsible for some of the clinical benefits of rituximab, surprisingly significant clinical improvements have been observed before any substantial change in the level of circulating auto-antibodies. In other words, lack of correlation between auto-antibody titres and disease response or relapse has often been reported [175]. Recent studies have suggested that B cell depletion may act through different pathways. In particular, B-cell depletion may interrupt multiple antibody-independent pathogenic B cell functions, including autoantigen-presentation and activation of effector T cells, production of pro-inflammatory cytokines, inhibition of regulatory T cells

and formation of ectopic lymphoid tissue within target organs [176]. Whatever the mechanism, rituximab has demonstrated activity at least in some forms of AD. 4.2.2. Rituximab in Sjögren's syndrome, rheumatoid arthritis and systemic lupus erythematosus Several clinical studies have investigated the tolerance and efficacy of rituximab in SS patients. Initial observations showed that rituximab may improve disease-related symptoms for variable periods of time [177–179]. Recently, a randomized placebo controlled trial unequivocally proved the efficacy of rituximab in SS. In the rituximab group, significant improvements were found in terms of stimulated whole saliva flow rate, serological assays, several laboratory and subjective parameters and extra-nodular manifestations [180]. Results from a recent meta-analysis have shown that a single course of rituximab is effective in reducing disease activity for about six to nine months. Re-treatment of responders resulted in a similar effect to initial treatment. When combined with corticosteroids during infusion, rituximab was shown to be safely administered. Thus, anti CD20 therapy can be considered an effective treatment option in patients with SS. However, large randomized controlled trials are still warranted in order to assess the long-term effects of rituximab in SS, to determine which SS patients will respond best to rituximab treatment, and to assess which re-treatment schedule should be followed [181]. Rituximab has also been employed in RA for a long time, usually for the management of patients refractory to conventional therapies. So far, three randomized trials have demonstrated the efficacy of rituximab in RA patients refractory to other treatments [182–184]. Depletion of peripheral blood B cells persisted throughout the 24 week follow-up in all three studies, with signs of clinical improvement. In 2006, the FDA approved rituximab for the treatment of patients with RA who were non-responsive to tumour necrosis factor (TNF)-blocking agents. The current recommended protocol is: two 1000 mg i.v. infusions two weeks apart; each infusion is preceded by 100 mg i.v. methylprednisolone (or equivalent); weekly MTX is administered as an adjuvant for increased efficacy. A second cycle of rituximab therapy should be taken into consideration after 24 weeks if there is still residual disease activity or if a relapse of symptoms occurs [185,186]. Following FDA approval, additional studies confirmed the efficacy of rituximab in RA. In 2010, a phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active RA who had inadequate response to MTX and who were naïve to prior biological treatment [187]. Rituximab added to MTX significantly improved clinical outcomes at week 24, with further improvements by week 48. Another recent phase 3, open label, multi-centre trial in RA patients failing a previous TNF inhibitor, confirmed the efficacy, including enhanced response in rheumatoid factor positive patients. Overall, at 24 weeks, 58%, 27%, and 7% of patients improved their American College of Rheumatology score to 20, 50, and 70, respectively [188]. The authors concluded that, based on its efficacy and safety profile, rituximab is an attractive treatment option for patients who have not responded to a TNF inhibitor. Lastly, rituximab has also been used in SLE, mostly in patients who are refractory to conventional immunosuppressive agents, disease modifying anti-rheumatic drugs and corticosteroids [189,190]. In a large trial, rituximab led to clinical response in 159 of 208 (79%) treated SLE patients, with improvements in both mean lupus assessment scores and renal function, thus allowing steroid dosage to be decreased. The favourable results observed with rituximab in SLE support the notion that pathogenesis of SLE is a consequence of the abnormal interaction between B and T cells. Rituximab efficacy for refractory SLE appears promising and rituximab seems to be well tolerated by most patients. However, two randomized trials on SLE led to the general conclusion that rituximab is not better than conventional therapy in SLE [191,192]. These negative results raise some questions regarding the potential of this drug to eliminate not

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only pathogenic but also regulatory B cells. Indeed, one might hypothesize that indiscriminate B cell depletion may not be the best strategy in all SLE cases. This concept is indirectly supported by the encouraging results recently reported with drugs that have weaker and more selective effects on different B cell subsets, such as belimumab and epratuzumab. However, the discouraging results reported in some trials stand in contrast to the accumulating experience that indicates the important clinical efficacy of rituximab in refractory SLE, alone or in combination with cyclophosphamide [193,194]. 4.2.3. Safety of rituximab in patients with autoimmune disorders In most clinical situations rituximab is used as two 1 g i.v. infusions, two weeks apart. In other studies, patients with autoimmune disease received the lymphoma protocol which involved four infusions of rituximab at a dose of 375 mg/m 2, given in four consecutive weeks. Concurrent medication with corticosteroids and antihistamines is typically used to minimize infusion reactions which may be more frequent in SLE. A 2005 report on the safety of rituximab in patients with cancer and RA found 84% of patients experiencing infusion related reactions, including nausea, headache, fatigue, rash and flu-like symptoms, with 97% of these reactions being of moderate, grade 1–2 intensity. The incidence and severity of these symptoms seem highest after the first infusion and decrease at each subsequent infusion [195]. A matter of concern is the increased risk of infectious complications as a consequence of B-cell depletion and immunosuppression induced by rituximab. Data from three randomized trials on RA patients showed that the incidence of serious infections was 2.3% in patients receiving 2 × 1000 mg infusions of rituximab, while no serious infections were observed in those treated with the 500 mg dose. While serious infections do not appear to be substantially increased, even with repeated administrations of rituximab, the report of some cases of progressive multifocal leukoencephalopathy (PML) in non-HIV, autoimmune patients treated with rituximab has created significant concern [196]. Five cases of PML have been reported in rituximab treated autoimmune disease: 2 cases of SLE, one case of RA and a single case with Wegener's granulomatosis and with vasculitis. In fact, the interpretation of these reports is uncertain since PML can occur in analogous clinical conditions in the absence of rituximab. Thus, whether this drug actually increases the risk of PML remains to be formally determined [173]. 4.3. Autologous haemopoietic stem cell transplantation in autoimmune disease Intensive chemotherapy with autologous stem cell transplantation (ASCT) is an additional option that has been mainly developed for lymphoma patients. ASCT is commonly used as salvage treatment for patients with refractory or relapsing disease after conventional chemotherapy [197–199]. The long experience with ASCT in lymphoma has made the procedure highly effective and well tolerated. Indeed, the greatest concern remains the risk of secondary myelodysplasia/acute leukaemia that in a recent survey has been calculated in the order of 3.09% and 4.52%, at 5 and 10 years, respectively [200]. During the past 15 years, based on the experience of experimental models and early clinical trials, ASCT has become a new option even for patients with severe AD, unresponsive to most conventional treatments. Immunologic studies in patients with multiple sclerosis (MS) treated with ASCT have provided further support to the concept that an extensive renewal of the adaptive immune system can be pursued by ASCT, with the T cell pool being gradually repopulated by thymus-derived naïve cells [201]. Since 1996, more than 1300 autoimmune disease patients receiving ASCT have been registered by the European Group for Blood and Marrow Transplantation (EBMT) and almost 500 patients by the Centre for International Blood and Marrow Transplant Research (CIBMTR) [202]. ASCT is most commonly performed in patients with

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multiple sclerosis (MS) or systemic sclerosis (SSc). SLE, Crohn's disease, type I diabetes and juvenile idiopathic arthritis are other AD for which ASCT has been considered suitable [203]. The current use of ASCT for severe AD has been reported in a recent observational study by the EBMT Working Party on Autoimmune Disease [204]. All consecutive patients with autoimmune diseases reported to the EBMT registry database from 1996 to 2007 were included in the study. Overall, 900 ASCT were performed. Peripheral blood stem cells were used as the source of stem cells in the majority of patients (93%). The conditioning regimen consisted of either total body irradiation (TBI) (7%) or various combinations of chemotherapy alone (93%), including combinations based on cyclophosphamide, busulfan and BEAM (carmustine, cytarabine, melphalan and etoposide). 5-year survival among all patients was 85% and progression-free survival was 43%, although the rates varied widely according to the type of autoimmune disease (45% for MS, 55% for SSc and 18% for RA). The 100-day transplant-related mortality was 5%, mostly due to infections. Multivariate analysis showed that age below 35 years, transplantation after 2000, and diagnosis were associated with progression-free survival. At present, there are several on-going trials aimed at defining the role of ASCT in the treatment strategy for AD with highly unfavourable prognostic features. The results so far available allow us to conclude that ASCT represents one more bridge linking AD and malignant lymphoma. Indeed, as is the case for lymphoma, the ASCT procedure is a complex but effective treatment option even in AD that might help in the management of patients with potentially incurable immunological diseases. 5. Conclusions The present review has focused on the many aspects that are common to the two most relevant immunological disorders, i.e. autoimmune diseases and malignant lymphoma. The possible transformation into a malignant NHL is a well known complication of most AD. The rate of NHL occurrence has been reviewed in SS, RA and SLE, which are among the AD with the highest risk of NHL development. In these forms of AD, various risk factors favouring or predicting NHL occurrence have been described. The study of NHL developing in AD has also helped to elucidate the pathways that contribute to lymphomagenesis. According to the most recent studies, B-cell activation and proliferation along with chronic antigen stimulation and inflammation are the essential factors for the onset of malignant cell clones in the deregulated immunological environment. Lastly, the goal of targeting deregulated or malignant B-cells can be reached by treatment approaches that are effective in both AD and NHL. The prototype is the anti-CD20 rituximab that has substantially modified the prognosis of B-cell NHL and is also an effective new treatment opportunity in some AD. Similarly, intensified treatments with ASCT which have been developed for high-risk lymphoma are now under advanced investigation for some refractory AD. Shared treatments such as rituximab and ASCT emphasize the close link between AD and malignant lymphoma. These therapeutic approaches may help in the management of patients with potentially incurable immunological diseases and are among the most effective options available for the management of lymphoma arising in AD. Take-home messages • The association between lymphoma and autoimmunity is well established and the RR has been accurately evaluated in SS, RA and SLE. • RA, SS, and SLE are associated with increased risk of B-cell lymphoma, while coeliac disease is most often associated with T-cell NHL. • B-cell activation and proliferation are essential factors for the onset of malignant cell clones in a deregulated immunological environment. • Rituximab and ASCT are effective treatments in both NHL and AD, further emphasizing the close link between these two entities.

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Does varicella vaccine is safe and efficacious in paediatric patients with systemic lupus erythematosus previously exposed to varicella zoster virus? Several studies confirmed that patients with systemic lupus erythematosus (SLE) have a high incidence of herpes zoster (HZ) infection. HZ might be prevented in healthy elderly subjects by boosting live varicella zoster virus (VZV) live vaccine. By contrast, in patients affected with SLE, especially if taking immunosuppressant, the use of live vaccines is contraindicated. However, although some Authors suggest the possibility to vaccinate with VZV vaccine patients with immune-mediate diseases, no data are available on the risk/benefit ratio of VZV vaccine in SLE patients. Barbosa et al. (Clin Exp Rheumatol 2012;30:791-8) in a prospective, blind randomized and controlled study enrolled 54 paediatric SLE patients (28 underwent to vaccination and 26 did not) and 28 healthy controls. Patients taking mycophenolate mofetil, intravenous immunoglobulin, cyclophosphamide in the last three month were excluded from the study. Azathioprine, methotrexate and cyclosporine were allowed and used in 39.2% of patients. Up to 80.7% of patients and 60.7% of controls had a previous VZV infection. No difference between SLE patients in lymphocyte immunophenotyping and no differences were found between patients and controls in the increase of cellular (CD4 and CD8 T specific VZV interferon-γ producing cells) and humoral immune response against VZV. The antibody titres were appropriate. Furthermore, after the mean 35.6 month of follow-up 4 HZ cases occurred in the unvaccinated group and no cases in the vaccinated groups. Only mild adverse events were reported after the vaccination, without any difference among the three groups. The frequency of SLE flares was similar between the two groups. According to the results of this study varicella booster vaccine might be a safe opportunity for SLE patients to reduce the incidence of HZ infection. However, these preliminary data obtained in a small number of SLE patients are promising, but not conclusive. Larger studies are needed to confirm these results. Luca Iaccarino