**12. Risk of lymphoma in patients treated with anti-TNF drugs**

It is difficult to assess the specific risk of anti-TNF drugs in IBD patients because most patients will have had thiopurine or methotrexate exposure prior to using this modality of treatment. The bulk of the literature regarding anti-TNF drugs is for the use of infliximab in Crohn's disease and little is known regarding differences in safety when used in UC.

A meta-analysis has recently been carried out by Siegel et al with very comprehensive methodology (Siegel et al., 2009). In this meta-analysis, 26 studies with a total of 8905 patients with 21,178 patient-years of exposure to anti-TNF drugs were included (see Table 2). 22 studies were regarding infliximab, 3 regarding adalimumab and only one regarding certolizumab. All the included studies were for the treatment of Crohn's disease through randomised controlled trials, cohort studies and case series. There were 13 cases of NHL with a mean age at presentation of 52 years and 62% male. 10 out of the 13 patients with NHL had received dual therapy with immunomodulators and anti-TNFs. The SIR for the risk of lymphoma in patients treated with anti-TNF drugs was 3.23 (95% CI 1.5 to 6.9) compared to SEER statistics (see Table 3). However, the majority of the lymphoma patients had previously had exposure to immunomodulators and the SIR calculated for anti-TNF therapy should actually be referred to as the risk of combination therapy. This numerical result is in the same order of magnitude as the risk for immunomodulator therapy alone (as calculated by the meta-analysis in this dissertation and other studies). This may suggest that immunomodulator therapy may play the dominant role in lymphoma risk even in settings where combination therapy is used.

of these patients had also received cyclosporin A. As discussed earlier, the authors of this study found risk of lymphoma in their IBD cohort to be much higher than is reported elsewhere and this deviation may have resulted from a clustering of lymphoma diagnosis at the time of investigation. No reliable determination of risk can be obtained from this study. In the large CESAME study, almost 700 patients (4%) had on-going or previous MTX use

Some information can be extrapolated from studies of other inflammatory conditions though this data must be applied with caution in IBD because the risk of the drug cannot be easily separated from the risk of the disease itself. Lymphoma associated with methotrexate

A large observational study of rheumatoid arthritis patients treated with methotrexate and/or anti-TNF drugs followed up 18,572 patients biannually found an SIR of 1.7 (95% CI 0.9 to 3.2). The authors concluded that there was no significant increased risk of lymphoma with methotrexate therapy over baseline (Wolfe and Michaud, 2004). A French 3 year prospective population study of RA patients treated with methotrexate identified 18 cases of NHL and 7 cases of HL. Compared to national population statistics, the authors found no increased risk of NHL but a Standardised Mortality Ratio of 7.4 (95% CI 3.0 to 15.3) for HL

There are no similar studies in IBD and it is not possible to evaluate a relative or absolute risk of lymphoma with methotrexate therapy. However, it would appear that the risk of

It is difficult to assess the specific risk of anti-TNF drugs in IBD patients because most patients will have had thiopurine or methotrexate exposure prior to using this modality of treatment. The bulk of the literature regarding anti-TNF drugs is for the use of infliximab in

A meta-analysis has recently been carried out by Siegel et al with very comprehensive methodology (Siegel et al., 2009). In this meta-analysis, 26 studies with a total of 8905 patients with 21,178 patient-years of exposure to anti-TNF drugs were included (see Table 2). 22 studies were regarding infliximab, 3 regarding adalimumab and only one regarding certolizumab. All the included studies were for the treatment of Crohn's disease through randomised controlled trials, cohort studies and case series. There were 13 cases of NHL with a mean age at presentation of 52 years and 62% male. 10 out of the 13 patients with NHL had received dual therapy with immunomodulators and anti-TNFs. The SIR for the risk of lymphoma in patients treated with anti-TNF drugs was 3.23 (95% CI 1.5 to 6.9) compared to SEER statistics (see Table 3). However, the majority of the lymphoma patients had previously had exposure to immunomodulators and the SIR calculated for anti-TNF therapy should actually be referred to as the risk of combination therapy. This numerical result is in the same order of magnitude as the risk for immunomodulator therapy alone (as calculated by the meta-analysis in this dissertation and other studies). This may suggest that immunomodulator therapy may play the dominant role in lymphoma risk even in settings

Crohn's disease and little is known regarding differences in safety when used in UC.

**12. Risk of lymphoma in patients treated with anti-TNF drugs** 

but no cases of lymphoma were identified in these patients (Beaugerie et al., 2009a).

has been reported in the rheumatology literature.

in their cohort (Mariette et al., 2002).

lymphoma in this patient group is low.

where combination therapy is used.


Table 2. Studies included in meta-analysis By Siegel et al 2009. (ADA adalimumab; CTZ certolizumab, MTX methotrexate, AZA azathioprine, CD Crohn's disease, RCT randomised controlled trial, f/u follow up, OLE open label extension).

Evaluating Lymphoma Risk in Inflammatory Bowel Disease 335

et al., 2008, Tey et al., 2008). Diagnosis is made by liver, splenic or bone marrow biopsy exhibiting atypical medium-sized lymphoid cells with round nuclei, small distinct nucleoli, loosely condensed chromatin, moderate pale cytoplasm and particular immunophenotypic

The aberrant cells infiltrate into the sinusoids of the spleen, liver and bone marrow resulting in the classical presentation of hepatosplenomegaly with thrombocytopenia but no lymphadenopathy. Systemic B symptoms of fever, night sweats and weight loss may affect up to 80% of patients. Other findings may include anaemia, abnormal liver function tests and less frequently atypical lymphocytes on peripheral blood film (Falchook et al., 2009).

The tumour cells express CD2, surface CD3, CD7 and CD16 but there is absence of CD4, CD5, CD8 and the B-cell surface marker CD20 (Swerdlow et al., 2008). Most cases express the γ/δ T-cell receptor (TCR-γ positive) but rarer cases express the α/β T-cell receptor (TCR-

A recent systematic review investigating chromosomal abnormalities in IBD patients diagnosed with HSTCL identified the development of isochrome 7q in 57.1%, aberrations of chromosome 8 in 35.7%, trisomy 8 in 21.4% and loss of the Y chromosome in 14.3 % of cases (Kotlyar et al., 2010). The group were intrigued by the cases with loss of the Y chromosome as almost all cases of HSTCL have presented in men. These chromosomal abnormalities are

HSTCL is not linked to EBV infection. However, the risk of HSTCL does seem to be related to thiopurine and anti-TNF therapy. DNA damage specific to chromosome 7 has been seen in a dose dependent manner with thiopurine agents (Piccin et al., 2010) and inhibition of TNF may result in decreased effectiveness of immune surveillance eliminating cells with

Early concern was regarding a risk of HSTCL in IBD patients who had previous exposure to both thiopurines and anti-TNF drugs but more and more cases have been identified with only thiopurine exposure. Anti-TNF drugs are frequently used in non-IBD conditions, such as rheumatoid arthritis, ankylosing spondylitis and psoriasis, but they are rarely used in combination with other immunomodulators. It is interesting that, HSTCL has only been reported in a single non-IBD patient who received adalimumab for rheumatoid arthritis (Shale et al., 2008). Conversely, there are a number of case reports of patients developing HSTCL whilst on immunosuppression in the post-transplant setting (Roelandt et al., 2009,

Kotlyar et al recently presented a systematic review investigating medications, duration of therapy and ages of IBD patients diagnosed with HSTCL (Kotlyar et al., 2011). 36 cases of HSTCL have occurred in IBD patients since 1996, all of whom had a history of thiopurine exposure. 20 of these patients also had also received anti-TNF therapy. Four patients had

β positive) and studies demonstrate clonal rearrangements of the TCR gene.

expression which will be discussed further (Swerdlow et al., 2008).

**13.2 Immunophenotypic and genetic features** 

aberrant abnormal chromosomal pattern (Shale et al., 2008).

Tey et al., 2008, Steurer et al., 2002) where anti-TNF drugs are not used.

**13.1 Clinical presentation** 

not specific to IBD patients.

**13.3 HSTCL in IBD** 


Table 3. Results of meta-analysis by Siegel et al 2009.

The majority of these studies have relatively small numbers of patients, short follow up and were not designed to evaluate efficacy. However, the TREAT registry data includes the largest number of patients and has the longest follow up. The TREAT (Crohn's Therapy, Resource, Evaluation and Assessment Tool) registry is a large prospective, observational, multi-centre, long-term registry of Crohn's disease patients designed to evaluate the safety of infliximab and is a form of post-marketing surveillance. The TREAT registry is hoped to represent *real world* patients without the biases inherent to patients included in trials. No cases of lymphoma were reported in the registry.

The CESAME study data was not included in the meta-analysis by Siegel et al. Beaugerie et al calculated SIRs depending on anti-TNF and thiopurine combination or mono-therapy as well as whether drugs were continued or discontinued (Beaugerie et al., 2009a). These results are presented in Table 4. The results cannot confirm an increased risk of lymphoma in those continuing anti-TNF therapy because the confidence interval crosses 1.0. However, there does appear to be an increased risk when anti-TNF drugs have been used with thiopurines, particularly when combination therapy is continued.


Table 4. SIRs in patients treated with thiopurines and anti-TNF drugs (Beaugerie et al 2009)

### **13. Hepatosplenic T-cell lymphoma**

Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of peripheral non-Hodgkin's lymphoma. In the majority of incidences, it results from a clonal expansion of γ/δ T-cells but α/β T-cell receptors can also be expressed in some cases (Gaulard et al., 1990). Only 100 to 200 cases of HSTCL in the entire medical literature have been reported (Belhadj et al., 2003) but there has been recent concern regarding the safety of thiopurines and anti-TNF therapy, particularly when used in combination, for the management of IBD. To date, 36 cases of HSTCL have been reported in IBD patients (Kotlyar et al., 2011), mostly affecting young men and the prognosis has been invariably fatal. Despite treatment with chemotherapy and stem cell transplantation, median survival is only 11 months (Falchook et al., 2009) but novel treatment strategies have shown some promise in isolated cases (Jaeger et al., 2008, Tey et al., 2008). Diagnosis is made by liver, splenic or bone marrow biopsy exhibiting atypical medium-sized lymphoid cells with round nuclei, small distinct nucleoli, loosely condensed chromatin, moderate pale cytoplasm and particular immunophenotypic expression which will be discussed further (Swerdlow et al., 2008).

### **13.1 Clinical presentation**

334 New Advances in the Basic and Clinical Gastroenterology

Anti-TNF vs SEER 6.1 3.23 1.5 to 6.9 Anti-TNF vs IM alone 6.1 1.7 0.5 to 7.1

The majority of these studies have relatively small numbers of patients, short follow up and were not designed to evaluate efficacy. However, the TREAT registry data includes the largest number of patients and has the longest follow up. The TREAT (Crohn's Therapy, Resource, Evaluation and Assessment Tool) registry is a large prospective, observational, multi-centre, long-term registry of Crohn's disease patients designed to evaluate the safety of infliximab and is a form of post-marketing surveillance. The TREAT registry is hoped to represent *real world* patients without the biases inherent to patients included in trials. No

The CESAME study data was not included in the meta-analysis by Siegel et al. Beaugerie et al calculated SIRs depending on anti-TNF and thiopurine combination or mono-therapy as well as whether drugs were continued or discontinued (Beaugerie et al., 2009a). These results are presented in Table 4. The results cannot confirm an increased risk of lymphoma in those continuing anti-TNF therapy because the confidence interval crosses 1.0. However, there does appear to be an increased risk when anti-TNF drugs have been used with

Continuing anti-TNF therapy 2 4.53 0.55 to 16.4 Discontinued anti-TNF therapy 3 6.92 1.43 to 20.2 Continuing thiopurines and anti-TNF therapy 2 10.2 1.24 to 36.9 Continuing thiopurines but discontinued or never anti-TNFs 13 6.53 3.48 to 11.2 Table 4. SIRs in patients treated with thiopurines and anti-TNF drugs (Beaugerie et al 2009)

Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of peripheral non-Hodgkin's lymphoma. In the majority of incidences, it results from a clonal expansion of γ/δ T-cells but α/β T-cell receptors can also be expressed in some cases (Gaulard et al., 1990). Only 100 to 200 cases of HSTCL in the entire medical literature have been reported (Belhadj et al., 2003) but there has been recent concern regarding the safety of thiopurines and anti-TNF therapy, particularly when used in combination, for the management of IBD. To date, 36 cases of HSTCL have been reported in IBD patients (Kotlyar et al., 2011), mostly affecting young men and the prognosis has been invariably fatal. Despite treatment with chemotherapy and stem cell transplantation, median survival is only 11 months (Falchook et al., 2009) but novel treatment strategies have shown some promise in isolated cases (Jaeger

SEER (all ages) 1.9 IM alone 3.6

Table 3. Results of meta-analysis by Siegel et al 2009.

cases of lymphoma were reported in the registry.

**13. Hepatosplenic T-cell lymphoma** 

thiopurines, particularly when combination therapy is continued.

**NHL rate per 10,000 patient-years SIR 95% CI** 

**NHL cases** 

**SIR 95% CI** 

The aberrant cells infiltrate into the sinusoids of the spleen, liver and bone marrow resulting in the classical presentation of hepatosplenomegaly with thrombocytopenia but no lymphadenopathy. Systemic B symptoms of fever, night sweats and weight loss may affect up to 80% of patients. Other findings may include anaemia, abnormal liver function tests and less frequently atypical lymphocytes on peripheral blood film (Falchook et al., 2009).
