**8. Baseline risk of lymphoma in IBD**

An estimate of the baseline lymphoma risk has been made for this chapter using a metaanalysis technique. Populations and cohort studies were identified using the MEDLINE database provided by the US National Library of Medicine (NLM). Statistical analysis was carried out using the Review Manager (RevMan) Version 5 software which is provided by The Cochrane Collaboration, Copenhagen, for preparing and maintaining Cochrane reviews and meta-analyses. Dichotomous data was entered and analysed using the Mantel-Haentszel statistical technique and a 95% confidence interval assuming a Poisson distribution of lymphoma incidence. Studies were only weighted by their size. Graphical representation of results is performed with a Forest plot indicating 95% confidence intervals.

A total of 145,208 patients from 16 trials were included in the meta-analysis (see Figure 4). This produced a cumulative Risk Ratio of 1.29 (95% CI of 1.10 to 1.51, p=0.002). However, this included hospital-based and specialist clinic cohorts which can introduce selection bias. The meta-analysis was repeated only including the 12 population-based studies (see Figure 5). 133,463 patients were included. This did not have a very large effect on the results and the Risk Ratio falls slightly to 1.23 (95% CI 1.05 to 1.45, p=0.01). In both analyses, the test for heterogeneity was not significant and the test for overall effect was 3.15 and 2.52 respectively.


Fig. 4. Meta-analysis of population and cohort studies to evaluate the baseline risk of lymphoma.

Evaluating Lymphoma Risk in Inflammatory Bowel Disease 331

Meta-analytical techniques were used to quantify the risk of intestinal, extra-intestinal and haemopoietic malignancies in Crohn's patients. 34 studies were included with a total of 61,122 patients. Overall pooled estimates were obtained using a random-effects model. The relative risk of lymphoma was 1.42 (95% CI 1.16 to 1.73). This publication, similar to the meta-analysis presented in this dissertation, suggests only a slight increased baseline risk of

**Increased Risk of Lymphoma among Inflammatory Bowel Disease Patients Treated with** 

This meta-analysis sought to provide an estimate of the relative risk of lymphoma among IBD patients treated with thiopurine therapy. Inclusion criteria were strict with only cohort studies in the English language, where the exposed group had received AZA or 6MP and the study had been specifically designed to evaluate the risk of cancer. 6 studies were included with a total of 3891 IBD patients. Similar methodology was used to the presented meta-analysis in this dissertation. Results were also pooled using a Mantzel-Haenszel method but weighting

The pooled data identified 11 cases of lymphoma whilst the expected number of cases was 2.63, resulting in an SIR of 4.18 (95% CI 2.07 to 7.51). This is similar in magnitude to the SIR in the meta-analysis presented here at 3.54. However, Kandiel et al found a significant test of heterogeneity explained by the substantially higher rates of lymphoma in two of the included studies (Farrell et al 2000 and Connell et al 1994). Exclusion of these studies did not

**Meta-Analysis of Risk of Malignancy with Immunosuppressive Drugs in Inflammatory** 

This group aimed to compare the risks of developing malignancy in IBD patients receiving immunosuppressants with those who were not. 9 cohort studies met the inclusion criteria. Where a control group for comparison was not available in these studies, Masunaga et al compared incidence of lymphoma with that of the University of Manitoba IBD Database used by Bernstein et al in their population study. The meta-analysis technique calculated a Weighted Mean Difference (WMD) rather than SIR at 0.0 (95% CI -0.8 to 0.7). These results were not significant and the authors concluded that there was no increased risk of lymphoma in IBD patients treated with immunosuppressives. This result seems to deviate from the findings of the larger recent population studies (such as the CESAME study), that of the meta-analysis performed by Kandiel et al and the meta-analysis presented in this dissertation. This may be due to bias introduced by the arbitrary control method used to calculate expected lymphoma rates in control groups in this meta-analysis. (Masunaga et al.,

There is virtually no data for the risk of lymphoma in IBD patients taking methotrexate. Only 2 cases of lymphoma associated with MTX treatment for inflammatory bowel disease have been reported in the literature (Farrell et al., 2000). In this study, 31 patients were receiving methotrexate and two of them were subsequently diagnosed with lymphoma. One

**The Risk of Cancer in Patients with Crohn's Disease (Von Roon et al 2007)** 

lymphoma compared to the general population. (von Roon et al., 2007)

was proportioned to the inverse variance rather than the population size.

produce a large impact on the pooled SIR. (Kandiel et al., 2005)

**11. Risk of lymphoma in patients treated with methotrexate** 

**Bowel Disease (Masunaga et al 2007)** 

2007)

**Azathioprine and 6-Mercaptopurine (Kandiel et al 2005)** 


Fig. 5. Meta-analysis of population studies only to evaluate risk of lymphoma.

These findings would suggest that there is only a small (if any) increased risk of lymphoma in IBD patients compared to the general population.

#### **9. Risk of lymphoma with thiopurines**

The risk of lymphoma in patients treated with thiopurines has been analysed by including all cohort and population-based studies (see Figure 6). There were 35805 patients included from 7 studies. The test for heterogeneity was not significant and the test for overall effect was 4.03. Overall Risk Ratio is calculated at 3.54 (95% CI 1.91 to 6.54, p<0.0001) confirming the suspected increased risk of lymphoma in patients treated with azathioprine or mercaptopurine.


Fig. 6. Meta-analysis to evaluate the risk of lymphoma in patients treated with thiopurines.

#### **10. Comparison to other published meta-analyses**

Only three meta-analyses have investigated the background risk and the thiopurineassociated risk of lymphoma in IBD patients. Results from Von Roon et al and Kandiel et al support the findings of the meta-analyses produced here but the work by Masunaga et al shows some disparity.

Fig. 5. Meta-analysis of population studies only to evaluate risk of lymphoma.

in IBD patients compared to the general population.

**9. Risk of lymphoma with thiopurines** 

mercaptopurine.

shows some disparity.

These findings would suggest that there is only a small (if any) increased risk of lymphoma

The risk of lymphoma in patients treated with thiopurines has been analysed by including all cohort and population-based studies (see Figure 6). There were 35805 patients included from 7 studies. The test for heterogeneity was not significant and the test for overall effect was 4.03. Overall Risk Ratio is calculated at 3.54 (95% CI 1.91 to 6.54, p<0.0001) confirming the suspected increased risk of lymphoma in patients treated with azathioprine or

Fig. 6. Meta-analysis to evaluate the risk of lymphoma in patients treated with thiopurines.

Only three meta-analyses have investigated the background risk and the thiopurineassociated risk of lymphoma in IBD patients. Results from Von Roon et al and Kandiel et al support the findings of the meta-analyses produced here but the work by Masunaga et al

**10. Comparison to other published meta-analyses** 

#### **The Risk of Cancer in Patients with Crohn's Disease (Von Roon et al 2007)**

Meta-analytical techniques were used to quantify the risk of intestinal, extra-intestinal and haemopoietic malignancies in Crohn's patients. 34 studies were included with a total of 61,122 patients. Overall pooled estimates were obtained using a random-effects model. The relative risk of lymphoma was 1.42 (95% CI 1.16 to 1.73). This publication, similar to the meta-analysis presented in this dissertation, suggests only a slight increased baseline risk of lymphoma compared to the general population. (von Roon et al., 2007)

#### **Increased Risk of Lymphoma among Inflammatory Bowel Disease Patients Treated with Azathioprine and 6-Mercaptopurine (Kandiel et al 2005)**

This meta-analysis sought to provide an estimate of the relative risk of lymphoma among IBD patients treated with thiopurine therapy. Inclusion criteria were strict with only cohort studies in the English language, where the exposed group had received AZA or 6MP and the study had been specifically designed to evaluate the risk of cancer. 6 studies were included with a total of 3891 IBD patients. Similar methodology was used to the presented meta-analysis in this dissertation. Results were also pooled using a Mantzel-Haenszel method but weighting was proportioned to the inverse variance rather than the population size.

The pooled data identified 11 cases of lymphoma whilst the expected number of cases was 2.63, resulting in an SIR of 4.18 (95% CI 2.07 to 7.51). This is similar in magnitude to the SIR in the meta-analysis presented here at 3.54. However, Kandiel et al found a significant test of heterogeneity explained by the substantially higher rates of lymphoma in two of the included studies (Farrell et al 2000 and Connell et al 1994). Exclusion of these studies did not produce a large impact on the pooled SIR. (Kandiel et al., 2005)

#### **Meta-Analysis of Risk of Malignancy with Immunosuppressive Drugs in Inflammatory Bowel Disease (Masunaga et al 2007)**

This group aimed to compare the risks of developing malignancy in IBD patients receiving immunosuppressants with those who were not. 9 cohort studies met the inclusion criteria. Where a control group for comparison was not available in these studies, Masunaga et al compared incidence of lymphoma with that of the University of Manitoba IBD Database used by Bernstein et al in their population study. The meta-analysis technique calculated a Weighted Mean Difference (WMD) rather than SIR at 0.0 (95% CI -0.8 to 0.7). These results were not significant and the authors concluded that there was no increased risk of lymphoma in IBD patients treated with immunosuppressives. This result seems to deviate from the findings of the larger recent population studies (such as the CESAME study), that of the meta-analysis performed by Kandiel et al and the meta-analysis presented in this dissertation. This may be due to bias introduced by the arbitrary control method used to calculate expected lymphoma rates in control groups in this meta-analysis. (Masunaga et al., 2007)

#### **11. Risk of lymphoma in patients treated with methotrexate**

There is virtually no data for the risk of lymphoma in IBD patients taking methotrexate. Only 2 cases of lymphoma associated with MTX treatment for inflammatory bowel disease have been reported in the literature (Farrell et al., 2000). In this study, 31 patients were receiving methotrexate and two of them were subsequently diagnosed with lymphoma. One

Evaluating Lymphoma Risk in Inflammatory Bowel Disease 333

Colombel et al 2007 PRECISE RCT CTZ 905 53 0 Colombel et al 2007 OLE of GAIN and CHARM ADA 1169 58 0 Sandborn et al 2007 CLASSIC II RCT ADA 276 56 1 Lemann et al 2006 RCT IXB + AZA IXB 57 52 0

Mantzaris et al 2004 RCT IXB + AZA IXB 45 60 0 Sands et al 2004 IXB for fistulising CD IXB 282 54 0 Hanauer et al 2002 ACCENT I IXB 573 54 1 Rutgeerts et al 1999 RCT IXB 73 48 6

al 2007 TREAT registry IXB 3396 201 0

Biancome et al 2006 Matched pair study IXB 404 109 1 Doumit et al 2004 Cohort study IXB 322 104 0 Carbone et al 2007 Case series IXB 34 52 0

Hyder et al 2006 Case series for fistulising CD IXB 22 91 0 Pacault et al 2006 Case series IXB 137 150 0 Talbot et al 2005 Case series for perianal CD IXB 21 87 0 Choi et al 2005 Case series from Korea IXB 13 57 0

al 2004 Case series for perianal CD IXB 20 67 0

Rodrigo et al 2004 Case series for fistulising CD IXB 44 72 0

Sciderer et al 2004 Cohort study IXB 92 113 0 Ljung et al 2003 Population-based cohort IXB 191 52 3 Kinney et al 2003 Case series IXB 117 52 0 Cohen et al 2000 Case series IXB 129 52 0

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

IXB + MTX IXB 19 48 0

ADA ADA 52 52 0

Clinic IXB 500 74 1

fistulising CD IXB 12 57.6 0

**Median f/u (weeks)** 

**NHL cases** 

**Study Year Setting Drug N** 

Schroder et al 2006 Controlled pilot study of

Biroulet et al 2007 Case series for switch to

Colombel et al 2004 Case series from Mayo

Schroder et al 2004 Case series IXBMTX in

controlled trial, f/u follow up, OLE open label extension).

Lichtenstein et

Peyrin-

Ardizzone et

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

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 has been reported in the rheumatology literature.

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

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 lymphoma in this patient group is low.
