**16. Summary of findings and application to clinical practice**

This systematic review and the meta-analyses carried out in this chapter have made some key findings:


It is the role of the IBD physician to help patients balance up the risks and benefits of these drugs and make the right choice for themselves. Due to the significant morbidity associated with IBD, simply avoiding these drugs is frequently not an option. It is mandatory to provide clear communication of risks and benefits and to individualise this to the patient because lymphoma risk in IBD patients is not uniform nor is the risk of complicated disease. A recent study found that patients were more likely to tolerate the risk of adverse events due to IBD drug therapy for moderately symptomatic Crohn's disease than gastroenterologists would choose for their patients (Johnson et al., 2010).

Patient selection is paramount. The risk of most forms of lymphoma appears to be higher in males and in older age groups. HSTCL is particularly relevant to men under the age of 35 years. Special consideration of the risks must be made in these groups. A number of predictors

Vitamin D deficiency is common amongst IBD patients. Recent studies have shown suboptimal levels of Vitamin D in 57 to 78% of recently diagnosed patients with IBD (Leslie et al., 2008, Bours et al., 2010). The protective role of Vitamin D has been investigated in a number of malignancies including prostate, colon, lung, pancreatic, endometrial, breast and even skin cancer (Schwartz and Skinner, 2007). The paracrine and autocrine effects of extrarenal 25-hydroxy-Vitamin-D3 via the nuclear Vitamin D Receptor (VDR) include regulation of cell cycle proliferation, induction of apoptosis and increased cell differentiation

Recent epidemiologic studies demonstrate a reduction in NHL risk with increased sunlight exposure (Armstrong and Kricker, 2007). As sunlight is a major vitamin D source, it has been suggested that vitamin D status may mediate this observed association. A recent review of the literature could not conclude or dismiss a link between vitamin D insufficiency and lymphoma due to confounding findings in a number of studies and the limitations on the accuracy of dietary history taking which was the most frequent methodology in these

The role of Vitamin D in lymphomagenesis in the IBD population has not been investigated

This systematic review and the meta-analyses carried out in this chapter have made some

 Treatment with anti-TNF drugs appears to confer an increased risk of lymphoma in IBD patients. However, this may reflect previous or concurrent immunomodulator exposure

HSTCL is associated with long term thiopurine therapy. Additionally, anti-TNF therapy

It is the role of the IBD physician to help patients balance up the risks and benefits of these drugs and make the right choice for themselves. Due to the significant morbidity associated with IBD, simply avoiding these drugs is frequently not an option. It is mandatory to provide clear communication of risks and benefits and to individualise this to the patient because lymphoma risk in IBD patients is not uniform nor is the risk of complicated disease. A recent study found that patients were more likely to tolerate the risk of adverse events due to IBD drug therapy for moderately symptomatic Crohn's disease than

Patient selection is paramount. The risk of most forms of lymphoma appears to be higher in males and in older age groups. HSTCL is particularly relevant to men under the age of 35 years. Special consideration of the risks must be made in these groups. A number of predictors

 There is only a small (if any) increased overall risk of lymphoma in IBD patients. Thiopurine therapy results in a 3 to 4-fold increased risk of lymphoma in IBD patients. The risk of lymphoma with methotrexate therapy cannot be evaluated adequately but

**16. Summary of findings and application to clinical practice** 

gastroenterologists would choose for their patients (Johnson et al., 2010).

**15.3 Vitamin D and sunlight exposure** 

signalling.

key findings:

studies (Kelly et al., 2009).

and warrants further study.

appears to be low.

may increase this risk.

rather than the risk of anti-TNFs alone.

for severe or complicated disease are now being identified which should allow selection of patients who are most likely to gain from aggressive treatment (Beaugerie et al., 2006).

There is ample evidence that immunomodulators and anti-TNF drugs are very effective for the treatment of IBD. In a 30 year review, Fraser et al found that there were 64% and 87% remission rates at 6 months for patients treated with AZA for Crohn's disease and ulcerative colitis respectively (Fraser et al., 2002). Feagan et al found 65% remission at 40 weeks with MTX for Crohn's disease (Feagan et al., 2000). In the SONIC study, there was 57% remission at 1 year for combined AZA and IXB therapy (Colombel et al., 2010). The CHARM study and its open label extension, ADHERE, for adalimumab in Crohn's disease found improved fistula healing rates, 57% decreased hospitalisation and improved Work Productivity Scores (Panaccione et al., 2010). A Markov model found that the benefits of azathioprine for the treatment of Crohn's disease outweighed the risk of lymphoma but such calculations are inherently based on estimations and assumptions (Lewis et al., 2000).

Additionally, there is evidence that stopping these drugs may be harmful to patients. Azathioprine withdrawal leads to relapse within 18 months at 21% vs 8% (p=0.02, NNH=8) (Lemann et al., 2005). Methotrexate withdrawal leads to relapse within 40 weeks in 61% vs 35% (p=0.04, NNH=4) (Feagan et al., 2000). Infliximab withdrawal leads to hospitalisation within 1 year in 38% vs 23% (p=0.05, NNH=7) (Rutgeerts et al., 2004). However, the CESAME study did suggest that stopping immunomodulator therapy did return the risk of lymphoma back to baseline.

No form of screening is able to predict lymphoma development. Although, the role of vitamin D status and TPMT expression on lymphoma risk is intriguing, there is insufficient evidence to recommend the routine testing of these parameters to guide patient management. Prophylactic use of antivirals in renal transplant recipients has been shown to reduce the risk of post-transplant lymphoproliferative disorders by as much as 83% and the use of this strategy in IBD patients on immunosuppression is warranted (Funch et al., 2005).

The morbidity associated with IBD, the efficacy of these drugs and the risks of stopping them are important factors in making management decisions with patients. In many patients, the benefits will outweigh the risks.
