N> a p < 0.05; RR = relative risk; CI = confidence interval. Relative risks with CI that include 1 are not significant.

have been used in the past and are currently used for the treatment of RA. This includes cyclophosphamide, chlorambucil, azathioprine, methotrexate, cyclosporine and others.

Cyclophosphamide had been used for the treatment of RA during the sixties and seventies. In controlled studies [26] of RA patients treated with cyclophosphamide and other DMARDs, a 2.3-fold increased risk for cancer was observed among RA patients treated with cyclophosphamide compared to RA patients receiving other drugs. Bladder, haematopoietic and skin cancer were specifically associated with cyclophosphamide. None of the control patients developed skin or bladder cancers [26].

Similarly, 20% of 39 patients with RA treated with chlorambucil developed cutaneous or lymphoid malignancies. The cancers in the chlorambucil treated patients were multiple and recurrent [58],

In several case studies, RA patients treated with azathioprine or methotrexate were found to develop various lymphoproliferative malignancies including NHL and acute and chronic leukemia [10-12, 32, 33, 37]. Georgescu et al. [31] reviewed 25 cases of lymphoma occurring in RA patients treated with methotrexate. Most of the patients had large B-cell lymphoma. The most striking finding in that series, is the spontaneous appearance of lymphoma in 8 cases shortly after the withdrawal of the treatment with methotrexate, suggesting a causal role for methotrexate in the development of lymphoma in patients with RA.

In a long-term follow-up study [17] of 202 RA patients treated with high doses of azathioprine (300 mg/d), and 202 RA untreated with azathioprine, it was found that compared to the general population the risks for development of lymphoma were 10-fold in the azathioprine treated patients and 5-fold in the nonazathioprine treated RA patients.

In a review paper of all published cohort studies of RA patients who developed lymphomas, the risk for lymphoma compared to the general population was 9.7 among RA patients who received immunosuppressive agents and 2.5 among patients untreated with these drugs [59], However, the role of other factors, including disease severity, genetic factors, disease duration and others, was not included in the analyses. Therefore, it is unclear which proportion of all lymphoproliferative cancers is directly related to the use of cytotoxic drugs. Several studies have suggested that the risk of lymphoproliferative malignancies associated with cytotoxic drugs is likely to be comparatively small [60,61],

Cytotoxic drugs may increase the risk of lymphoproliferative malignancies by several mechanisms including; prolonged immunosuppression, high rate of chronic and latent infection and induction of chromosomal aberrations [62-70].

Cytotoxic drugs were found to reduce the number of cytotoxic lymphocytes and to induce a state of immunosuppression of the cell mediated immune system. Profound immunosuppression may occur in patients treated with cyclophosphamide, chlorambucil and cyclosporine [62], Treatment with a low dose of methotrexate is rarely associated with global immunosuppression [63],

The rate of infections was found to be higher in patients with RA treated with various cytotoxic drugs compared to those who did not received these drugs [64]. The impaired immune surveillance among patients treated with cytotoxic drugs may lead to persistence of viral infections, particularly EBV. Chronic infection with EBV may lead to malignant transformation of B cells and development of lymphoma [65-66],

Cytotoxic drugs may have a direct oncogenic effect. In vitro and in vivo studies have shown that MTX was associated with chromosomal aberrations and cellular morphological transformation [67-70], Treatment with MTX and cyclophosphamide was associated with a dramatic increase of sister chromatid exchanges frequency, which indicate an instability of DNA or a deficiency of DNA repair. The chromosomal aberration were observed in patients taking relatively low doses of MTX or cyclophosphamide. Those aberrations may persist over many years after the chemotherapy [68].

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