Gridley et al. [6] Men Women Total

2.38 (1.5-3.6) 1.73 (1.1-2.5) 1.98 (1.5-2.6)

1.79 (1.2-2.9) 1.88 (1.32-2.6)

4.61 (2.1-8.8) 0.95 (0.2-2.8) 2.34 (1.2-4.1)

1.86(1.0-3.1) 0.79 (0.4-1.5) 1.23 (0.8-1.8)

2.34 (1.1-4.4) 0.52(0.1-1.9) 1.43 (0.7-2.6)

1.83(0.8-3.5) 0.8(0.3-1.6) 1.17 (0.7-1.9)


RR = relative risk. CI = confidence intervals. a p < 0.05; relative risks with CI that include 1 are not significant. b Leukemia were not included in the analysis.

risk for all lymphoproliferative cancers to be 10.9 for men and 6.9 for women with RA compared to the general population. Gridley et al. [6] found a 2.6fold increased risk for lymphoproliferative cancers in men with RA, however, no increased risk for lymphoproliferative cancer was identified among women with RA in the same study. A 8.05-fold increased risk for lymphoproliferative malignancies was seen in men with Felty's syndrome [25], suggesting that the risk for malignancies is higher in patients with severe disease.

A literature review has revealed numerous case reports of patients with RA who developed Hodg-kin's (HL) and non-Hodgkin's lymphoma (NHL) [10, 31-33], Lymphomas occurred in patients with mild and severe form of RA. Nodal and extra-nodal cases of lymphomas were reported among patients of RA. Cases of lymphomas localized to the joints and presenting as monoarticular swelling have also been reported [34-35],

Several cases have indicated a link between NHL and treatment with DMARDs [31-38]. Whether lymphoma in patients with RA develops as a result of the disease state, or its treatment with cytotoxic agents, remains controversial. In a review of 20 cases of patients with RA and lymphoma, the mean interval between the development of lymphoma and RA was 13.2 years. No predominance of specific clinical or histological type was noted and none of the patients received cytotoxic drugs in that series [10]. In an another review of methotrexate treated RA patients who developed lymphoma, the interval between the development of lymphoma and RA was only 2.4 years [31]. The role of cytotoxic drugs in the development of lymphoma in patients with RA will be detailed later in this chapter.

Table 2 shows the risk for development of HL, NHL and all lymphomas in patients with RA compared to the general population. In large population-based studies from Scandinavia, compared to the general population the risks for development of NHL in patients with RA were 2.67 in Finland [5], 1.88 in Sweden [6] and 2.4 in Denmark. However, two studies from Saskatchewan, Canada, have failed to identify an increased risk for lymphoma among RA patients [24, 29], On the other hand, a strikingly increased risk for development NHL was seen in male RA patients with Felty's syndrome (observed /expected ratio of 12.7) [25],

The presence of Sjogren's syndrome was found to increase the risk for development of lymphoma. Compared to the general population in Finland the risk for development of NHL was 2.2 for patients with RA, 4.5 for patients with secondary Sjogren's syndrome and 8.7 for patients with primary Sjogren's syndrome [30].

Numerous studies have described patients with RA who developed acute [10] or chronic leukemia [11], including chronic lymphocytic leukemia (CLL) [11], acute nonlymphoblastic leukemia (ANLL) [39], hairy cell leukemia [40] and others [41], Leukemia developed mainly in patients treated with cytotoxic drugs [11] including cyclophosphamide [42], chlorambucil [43], azathioprine [44] and methotrexate [45], However, leukemia were also reported among RA patients who received only gold [46] or penicillamine [47], suggesting that the disease itself increases the risk for the development of leukemia.

Patients with RA may present with primary ANLL, or they may develop ANLL as a result of blast transformation of myelodesplastic syndrome. Out of 6 cases of ANLL in patients with RA and other autoimmune diseases treated with methotrexate, 4 had ANLL with differentiation (M2), 1 had acute myelomonocytic leukemia and another was diagnosed with ANLL M4 associated with Inv 16 [48].

Epidemiological studies (Table 2) have revealed an increased risk for the development of leukemia and CLL only in men with RA [5-7], The risk for the development of leukemia in men with RA was 2.34 in Finland [5], 1.86 in Sweden [6] and 7.6 in patients with Felty's syndrome [25], A 2.34-fold increased risk for CLL was found among men with RA living in Sweden [6] and a 2.4-fold increased risk for the development of ANLL was identified among men with RA living in Denmark [7],

It has been reported that the prevalence of monoclonal paraproteins is increased in patients with RA and their presence is associated with a high rate of B-cell malignant transformation [49]. Out of 23 RA patients with monoclonal band, 5 developed myeloma and 2 developed NHL during a mean follow-up of 4 years [50],

In the large population-based studies, no risk for the development of myeloma was noted in two studies [6, 7], however, a 2.2-fold increased risk for myeloma was found among RA patients living in Finland [5]. Eriksson [51] in a case-control study, matched 275 patients with myeloma to as many con trols, and found myeloma to be associated with both rheumatic diseases in general and RA specifically.

In summary, the data suggest that lymphoprolif-erative disorders are more common in RA patients compared to the general population.

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