For several decades, it has been known that patients with rheumatoid arthritis (RA) have an increased risk of developing malignant lymphoma (1–5). The reason for this association is still incompletely understood, but immunosuppressive therapy in RA (6–10) as well as Epstein-Barr virus (EBV) infection may play a role in the development of these lymphomas (11–15). Additionally, both we (16) and others (17) have reported that high RA disease activity in itself may be associated with an increased lymphoma risk. For further studies of the mechanisms of lymphoma development in RA patients, and to understand whether immunosuppression, immunostimulation, or both contribute to lymphoma development in RA, there is a need for more information about the characteristics of these lymphomas.
As a consequence of the present widespread use of disease-modifying antirheumatic drugs (DMARDs) in RA patients, most data concerning lymphoma features in RA patients are derived from studies and case reports in which patients were treated with different immunosuppressive drugs (12, 14, 18–26). Information about lymphoma characteristics in RA patients not influenced by immunosuppressive drug treatment is limited. It is thus not clear whether RA patients develop specific subtypes of lymphomas, and, in particular, there is a lack of information about possible associations between clinical features of RA, such as disease severity, and different lymphoma subtypes.
In this study, we investigated lymphoma biopsy samples obtained from individuals in a previously described cohort of RA patients with lymphoma (16). The lymphoma subtypes were classified, and occurrence of EBV was examined by in situ hybridization (ISH). Using this approach, we could take advantage both of detailed data from the patient records of disease characteristics (such as disease activity and drugs received) and of the fact that the lymphomas were diagnosed during the period 1965–1984, an era when aggressive immunosuppressive therapy in RA was still rare.
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- PATIENTS AND METHODS
One of the original 42 patients was excluded for not fulfilling the ACR criteria for RA. This patient had primary Sjögren's syndrome. Another 6 patients were excluded, 5 because their lymphoma tissues either could not be located or were of too poor quality for a reliable review, and 1 because the diagnosis of lymphoma could not be confirmed.
Thus, the study finally included 35 reviewed cases of patients with RA and lymphoma. The clinical data are summarized in Table 2. One of the patients had secondary Sjögren's syndrome. Tissue samples from 5 of the 35 patients could not be examined for EBV due to a shortage of lymphoma tissue.
Table 2. Clinical data of 35 reviewed cases of patients with rheumatoid arthritis (RA) and lymphoma
|Sex, no. of men/no. of women||18/17|
|Age at RA onset, mean (range) years||54 (30–80)|
|Age at lymphoma diagnosis, mean (range) years||70 (49–89)|
|RA disease activity, no. low/medium/high*||2/14/19|
There were no notable differences in sex, age at onset of RA or at diagnosis of lymphoma, RA disease activity, and treatment for RA between patients whose cases were reviewed and those whose cases were not reviewed. Of the 35 lymphomas, 2 were HLs and 33 were non-HLs (NHLs). Among patients with NHL, there was a predominance of diffuse large B cell lymphoma (DLBCL), diagnosed in 22 of the 33 patients (67%). Five of the remaining 11 patients with NHL were diagnosed as having hepatosplenic T cell lymphoma (n = 1), follicular lymphoma (n = 2), lymphoplasmacytic lymphoma (n = 1), or Burkitt's lymphoma (n = 1). In 6 cases of NHL, it was not possible to make an exact diagnosis according to the WHO classification due to insufficient quality of the material. However, 3 of these were diagnosed as high-grade NHLs, either B cell lymphoma (n = 1) or unspecified NHL (n = 2), whereas the other 3 included 1 unspecified B cell lymphoma, 1 unspecified low-grade NHL, and 1 unspecified NHL (Table 3).
Table 3. Distribution of lymphoma subtypes in 35 reviewed cases of patients with rheumatoid arthritis and lymphoma and results of in situ hybridization for Epstein-Barr virus (EBV) in 30 lymphomas from these patients
|Lymphoma subtype, WHO classification*||All lymphomas (n = 35)||Lymphomas examined for EBV (n = 30)||EBV-positive lymphomas (n = 5)|
|Mature B cell neoplasms|| || || |
| Diffuse large B cell lymphoma||22||22||4|
| Follicular lymphoma||2||2||0|
| Lymphoplasmacytic lymphoma||1||1||1|
| Burkitt's lymphoma||1||1||0|
| Unspecified high-grade B cell lymphoma†||1||1||0|
| Unspecified B cell lymphoma†||1||0||–|
|Mature T cell and NK cell neoplasms|| || || |
| Hepatosplenic T cell lymphoma||1||0||–|
|Hodgkin's lymphoma|| || || |
| Classic Hodgkin's lymphoma, nodular sclerosis||2||1||0|
|Unspecified lymphomas|| || || |
| Unspecified high-grade NHL†||2||0||–|
| Unspecified low-grade NHL†||1||1||0|
| Unspecified NHL†||1||1||0|
Compared with the initial diagnosis of lymphoma (according to the Willis classification from 1948 , the Rappaport classification from 1966 , and the Kiel classification from 1974 ), 21 of the 35 cases (60%) had a diagnosis, after review, that was in accordance with, or not excluding, the initial one. The most frequent discrepancy was an initial diagnosis of Hodgkin's disease (HD) changing to a diagnosis of DLBCL after review in 9 of 14 changed diagnoses. This overdiagnosis of HD in earlier periods has been described previously (33).
EBV, searched for by ISH in 30 of the lymphomas, was detected in 4 of the 22 patients with DLBCL and in the patient with a lymphoplasmacytic lymphoma (Table 3). Of the 22 patients with DLBCL, 20 had RA characterized by high (n = 12) or medium (n = 8) inflammatory activity. Four of the 5 EBV-positive cases occurred in patients with high inflammatory activity (Table 4). In addition, these 4 patients had been treated with DMARDs (patient 1, sulfasalazine for 9 months; patient 2, intramuscular [IM] gold for 3 months and antimalarials for 2 years; patient 3, antimalarials for 10 months; and patient 4, antimalarials for 2 years, penicillamine for 1 year, and Prorecid [a drug containing podophyllotoxin which was used particularly in the Nordic countries during this time period] for 1 year until lymphoma diagnosis; in patients 1, 2, and 3, DMARD therapy preceded lymphoma diagnosis by 3, 10, and 15 years, respectively).
Table 4. Rheumatoid arthritis (RA) disease activity, lymphoma subtype, and EBV in 35 RA patients with lymphoma*
|RA disease activity/no. (%) of patients||Lymphomas, no./subtype||No. of EBV-positive lymphomas†|
|High/19 (54)||12/diffuse large B cell lymphoma||4|
| ||1/follicular lymphoma|| |
| ||1/unspecified high-grade B cell lymphoma|| |
| ||1/unspecified B cell lymphoma|| |
| ||1/unspecified high-grade NHL|| |
| ||1/unspecified low-grade NHL|| |
| ||1/unspecified NHL|| |
| ||1/Hodgkin's lymphoma|| |
|Medium/14 (40)||8/diffuse large B cell lymphoma|| |
| ||1/follicular lymphoma|| |
| ||1/lymphoplasmacytic lymphoma||1|
| ||1/Burkitt's lymphoma|| |
| ||1/hepatosplenic T cell lymphoma|| |
| ||1/unspecified high-grade NHL|| |
| ||1/Hodgkin's lymphoma|| |
|Low/2 (6)||2/diffuse large B cell lymphoma|| |
At the time the lymphoma was diagnosed, a majority of the 35 patients with lymphoma (54%) had a disseminated disease with both nodal and extranodal involvement. According to the Ann Arbor classification system (34), 23 of the patients (66%) had generalized stage IV disease (Table 5). In the 7 patients with extranodal involvement only, the lymphoma was localized in the colon/rectum (2 patients), palate/jawbone (2 patients), and bone marrow, skin, and stomach (1 patient each). The extranodal sites in the patients with both nodal and extranodal involvement were the bone marrow and liver (6 patients each), the lung (5 patients), the skin (4 patients), the spleen (3 patients), the kidney and bone (2 patients each), and the pancreas and pharynx/tongue (1 patient each). Ten of the patients had involvement of more than one extranodal site. The patient with a verified diagnosis of secondary Sjögren's syndrome had a generalized DLBCL that did not affect the salivary glands or mucosal tissue. The median survival time of the 22 patients with DLBCL was short (6 months from diagnosis [range 2 weeks–13 years]) compared with the median survival time of the remaining 13 patients (27 months [range 3 weeks–13 years]).
Table 5. Characteristics of the 35 reviewed lymphomas
| ||Patients, no. (%)|
|Nodal involvement only||9 (26)|
|Extranodal involvement only||7 (20)|
|Both nodal and extranodal involvement||19 (54)|
|Ann Arbor stage*|
| I||1 (3)|
| IE||1 (3)|
| II||4 (11)|
| IIE||2 (6)|
| III||4 (11)|
| IIIE||0 (0)|
| IV||23 (66)|
Of all 35 lymphoma patients, 17 had never received DMARD therapy. The DMARDs used in the treated patients included antimalarials (n = 13), D-penicillamine (n = 2), IM gold (n = 9), sulfasalazine (n = 1), and Prorecid (n = 2). (Note that one patient could have been treated with more than one drug; 5 patients had received 2 DMARDs, 2 patients had received 3 DMARDs, and 11 patients had received 1 DMARD each.) The duration of treatment with DMARDs was often short, and only 8 patients had been treated with a DMARD for ≥1 year during the entire RA disease period before the lymphoma diagnosis was made (median time of treatment 5 years, range 27 months–10 years). These 8 patients also had RA with high disease activity, and all continued to have active disease in spite of therapy.
When we divided the patients into groups according to treatment with DMARDs (never treated [n = 17], treated <1 year [n = 10], and treated ≥1 year [n = 8]), the different lymphoma subtypes were distributed in a similar way into the different categories (Table 6). The 2 patients with follicular lymphoma had never received DMARD therapy. Of the 2 patients with HL, 1 was never treated with DMARDs and 1 had been treated with antimalarials for 10 years. The only patient with a T cell lymphoma had been treated with antimalarials for 3 months.
Table 6. Disease-modifying antirheumatic drug (DMARD) treatment, lymphoma subtypes, rheumatoid arthritis (RA) disease activity, and EBV in 35 RA patients with lymphoma*
|DMARD therapy/no. (%) of patients||Lymphomas, no./subtype||RA disease activity||No. of EBV-positive lymphomas†|
|Never/17 (49)||8/diffuse large B cell lymphoma||Low (n = 2), medium (n = 5), high (n = 1)|| |
| ||2/follicular lymphoma||Medium (n = 1), high (n = 1)|| |
| ||2/unspecified high-grade NHL||Medium (n = 1), high (n = 1)|| |
| ||1/unspecified B cell lymphoma||High|| |
| ||1/Burkitt's lymphoma||Medium|| |
| ||1/unspecified low-grade NHL||High|| |
| ||1/lymphoplasmacytic lymphoma||Medium||1|
| ||1/Hodgkin's lymphoma||Medium|| |
|<1 year/10 (29)‡||8/diffuse large B cell lymphoma||Medium (n = 3), high (n = 5)||2|
| ||1/hepatosplenic T cell lymphoma||Medium|| |
| ||1/unspecified NHL||High|| |
|≥1 year/8 (23)§||6/diffuse large B cell lymphoma||High (n = 6)||2|
| ||1/high-grade B cell lymphoma||High|| |
| ||1/Hodgkin's lymphoma||High|| |
At the time of diagnosis of the lymphoma, only 2 patients were receiving DMARD therapy, and both were taking Prorecid. These patients had a diagnosis of DLBCL and RA with longstanding high disease activity. One of them was EBV positive. Treatment with Prorecid was stopped at diagnosis of lymphoma, and chemotherapy for the lymphoma was started immediately in both cases; it cannot be evaluated whether withdrawal of Prorecid led to any regression of the lymphoma. Oral steroids had been used by 10 patients (by 4 of these patients for >1 year), and there was no obvious relationship between steroid treatment and lymphoma subtype. Most patients had been treated with nonsteroidal antiinflammatory drugs (n = 32) or aspirin (n = 32), often in combination and for periods exceeding 10 years. No correlation with a specific lymphoma subtype was evident.
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- PATIENTS AND METHODS
The main finding of this study of lymphomas in RA patients who had not been treated with methotrexate and who had had no treatment, or only short-term treatment, with other DMARDs was the striking predominance of one specific lymphoma subtype, DLBCL. In the general population, ∼30–40% of NHLs are DLBCLs (35), compared with 67% in this study. When considering the increasing incidence of DLBCL with time (28, 36), and therefore the lower background risk for DLBCL at the time of our study (1964–1984) (33), we estimate that our data may correspond to a 2–3-fold increase in DLBCL incidence in these patients. To our knowledge, a predominance of one lymphoma subtype, not associated with a specific DMARD treatment, has not previously been described in RA patients.
Interestingly, in patients with primary Sjögren's syndrome, the other rheumatic disease with a well-described increased risk of lymphoma (37), another lymphoma subtype predominates. In patients with Sjögren's syndrome, extranodal marginal-zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) is the most common lymphoma, often located in salivary glands and associated with a good prognosis (38). None of the RA patients in our study, including the patient with secondary Sjögren's syndrome, had a MALT lymphoma, and although 11 of the patients had mucosal involvement, none had lymphoma localized in the salivary glands. This indicates different mechanisms underlying lymphoma development in RA and Sjögren's syndrome patients.
The main known risk factor for DLBCL is an underlying immunodeficiency, and in patients with primary immune disorders as well as in patients infected by human immunodeficiency virus and in posttransplant patients, the incidence of DLBCL is increased (39). It is therefore of particular interest that the RA patients in this study had not had strong exposure to immunosuppressive therapy. Instead, many of them had an untreated, longstanding, active and destructive RA disease associated with a persistent stimulation of the immune system rather than with a state of immunosuppression. An interesting possible explanation, and one that supports the notion of a role for inflammatory activity in the development of lymphomas, was found in a study by Wahl et al (40) and subsequently confirmed by many groups, including our own (41). In these studies, it has been shown that apart from being associated with a stimulation of certain immune functions, RA may also cause suppression of other functions. An impaired T cell function, as reported in patients with active RA in the studies by Wahl et al and others, could be relevant to an impairment of immune responses toward EBV as well as against emerging malignant B cells.
The presence of EBV in the lymphomas is also one of the features of lymphomas in immunosuppressed patients (39). In our patients, EBV was detected by ISH in the lymphomas of 5 of 30 patients (17%). EBV was slightly more frequent in our patients than in the general population, but still not as frequent as in immunosuppressed patients; for example, in posttransplant patients, the majority (50–80%) of the lymphomas are EBV positive (28, 39). In RA patients treated with methotrexate, studies have shown varying results. EBV has been detected in 16–44% of lymphomas (14, 15, 26), and, as in the present study, a role for EBV in lymphoma development cannot be ruled out.
Four of the 5 EBV-positive cases occurred in patients with high inflammatory activity, which raises the question of whether there is an association between inflammation and EBV. No conclusions can be drawn from this low number of EBV-positive patients, and, as pointed out, these 4 patients had also been treated with DMARDs, the importance of which is impossible to estimate. Nonetheless, we believe that the immunosuppressive impact of the treatment is likely to have been small in the 3 patients treated with antimalarials, IM gold, or sulfasalazine for relatively short periods and years apart from the diagnosis of the lymphoma. For the patient with ongoing DMARD therapy (Prorecid) at the time of the lymphoma diagnosis, a drug-induced immunosuppression is possible. The remaining EBV-positive patient with a lymphoplasmacytic lymphoma and medium inflammatory RA activity had never been treated with DMARDs. For the evaluation of a relationship between EBV infection and inflammatory activity, we suggest inclusion of information about RA disease severity and inflammatory activity, as well as about RA treatment and EBV findings, in future studies of lymphomas in RA patients.
We used the Swedish Hospital Discharge Register and the Swedish Cancer Register to identify a population-based cohort of RA patients. The reporting to these nationwide registers is mandatory, and quality evaluations have confirmed high reporting rates of ≥95% (42). We therefore estimate that the present study covers virtually all patients discharged from a hospital with a diagnosis of RA and a subsequent lymphoma diagnosis in this region of Sweden.
This approach to studying RA patients, who have been hospitalized at some point, may of course bring a selection bias toward more severe cases. To increase the identification of RA patients with variable indications for hospital care and not only those treated for severe RA, patients with RA as both the main and secondary diagnoses were included. Data from another study (43) indicate that this approach incorporates ∼75% of all RA patients in a particular referral area. From the results of the present study, it is clear that the lymphoma cases represent a subgroup of RA patients with severe disease, however, and that this must be considered when addressing lymphomas among RA patients in general.
In spite of the retrospective approach, medical records of all patients were obtained, and it was possible to compile data about treatment and disease characteristics. The fulfillment of the 1987 ACR criteria for RA could be investigated in all cases, and only 1 patient was excluded due to incorrect diagnosis. We faced more difficulties in finding all lymphoma tissues, and age had also influenced the quality of the lymphoma material in some cases. This led to the exclusion of 6 of the cases and to problems with applying the WHO classification in another 6 cases. Still, 35 of 41 cases (85%) could be reclassified. The excluded cases did not differ in clinical characteristics from those that were reviewed. The lymphomas in the excluded patients were highly malignant, and the patients had short durations of survival after diagnosis. We therefore have no reason to believe that inclusion of the missing cases would have altered the main results.
When discussing and comparing data about lymphoma subtypes, one must also be aware that the lymphoma classification systems have been modified several times during the past decades, and that the classification of lymphomas has been inconsistent between different countries. The worldwide consensus classification (the WHO classification of tumors of hematopoietic and lymphoid tissues, which was used in this study) was first introduced in 2001. The rather low concordance between the initial diagnosis and the WHO diagnosis after review is not surprising. Many of the lymphoma entities in the WHO classification were not recognized in earlier classification systems.
In two smaller studies of case series from hospitals, the reported findings were similar to those in the present study. Thus, an increase in DLBCL was reported in the study by Kamel et al of lymphomas in 15 RA patients (11), and the recent study by Dawson et al in 19 RA patients with lymphoma revealed similar results (15). In both studies, most patients were treated with methotrexate or other immunosuppressive drugs, and the increased frequency of DLBCL as well as the high number of EBV-positive lymphomas were suspected to be related to the immunosuppressive therapy. Unfortunately, reports from both studies lack information about the severity of the RA disease.
There is only one reasonably large study of arthritis-associated lymphomas in which lymphoma subtypes have been investigated, and that study, using a case–control approach, yielded somewhat different results. In that study, 42 patients with arthritis and lymphomas were identified from the general population (44), and occurrence of DLBCL was reported in 38% of the patients. No difference in lymphoma subtypes between patients with and those without RA was evident. However, the study had factors of uncertainty. Arthritis was self reported, with RA diagnosis confirmed by the treating physician in only 11 of 42 patients, and no data were available describing RA disease status.
In conclusion, the present study provides data indicating that high and longstanding inflammatory activity in RA may by itself contribute to the development of lymphomas which are preferentially of the aggressive, diffuse, large B cell type with a poor prognosis. Since the time period of the study was chosen to encompass an era during which immunosuppressive therapy was rare, we cannot draw any conclusions about the impact of today's more aggressive treatment in RA. However, we believe that data describing the lymphoma risk and lymphoma characteristics, in a situation with a limited influence of immunosuppressive drugs, should help us in the difficult task of determining the relative roles of disease activity and drug treatment in the present day, in which RA is treated aggressively with DMARDs as well as with new targeted therapies such as tumor necrosis factor–blocking agents.