Lymphoma in Rheumatoid Arthritis - The Effect of Methotrexate and Anti-Tumor Necrosis Factor Therapy in 18,572 Patients
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ARTHRITIS & RHEUMATISM
Vol. 50, No. 6, June 2004, pp 1740–1751
DOI 10.1002/art.20311
© 2004, American College of Rheumatology
Lymphoma in Rheumatoid Arthritis
The Effect of Methotrexate and Anti–Tumor Necrosis Factor Therapy
in 18,572 Patients
Frederick Wolfe1 and Kaleb Michaud2
Objective. The risk of lymphoma is increased in infliximab (with or without etanercept) was 2.6 (95% CI
patients with rheumatoid arthritis (RA), and spontane- 1.4–4.5). For etanercept, with or without infliximab, the
ous reporting suggests that methotrexate (MTX) and SIR was 3.8 (95% CI 1.9–7.5). The SIR for MTX was 1.7
anti–tumor necrosis factor (anti-TNF) therapy might be (95% CI 0.9–3.2), and was 1.0 (95% CI 0.4–2.5) for those
associated independently with an increased risk of not receiving MTX or biologics. Lymphoma was associ-
lymphoma. However, data from clinical trials and clin- ated with increasing age, male sex, and education.
ical practice do not provide sufficient evidence concern- Conclusion. Lymphomas are increased in RA.
ing these issues because of small sample sizes and Although the SIR is greatest for anti-TNF therapies,
selected study populations. The objective of this study differences between therapies are slight, and confidence
was to determine the rate of and standardized incidence intervals for treatment groups overlap. The increased
ratio (SIR) for lymphoma in patients with RA and in RA lymphoma rates observed with anti-TNF therapy may
patient subsets by treatment group. Additionally, we
reflect channeling bias, whereby patients with the high-
sought to determine predictors of lymphoma in RA.
est risk of lymphoma preferentially receive anti-TNF
Methods. We prospectively studied 18,572 pa-
therapy. Current data are insufficient to establish a
tients with RA who were enrolled in the National Data
causal relationship between RA treatments and the
Bank for Rheumatic Diseases (NDB). Patients were
development of lymphoma.
surveyed biannually, and potential lymphoma cases
received detailed followup. The SEER (Survey, Epide-
During the years 1992–1998, the age-adjusted US
miology, and End Results) cancer data resource was
incidence rate of lymphoma was 18.3 per 100,000 (15.7
used to derive the expected number of cases of lym-
per 100,000 for non-Hodgkin’s lymphoma and 2.6 per
phoma in a cohort that was comparable in age and sex
with the RA cohort. 100,000 for Hodgkin’s lymphoma) (1). These rates in-
Results. The overall SIR for lymphoma was 1.9 crease with age. Between the ages of 60 and 64 years, the
(95% confidence interval [95% CI] 1.3–2.7). The SIR for modal age group for patients with rheumatoid arthritis
biologic use was 2.9 (95% CI 1.7–4.9) and for the use of (RA), the rate of Hodgkin’s lymphoma is 3.1 per 100,000
for both sexes, 4.2 per 100,000 for males, and 2.1 per
100,000 for females; for patients in the same age group
The National Data Bank for Rheumatic Diseases has received
grant support from Amgen, Aventis, Bristol-Myers, Centocor, Merck, with non-Hodgkin’s lymphoma, the respective rates are
Novartis, Pharmacia, Pfizer, Squibb, and Wyeth-Australia. The Inflix- 44.2 per 100,000, 51.5 per 100,000, and 37.7 per 100,000.
imab Safety Registry is supported by grants from Centocor.
1
Frederick Wolfe, MD: National Data Bank for Rheumatic
The risk of lymphoma is increased in patients
Diseases, and University of Kansas School of Medicine, Wichita; with RA in most studies. Following hospitalization for
2
Kaleb Michaud, MS: National Data Bank for Rheumatic Diseases, RA, at a disease duration of 5–15 years the relative risk
Wichita, Kansas.
Address correspondence and reprint requests to Frederick of Hodgkin’s and non-Hodgkin’s lymphoma was 3.9 and
Wolfe, MD, National Data Bank for Rheumatic Diseases, Arthritis 2.3, respectively among 20,699 patients in a Danish
Research Center Foundation, 1035 North Emporia, Suite 230, Wich- registry (2). In a Swedish registry of 11,683 RA patients
ita, KS 67214. E-mail: fwolfe@arthritis-research.org.
Submitted for publication March 15, 2003; accepted in revised who were seen between 1965 and 1983, the standardized
form February 23, 2004. incidence ratio (SIR) was 1.98 (95% confidence interval
1740LYMPHOMA IN RA 1741
[95% CI] 1.5–2.6) (3). The risk ratios (determined by system lacks an adequate denominator, and no associa-
dividing the observed number by the expected number) tion could be drawn between lymphoma and anti-TNF
for lymphoma incidence and mortality in other large therapy. In addition, given the absence of age data, it is
studies included a ratio of 2.7 for incidence reported by not known whether such rates are high or low. Of
Isomaki et al (4), a ratio of 1.9 for mortality reported interest, however, is the FDA report that in a number of
by Allebeck (5), a ratio of 1.2 for incidence reported by cases lymphoma developed shortly after the patient
Katusic et al (6), a ratio of 20.0 for incidence reported started therapy, and that regression of lymphoma oc-
by Prior et al (7), a ratio of 3.5 for mortality reported by curred in 2 patients following discontinuation of therapy.
Laasko et al (8), ratios of 4.1 and 2.2 for rheumatolo- Recently, adalimumab, another anti-TNF agent, was
gists’ patients and all patients, respectively, reported by approved for use in RA (55), and the rates of lymphoma
Tennis et al (9,10), and a ratio of 2.0 for mortality associated with use of this agent were increased com-
reported by Wolfe et al (11). pared with the rates in the general population (56).
Increased rates of lymphoma have been attrib- Among the issues that remain unresolved is
uted to RA severity, based on detailed epidemiologic whether the rate of lymphoma is increased by MTX,
studies (12,13) and Epstein-Barr virus studies (14,15), whether it is increased among patients receiving anti-
although there is some disagreement on this point (16). TNF agents, and whether such increases are related to
However, there has also been a general concern that the anti-TNF agents, the worse clinical status of patients
medications, by altering immune function and immuno- receiving anti-TNF therapy, or a combination of both. In
logic surveillance, might lead to lymphoproliferative addition, a contrary hypothesis—that lymphoma rates
cancer. This concern has been applied to medications might be lower in treated patients—has not been inves-
used in RA, including azathioprine (17–21) and metho- tigated.
trexate (MTX) (22–44). In addition, discontinuation of
MTX has been followed by disappearance of lymphoma
in some patients (reversible lymphoma) (23,25,45,46), PATIENTS AND METHODS
thus providing a temporal link between MTX and lym- Patients in the study were participants in the National
phoma. Nonetheless, some studies have not found in- Data Bank for Rheumatic Diseases (NDB) long-term study of
creased rates of lymphoma in MTX-treated patients the outcomes of RA. Patients were recruited from the prac-
with RA (32,47). There is evidence for a slight increase tices of 908 US rheumatologists, as previously described (57–
59), and are systematically followed up by NDB staff, using
in lymphoma rates among RA patients receiving aza- semiannual questionnaires. The diagnosis of RA was made by
thioprine (18,48), but no epidemiologic studies have the patient’s rheumatologist. Of the 18,572 patients in this
found an increase in lymphoma in MTX-treated patients report, 3,244 were enrolled at the time they started receiving
beyond what is expected in RA (32). Studies of cyclo- leflunomide, and 5,025 were enrolled as part of an infliximab
sporine have also found no increased risk (49). The safety registry. After the initial enrollment assessment, ⬃8% of
patients decline to participate each year. The NDB is an open
result of these studies has been to suggest that RA and cohort, and patients are added continuously. The current study
RA disease activity predispose to lymphoma, but that concerns 18,572 RA patients without previous lymphoma who
treatment may also play a role. Little consideration has completed 70,732 biannual questionnaires during consecutive
been given to the idea that effective treatment, by 6-month assessment periods beginning in January 1999 and
reducing disease activity, might also lower lymphoma ending in June 2002.
For each questionnaire assessment, patients report
rates. demographic and clinical variables (60–70), comorbid condi-
Recent concern about possible treatment effects tions, medications, and side effects of treatment. Patients also
and lymphoma has focused on anti-TNF drugs (50–53) report their cancer status. The identification and validation
because of their profound immunoregulatory effect. process for lymphoma is shown in Figure 1. At the time of
Reports from MedWatch (the postmarket adverse event enrollment into the NDB, patients report current (last 6
months) or past malignancies. They also report current malig-
surveillance system run by the US Food and Drug nancies in each biannual questionnaire they complete. If a
Administration [FDA]) concerning infliximab and etan- questionnaire is missed, patients are required to complete the
ercept led the FDA to estimate that the crude incidence past or “ever” questionnaire again.
rates of lymphoma are 19 per 100,000 patients treated For patients reporting a lymphoma or a description
with etanercept and 6.6 per 100,000 patients treated with suggestive of lymphoma, a validation process is begun (Figure
1). In general, the first contact with the patient is made by a
infliximab (54). Given the average age of patients with telephone call from a trained interviewer using a written
RA, these rates are lower than what might be expected questionnaire. Simple misunderstandings may be identified at
in the general population. However, the MedWatch this point. For example, patients may confuse lipoma with1742 WOLFE AND MICHAUD
Figure 1. Validation process for reports of lymphoma.
lymphoma or misidentify metastatic cancer with lymph node report, a total of 1,514 deaths (from all sources) was known to
involvement as lymphoma. The interviewer also identifies the NDB.
treatments received for the lymphoma, because this may All information obtained is reviewed, and the patient’s
provide clues as to the validity of the diagnosis. Patients are lymphoma is classified as “validated,” “refuted,” or “likely.” As
also asked about the type of lymphoma. A patient reporting indicated above, most of the difficulty in validation is associ-
“Hodgkin’s disease” or “non-Hodgkin’s lymphoma” provides ated with older cases. As examples of handling of evidence, if
evidence regarding the validity of the diagnosis for the subse- we are unable to obtain medical records but the patient states,
quent review process. In all instances, we attempt to contact “I had Hodgkin’s disease and was treated with radiation,” we
physicians and obtain medical records. In addition, we request accept such a diagnosis. However, if the patient reports having
all hospitalization and outpatient surgery records, and patients lymphoma and being treated with antibiotics, we consider the
report all medications, including chemotherapeutic agents. For diagnosis as refuted.
key records relating to lymphomas, we make multiple, re- Among patients who reported lymphoma in their
peated (if necessary) requests to physicians (including oncolo- biannual questionnaires, those in whom lymphoma is likely
gists) and hospitals to obtain records that include information might include patients who could not be contacted because of
regarding cell types. death, those who withdrew consent, those whose rheumatolo-
As a preliminary contact, we fax a short questionnaire gist of record was no longer seeing the patient and did not
to the patient’s rheumatologist inquiring about the diagnosis know about the lymphoma, or patients who had moved and
and validity, and we follow up as necessary by direct contact had no identifiable forwarding address or telephone number.
with the rheumatologist and by obtaining medical records. This Patients being followed up as part of the infliximab safety
registry were contacted regarding lymphoma immediately
process works very well with patients who report current
upon the receipt of such a report. Patients who were not in the
lymphoma. It works less well in terms of lymphomas that may
infliximab safety registry were contacted in 2002 regarding
have occurred prior to enrollment in the NDB, because
lymphomas reported on their biannual questionnaires for the
previous physicians and records may not be available. years 1998–2002 and previously; however, hospital and treat-
Death records are also reviewed, when available, and ment records for such patients had already been obtained as a
surviving relatives are contacted for consent to obtain medical part of NDB surveillance at the time of the report. Based on
records. Death information comes initially from relatives and validation experience (see Discussion), the probability that a
physicians, often during the process of tracing nonrespondents. patient who is classified as “likely” lymphoma actually has
We also systematically screen the National Death Index (NDI) lymphoma is ⬎0.9. Lymphoma cell types were extracted from
(71,72) at yearly intervals for death information and diagnosis. hospitalization reports, physician reports, and patient reports,
However, because of delays in the processing of death records in that order of precedence.
by the NDI, the death information from the NDI in this report Classification into treatment groups. Patients were
is complete only through the year 2000. At the time of this grouped into classes according to hierarchical lifetime treat-LYMPHOMA IN RA 1743
Table 1. Demographic and lymphoma status of patients in whom lymphoma developed during NDB participation*
Treatment category
Variable All Infliximab† Etanercept‡ MTX/no biologic No MTX/no biologic
No. of lymphomas 29 9 8 10 5
Age, mean ⫾ SD years 68.4 ⫾ 10.5 69.8 ⫾ 6.4 64.2 ⫾ 7.3 72.2 ⫾ 9.5 62.8 ⫾ 17.9
% male 51.7 33.3 62.5 60.0 40.0
% deceased 17.2 0.0 12.5 20.0 20.0
No. (%) fully validated lymphomas§ 82.8 (24) 100.0 (9) 87.5 (7) 70.0 (7) 80.0 (4)
Lymphoma type
Non-Hodgkin’s 22 9 7 6 3
Hodgkin’s 1 0 1 0 0
Unknown 6 0 0 4 2
* Except where indicated otherwise, values are the mean. NDB ⫽ National Data Bank. MTX ⫽ methotrexate.
† Includes 3 patients who also received etanercept.
‡ Includes 3 patients who also received infliximab.
§ See Patients and Methods for validation details.
ment exposure status. Patients who ever received infliximab or MTX/no biologics group and begins the observation time at
etanercept were placed in separate groups. Membership in the time of enrollment in the NDB. This second method, the
these groups was independent of any other treatment, such “switched” method, is preferred, because it protects against
that current or past use of MTX did not affect membership in patients who may have discontinued MTX many years in the
the 2 anti-TNF treatment groups. Patients who had ever past being counted in the MTX group. The consequences of
received MTX but not infliximab or etanercept were placed in using different methods for classifying observation times will
the MTX-only group. Patients who did not receive infliximab, be described in the Discussion section.
etanercept, or MTX were placed in the no MTX/no biologics Statistical analysis. The expected number of lym-
group. Patients who received anakinra but were not in any of phoma cases and the SIRs were calculated based on age- and
the other groups were placed in the anakinra group. Anakinra sex-matched data from the National Cancer Institute SEER
was received by 233 of the 18,572 patients, but only 58 of these (Surveillance, Epidemiology, and End Results) resource (1).
patients were not in any of the other groups. In the analyses The SIR analyses were used to determine the risk of lymphoma
described in Table 4, we identified persons in the no MTX/no associated with RA and with the various treatments com-
biologics group who received leflunomide, but not MTX, pared with the risk in the US population. Incidence rates
etanercept, infliximab, or anakinra, and analyzed them sepa- represent the number of lymphomas divided by person-years
rately. Treatments received by patients in the no MTX/no of exposure and are expressed in 100,000 patient-years of
biologics group at a rate of ⬎1% were prednisone (24%), exposure. Differences between patients with and without lym-
hydroxychloroquine (26%), injectable gold (4%), auranofin phoma were assessed by t-tests and logistic regression, on a
(1%), and leflunomide (17%). In 59 persons, lymphoma random observation for each patient. For confirmation, assess-
developed before entry into the NDB. These patients were ments were also performed using Cox regression. Analyses
excluded from analysis and are not further considered. were performed with Stata statistical software, version 8.0 (73).
Definition of observation time and exposure time. The The 5% significance level was used. All tests were 2-tailed.
observation and analysis time begins at the time the patient
was first exposed to treatment while participating in the NDB.
For example, if a patient enters the NDB at year 0 and starts RESULTS
MTX at year 1, the observation time begins at year 1. However,
if a patient begins a treatment, as defined in the classification Table 1 shows the age, sex, mortality, validation
method described above, at or before enrolling in the NDB, status, and lymphoma type for the patients with lym-
the observation time begins at the time of enrollment in the phoma, according to observation period and treatment
NDB (year 0). The observation time ends at the last observa- group. Overall, we identified 88 lymphomas, 59 of which
tion in the data bank. The median duration of followup for all occurred prior to NDB enrollment and 29 of which
study patients was 1.25 years (range 0.1–4.5 years) and was as
follows for the major treatment groups: for MTX, 1.5 years occurred after NDB enrollment and during the period of
(range 0.1–4.0 years); for etanercept, 1.3 years (range 0.1–4.0 intensive followup. In Table 1, patients are counted as
years); for infliximab, 1.0 years (range 0.1–3.5 years); and for being in the infliximab or etanercept group regardless of
leflunomide, 1.4 years (range 0.1–4.5 years). For patients who whether they received MTX (or anakinra) therapy, but
received MTX prior to their enrollment in the NDB and who patients in the MTX group did not receive infliximab or
were not receiving MTX at the time of enrollment, 2 methods
of treatment classification and observation time were used in etanercept therapy during the study followup. Patients
the analyses shown in Table 1. The first method is as described who received both infliximab and etanercept (n ⫽ 3) are
above. The second method places all such patients in the no counted in both groups. Only 233 patients received1744 WOLFE AND MICHAUD
Table 2. Cell types in patients with lymphoma* ment with those of patients in whom lymphoma did not
Treatment Lymphoma develop. Patients who reported lymphoma prior to en-
group/patient type Cell type rollment were excluded from these analyses. Patients
1 Non-Hodgkin’s Marginal zone MALT type with lymphoma were significantly older (67.3 years ver-
2 Non-Hodgkin’s Sclerosing lymphoma, mixed sus 60.3 years), had more comorbidities (3.1 versus 2.1),
small/large cell were more likely to be male (51.7% versus 23.3%), had
3 Non-Hodgkin’s Large cell
4 Non-Hodgkin’s T cell with pancytopenia more education (14.2 years versus 13.2 years), and were
5 Hodgkin’s Hodgkin’s more likely to be non-Hispanic whites (100.0% versus
Etanercept/ 89.4%; P ⫽ 0.066). Age, sex, disease duration, and
infliximab
6 Non-Hodgkin’s “Lymphocytic lymphoma” education were entered into a multivariate logistic re-
7 Non-Hodgkin’s “Low grade lymphoma” gression. The odds ratio (OR) for a 10-year increase in
8 Non-Hodgkin’s Mixed cell age was 1.7 (95% CI 1.2–2.4). Men were 2.6-fold more
Infliximab
9 Non-Hodgkin’s Large cell likely to have lymphoma than were women (OR 2.6,
10 Non-Hodgkin’s Large B cell with underlying 95% CI 1.2–5.5), and each year of education was asso-
small cell ciated with an increase in risk (OR 1.2, 95% CI 1.0–1.4).
11 Non-Hodgkin’s Unknown
12 Non-Hodgkin’s B cell, small cell The duration of RA remained nonsignificant (P ⫽
13 Non-Hodgkin’s Diffuse, large B cell 0.876) in the multivariate analysis. These analyses were
14 Non-Hodgkin’s Unknown repeated using Cox regression, with similar results. The
Methotrexate
15 Non-Hodgkin’s Immunoblastic Cox regression hazard ratios and 95% CIs for these
16 Non-Hodgkin’s Diffuse large cell, B cell variables were as follows: for age, 1.58 per 10-year
17 Non-Hodgkin’s Large cell T cell increase (95% CI 1.16–2.18); for male sex, 3.70 (95% CI
18 Non-Hodgkin’s “Malignant lymphoma”
19 Non-Hodgkin’s Large cell 1.79–7.68); for education level, 1.16 (95% CI 0.99–1.37);
20 Non-Hodgkin’s Unknown and for comorbidity, 1.30 (95% CI 1.10–1.54).
21 Unknown Unknown Table 4 shows the SIRs and lymphoma rates for
22 Unknown Unknown
23 Unknown Unknown patients in the various treatment groups. Because of
24 Unknown Unknown overlapping therapy for anti-TNF drugs, 3 methods were
No treatment used to describe these treatments. In the first method,
25 Non-Hodgkin’s Diffuse, large cell
26 Non-Hodgkin’s Large cell lymphoma patients who received infliximab or etanercept or both
27 Non-Hodgkin’s Large cell treatments were analyzed separately. In the second
28 Unknown Unknown method, patients who received infliximab regardless of
29 Unknown Unknown
whether they received etanercept were analyzed, and
* MALT ⫽ mucosa-associated lymphoid tissue. patients who received etanercept regardless of whether
they received infliximab were similarly analyzed. In the
third method, all patients who received anti-TNF ther-
anakinra (an interleukin-1 receptor antagonist), and no apy were studied as a single group.
lymphomas occurred in this group. As shown in Table 4, the overall SIR for lym-
Of the 29 patients in whom lymphomas devel- phoma, regardless of treatment, was 1.9 (95% CI 1.3–
oped after NDB enrollment, 17% were known to be 2.7). The SIR for lymphoma in patients receiving bio-
dead. Death rates among patients who received MTX logics was 2.9 (95% CI 1.7–4.9) and the SIR in those
without biologics (20%), etanercept (13%), infliximab receiving infliximab, with or without etanercept, was 2.6
(0%), or none of these therapies (20%) reflected pri- (95% CI 1.4–5.0). For patients receiving etanercept,
marily the shorter duration in the data bank of patients with or without infliximab, the SIR for lymphoma was
receiving the newer, anti-TNF therapies. Among pa- 3.8 (95% CI 1.9–7.5). For patients who received lefluno-
tients in whom lymphoma developed after NDB enroll- mide only, the SIR was 0 (no cases of lymphoma). In
ment, 22 cases of non-Hodgkin’s lymphoma and 1 case addition, the overall SIR for lymphoma in the 6,498
of Hodgkin’s lymphoma were identified. Data on lym- patients who had received leflunomide at any time and
phoma type were not available in 6 cases. Table 2 shows in any combination was 1.0 (95% CI 0.4–2.6). The
the reported cell types. A wide variety of cells types was analysis was also performed after restricting the sample
reported. to patients who were not receiving infliximab or etaner-
Table 3 shows a comparison of the characteristics cept prior to entry into the data bank. Among 3,024
of patients in whom lymphoma developed after enroll- “new starts” on infliximab, the SIR for lymphoma inLYMPHOMA IN RA 1745
Table 3. Characteristics of patients with or without lymphoma during NDB participation*
No lymphoma Lymphoma
Characteristic (n ⫽ 18,543) (n ⫽ 29) P
Age, years 60.3 ⫾ 13.4 67.3 ⫾ 10.6 0.005
Male, % 23.3 51.7 0.001
Disease duration, years 13.6 ⫾ 10.8 15.1 ⫾ 10.9 0.489
Education, years 13.2 ⫾ 2.4 14.2 ⫾ 2.1 0.027
Non-Hispanic white, % 89.4 100.0 0.066
Ever smoker, % 53 59 0.875
Total income, US dollars 44,074 ⫾ 28,605 48,400 ⫾ 35,757 0.451
Lifetime comorbidity score (0–11 scale) 2.12 ⫾ 1.6 3.1 ⫾ 1.8 0.002
HAQ (0–3 scale) 1.11 ⫾ 0.7 1.03 ⫾ 0.7 0.576
Methotrexate use ever, % 77 79 0.803
Biologic agent use ever, % 47 48 0.869
Infliximab use ever, % 35 31 0.665
Etanercept use ever, % 19 28 0.217
Leflunomide use ever, % 14 36 0.014
* Except where indicated otherwise, values are the mean ⫾ SD. Patients with lymphomas prior to National
Data Bank (NDB) enrollment are excluded. Comparisons are between the first visit at which lymphoma
was reported and a randomly selected visit for patients without lymphoma. See text for results of Cox
regression analyses. HAQ ⫽ Health Assessment Questionnaire.
those receiving infliximab only was 1.0 (95% CI 0.46– MTX/no biologics group. Without MTX switching, the
7.4). For new starts on etanercept only, the SIR was 0.95 SIR in the no MTX/no biologics group was 1.3 (95% CI
(95% CI 0.5–8.3). 0.5–3.1), and with switching it was 1.0 (95% CI 0.4–2.5).
The results for the MTX and no MTX/no bio- Overall, the lymphoma incidence rate per
logics groups differed according to whether patients who 100,000 patient-years was 99 (95% CI 69–142). For the
were classified in the MTX group but never received various durations of RA, the rates were as follows: for
MTX during their followup in the NDB were “switched” 0–5 years, 171 (95% CI 82–360), for 5–10 years, 70 (95%
to the no MTX/no biologics group. Without switching, CI 29–168), for 10–15 years, 20 (95% CI 3–145), and for
the SIR in those receiving MTX was 1.5 (95% CI ⬎15 years, 121 (95% CI 74–198).
0.8–2.7); with switching the rate was 1.7 (95% CI To further explain the potential differences in
0.9–3.2). Switching had a reciprocal effect on the no treatment groups, the characteristics of patients in the
Table 4. SIR and incidence rate for lymphoma in RA patients according to exposure group*
No. of lymphomas
No. of patients Time Incidence
Treatment group Actual Expected SIR 95% CI at risk at risk rate
All patients/treatments 29 15.5 1.9 1.3–2.7 18,572 29,314 98.9
All biologics 14 4.9 2.9 1.7–4.9 8,614 10,012 139.8
Infliximab or infliximab ⫹ etanercept 9 3.4 2.6 1.4–4.5 6,465 6,538 137.7
Etanercept or etanercept ⫹ infliximab 8 2.1 3.8 1.9–7.5 3,381 5,099 156.9
Infliximab 6 2.7 2.2 1.0–4.9 5,233 4,913 122.1
Etanercept 5 1.4 3.5 1.5–8.4 2,149 3,474 143.9
Infliximab ⫹ etanercept 3 0.7 4.3 1.4–13.2 1,232 1,624 184.7
Anakinra 0 0.2 0.0 – 58 33 0
Leflunomide only 0 0.5 0 – 758 1,024 0.0
Leflunomide only (switched) 0 0.9 0 – 1,184 1,850 0.0
No MTX/no biologics 5 3.9 1.3 0.5–3.1 3,504 7,122 70.2
No MTX/no biologics (switched) 5 4.8 1.0 0.4–2.5 4,399 8,938 55.9
MTX only 10 6.8 1.5 0.8–2.7 6,396 12,147 82.3
MTX only (switched) 10 5.8 1.7 0.9–3.2 5,501 10,331 96.8
* Time at risk is expressed in years. Incidence rates are expressed per 100,000 patient-years of exposure. For leflunomide, switched means patients
in the leflunomide-only group who did not receive leflunomide during National Data Bank (NDB) followup were counted as being in the no
methotrexate (MTX)/no biologics group. For MTX, switched means patients in the MTX-only group who did not receive MTX during NDB
followup were counted as being in the no MTX/no biologics group. SIR ⫽ standardized incidence ratio (adjusted for age and sex); RA ⫽ rheumatoid
arthritis; 95% CI ⫽ 95% confidence interval.1746 WOLFE AND MICHAUD
Table 5. Characteristics of patients with rheumatoid arthritis, by exposure group*
Infliximab Etanercept MTX No MTX/no biologics†
Variable (n ⫽ 6,433) (n ⫽ 2,729) (n ⫽ 5,593) (n ⫽ 4,474)
Age, years 60.7 ⫾ 13.4 56.4 ⫾ 12.4 61.2 ⫾ 13.0 60.4 ⫾ 14.1
% male 22.7 20.7 24.3 24.3
Disease duration, years 13.7 ⫾ 10.7 14.1 ⫾ 10.2 13.5 ⫾ 10.6 13.5 ⫾ 11.3
Education, years 13.1 ⫾ 2.5 13.6 ⫾ 2.2 13.2 ⫾ 2.3 13.3 ⫾ 2.5
Total income, US dollars 43,057 ⫾ 27,889 49,694 ⫾ 28,792 41,375 ⫾ 26,446 44,094 ⫾ 28,439
Lifetime comorbidities (0–11 scale) 2.2 ⫾ 1.5 2.6 ⫾ 1.8 2.4 ⫾ 1.8 2.5 ⫾ 1.9
HAQ (0–3 scale) 1.2 ⫾ 0.7 1.2 ⫾ 0.7 1.1 ⫾ 0.7 1.0 ⫾ 0.7
Pain (0–10 scale) 4.2 ⫾ 2.4 4.3 ⫾ 2.4 3.7 ⫾ 2.3 3.9 ⫾ 2.6
Global severity (0–10 scale) 3.9 ⫾ 2.2 3.8 ⫾ 2.1 3.4 ⫾ 2.1 3.5 ⫾ 2.4
VAS QOL scale (0–100 scale) 65.8 ⫾ 17.5 64.3 ⫾ 17.7 66.7 ⫾ 17.5 65.9 ⫾ 19.5
* Except where indicated otherwise, values are the mean ⫾ SD. Values represent statistics based on the mean for each patient. MTX ⫽
methotrexate; HAQ ⫽ Health Assessment Questionnaire; VAS ⫽ visual analog scale; QoL ⫽ quality of life.
† No exposure to infliximab, etanercept, or MTX while enrolled in the National Data Bank.
groups are presented in Table 5. In general, those in the agents was associated with an immediate risk of lym-
anti-TNF groups had slightly more severe disease, as phoma, we plotted the time from the start of therapy to
shown by increased scores for the Health Assessment the time of lymphoma development (Figure 1). No early
Questionnaire (HAQ) (60), pain, and global severity, pattern of lymphoma was detected.
and decreased scores for quality of life. Income and
education levels were higher in etanercept-treated pa-
tients, and patient age was lower in this group than in
other groups. There were no important differences
Table 6. Differences in severity measures between the last clinic visit
between groups for age (except for etanercept), sex, or before NBD enrollment and the last completed NBD survey*
disease duration.
Patient group/variable Mean ⫾ SD P
To further explore potential disease severity dif-
ferences between groups, we compared baseline and Non–registry-enrolled patient (n ⫽ 3,140)
Clinic HAQ score 1.09 ⫾ 0.72 0.763
followup measures of severity (Table 6). Clinic values Survey HAQ score 1.09 ⫾ 0.75
refer to data obtained in a patient’s rheumatologist’s Clinic pain score 4.33 ⫾ 2.62 ⬍0.000
office at the time the patient completed a short ques- Survey pain score 3.78 ⫾ 2.74
Clinic patient global score 4.03 ⫾ 2.54 ⬍0.000
tionnaire and enrolled in the data bank. Survey values Survey patient global score 3.48 ⫾ 2.52
are those data obtained in the NDB questionnaires that All infliximab-treated patients (n ⫽ 2,792)
were mailed to patients. Survey values are obtained an Clinic HAQ score 1.32 ⫾ 0.67 ⬍0.001
Survey HAQ score 1.19 ⫾ 0.72
average of 3.5 months after enrollment. For patients just Clinic pain score 4.66 ⫾ 2.71 ⬍0.001
beginning infliximab therapy (new starts; n ⫽ 1,644), the Survey pain score 4.06 ⫾ 2.72
difference between survey and clinic values can be Clinic patient global score 4.02 ⫾ 2.51 ⬍0.001
considered to represent the effect of treatment. As Survey patient global score 3.74 ⫾ 2.41
Infliximab new-start patients (n ⫽ 1,644)
shown in Table 6, patients in the infliximab “new start” Clinic HAQ score 1.41 ⫾ 0.64 ⬍0.001
group had much worse clinical status than did the 3,140 Survey HAQ score 1.19 ⫾ 0.71
patients enrolling from the practices of US rheumatolo- Clinic pain score 5.24 ⫾ 2.54 ⬍0.001
Survey pain score 4.15 ⫾ 2.73
gists who were not part of treatment registries. In Clinic patient global score 4.55 ⫾ 2.41 ⬍0.001
addition, all infliximab-treated patients (a group that Survey patient global score 3.81 ⫾ 2.41
included both new starts and those continuing to receive * Clinic values are those obtained in the patient’s rheumatologist’s
infliximab at the time of the rheumatologist’s evalua- office at the time the patient completed a short questionnaire and
tion) had more abnormal scores generally. In addition, enrolled in the data bank. Survey values are those obtained in the
National Data Bank (NDB) questionnaires that were mailed to
patients in the infliximab new start group had an im- patients. Survey values were obtained an average of 3.5 months after
provement in the HAQ score of 0.22 units, while the enrollment. For patients just starting infliximab therapy (new start),
HAQ score did not improve in non–registry-enrolled the difference between survey and clinic values can be considered to
represent the effect of treatment. Health Assessment Questionnaire
patients. (HAQ) scores were based on a 0–3 point scale; all other scores were
To investigate the possibility that use of anti-TNF based on a 0–10-point scale.LYMPHOMA IN RA 1747
DISCUSSION infliximab-treated patients, the RA SIR is 6.4 (95% CI
1.7–16.3), and among adalimumab-treated patients the
The results of this study show that lymphoma is
SIR is 5.4 (95% CI 2.6–10.0) (56). However, do these
increased in RA compared with the general population.
increased rates reflect adverse events related to treat-
Previous studies have shown the lymphoma risk in RA
ment, RA itself, or a combination of both? It is well
(as measured by ORs and risk ratios) to be 1.98 (3), 2.7
known that patients in anti-TNF clinical trials represent
(4), 1.9 (5), 1.2 (6), 20.0 (7), 3.5 (8), 4.1 (9), 2.2 (10), and
the most severe 15–20% of RA patients (74), and that
2.0 (11). The highest rates of lymphoma have been
such patients are at the greatest risk for lymphoma
found in older studies, and one study did not find an
development (12,13). This suggests that disease activity
increased risk (47). In general, in the 5 largest studies
might play a very important role.
the risk ratio for lymphoma is ⬃2.0. These data are
The article that expressed concern regarding the
consistent with the results of the current study in 18,572
potential risk of anti-TNF therapy pointed out that a
RA patients in the NDB, in which the overall SIR for
number of lymphoma cases reported to the FDA had
lymphoma was 1.9 (95% CI 1.3–2.7).
developed soon after administration of the anti-TNF
We also found that the SIR for lymphoma was 2.9
drugs (54). Such a temporal relationship is worrisome.
(95% CI 1.7–4.9) in patients receiving biologics, 2.6
However, problems with the FDA MedWatch system, in
(95% CI 1.4–5.0) in those receiving infliximab, with or
which unusual events are preferentially reported, might
without etanercept, and 3.8 (95% CI 1.9–7.5) in patients
be an explanation for this finding, because for treat-
treated with etanercept, with or without infliximab.
ments that have recently been released, the duration of
Using the “switching method” for MTX, the SIR was 1.7
treatment before development of lymphoma cannot be
(95% CI 0.9–3.2), and for patients receiving none of
long. By contrast, Figure 2 shows that the times of onset
these therapies the SIR was 1.0 (95% CI 0.4–2.5).
of lymphomas in the patients in this study were distrib-
Although lymphoma following MTX treatment
uted evenly over the duration of followup. Given the
has been a concern because of a possible causal rela-
remission or recession of lymphoma that has been noted
tionship (22–43), the study results do not show an
in some patients following withdrawal of treatment, we
increased SIR in patients receiving MTX compared with
suggest the possibility that in some instances treatment
those who were never exposed to MTX. These results
might be harmful, while in other instances it might be
are consistent with those in a study by Mariette et al
protective. Reversibility (causality) has been noted re-
(32), who found no increase in lymphoma in MTX-
treated patients compared with a population of French peatedly with MTX therapy (23,25,45,46). However, we
nationals. However, they also found no increase in the have reported that MTX may protect against mortality
rate of lymphoma in RA, and the incidence rate (⬃30 (75).
per 100,000) was based on estimates of use of MTX in Our study has a number of limitations that need
the population. to be understood. Although the cases presented as
Despite the differences among treatment groups lymphoma were fully validated in 83% of patients and
described above, even a sample of ⬎18,500 patients were considered highly likely in the other 17% (proba-
could not demonstrate significant differences among the bility ⬎0.9), it is possible that we overestimated the
studied groups, because of the rarity of lymphoma. In number of lymphomas. If this were the case, however,
the current study, lymphoma developed in only 29 of the the rates would be slightly lower, as would the SIRs.
18,572 patients, for an incidence rate of 98.9 per 100,000 However, the converse is also possible—that we failed to
patient-years. By observing the upper 95% confidence identify some cases of lymphoma. To explore the possi-
intervals, however, a “worse-case” can be obtained, bility of misclassifying lymphomas, we excluded those
suggesting that the risk ratio for lymphoma does not cases for which external validation was not possible.
exceed 3.1 for patients receiving no MTX and no Sixty-six cases of lymphoma were externally validated,
biologics, 3.2 for those receiving MTX, and 5.0 for those including those that were reported as occurring prior to
being treated with biologics. study enrollment. Three additional patient reports were
There is substantial evidence in support of the found not to be valid (1 case of lipoma and 2 cases of
association of lymphoma and anti-TNF therapy. In cancer in lymph nodes), for an overall patient reporting
clinical trials, the SIR for lymphoma in patients receiv- accuracy of 95.7 %. We also conducted analyses on other
ing etanercept is 2.3 (95% CI 0.9–5.0) or 3.5 (95% CI cancers, with similar high accuracy rates. The results of
1.6–6.6) if a larger number of cases is used (56). In these analyses do, in fact, suggest that accepting a1748 WOLFE AND MICHAUD
Figure 2. Number of months from the start of therapy to the development of lymphoma. Bars show the 5th and 95th percentiles.
patient’s report of lymphoma when external validation is observation time for the anti-TNF agents, given their
not possible is an acceptable method. recent introduction.
It is possible that death records that are not yet In addition, there is no really good way in which
available will show additional lymphoma cases. It is also to model MTX exposure in the current data set. Some
possible that patients in whom lymphoma develops patients may have had long exposures to MTX years
might drop out of the study and not report their prior to entry into the NDB, but no exposure while in
lymphoma. If such were the case, we would underesti- the NDB. The alternative (switched versus nonswitched)
mate the actual SIR. To understand whether such events methods for MTX indicate the effect of differing as-
occurred in the current study, we analyzed available data sumptions on SIRs for the MTX and no MTX/no
to determine whether we learned of any lymphomas only biologics groups. In spite of these differences in method,
by death records. Although the absence of cases is weak the actual SIRs do not differ substantially. Finally, it
supporting evidence of case ascertainment, we found no should be noted that by definition the no MTX/no
such cases. Although such misclassification might alter biologics group has to have the longest observation
the SIR, there is no evidence that differential misclassi- (exposure) time, because the start of drug therapy begins
fication could have occurred. Therefore, we can be at the time of cohort enrollment. Thus, we may slightly
confident as to the relative relationships in SIR among underestimate the risk associated with no MTX/no
the treatment groups. biologic therapy.
Incidence rates and SIRs can be affected by the Figure 2 is included to address the issue of how
method we chose to calculate observation time (expo- soon after the start of therapy lymphomas may occur.
sure). We assumed that once exposure to treatment We did not notice a clustering of very early cases. If
occurred, the observation time should continue to the lymphoma occurs soon after the start of treatment, this
end of followup. This assumption is reasonable because, may provide some evidence of a causal association, but
assuming there is a risk associated with anti-TNF ther- the lack of a temporal association provides no informa-
apy, 1) we do not know how long after exposure the risk tion on the likelihood that the medication causes lym-
continues, 2) lymphoma that might be caused by drug phoma. It also possible that inhibition of TNF␣ is not
treatment might develop after the drug is discontinued, causally related to lymphoma development but facili-
and 3) actual exposure time is a large fraction of tates the growth of tumors that are already present.LYMPHOMA IN RA 1749
Because of possibilities such as this, we did not set a imab, with or without etanercept, was 2.6 (95% CI
minimum treatment exposure time in this study. 1.4–5.0). For patients being treated with etanercept, with
Several methods are available to adjust for treat- or without infliximab, the SIR was 3.8 (95% CI 1.9–7.5).
ment assignment, including propensity scores and mar- The SIR for patients receiving MTX was 1.7 (95% CI
ginal structural models. We did not use these methods in 0.9–3.2), and that for patients in the no MTX/no bio-
this study, because baseline data that were crucial to logics group was 1.0 (95% CI 0.4–2.5). Lymphoma was
understanding treatment assignment were often unavail- associated with increasing age, male sex, and level of
able. In addition, potentially key variables such as the education. It seems possible that the apparently in-
C-reactive protein level or the ESR and the swollen joint creased rates of lymphoma are, in fact, reduced by
count were also unavailable. therapy, and that the “increase” may reflect channeling
Although we did not observe a relationship be- bias whereby patients with the highest risk of lymphoma
tween average disease severity among patients in whom preferentially receive anti-TNF therapy. It appears that
lymphoma developed and those in whom lymphoma did neither clinical trial data nor data from the current study
not develop, as has been shown previously when labora- are sufficient to establish a causal relationship between
tory and physical examination data were available, it is RA treatments and the development of lymphoma.
possible that the average values of the HAQ, pain, and
global severity scores that were measured during the
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