In the first large, systematic assessment of immune-related risk factors in relation to risk of developing WM, we found that autoimmune conditions such as rheumatoid arthritis, Sjögren’s syndrome, and Crohn’s disease were positively associated with WM, consistent with prior studies of NHL overall.24;25
Infections generally did not appear to be associated with WM risk, with a few exceptions, and allergies were not associated, although power was limited.
To our knowledge, the only previous study of chronic immune stimulatory conditions and WM is a case-control study of 65 WM patients and 213 hospital controls that could not evaluate specific, individual immune-related conditions due to the small number of cases.26
We found that the risk of developing WM was elevated 2- to 3-fold for autoimmune disorders with detectable autoantibodies but not for those without detectable autoantibodies. Thus, associations with WM may vary by category of autoimmune disease. We also found that specific autoimmune diseases (Sjögren’s syndrome, ITP, and Crohn’s disease) were the most strongly associated with WM risk, although these estimates were imprecise.
Based on small numbers, we found a prominent 14-fold risk for WM among persons with Sjögren’s syndrome. Previous studies have consistently shown increased risk of B-cell NHL among patients with Sjögren’s syndrome.25
Anatomically, these lymphomas are typically of indolent NHL subtypes, often of the mucosa associated lymphoid tissue (MALT) type.25
Recently, there has been some evidence that Sjögren’s syndrome patients might also have elevated risk of other lymphomas, such as diffuse large B-cell and anaplastic large T-cell lymphomas.29
To our knowledge, this study is the first to report an association between Sjögren’s syndrome and WM.
Both our study and the previous study by Linet et al.
found no association between infectious diseases overall and WM.26
However, in the current study we were able to evaluate specific, individual infections and found that some (e.g., hepatitis, HIV, and rickettsiosis) were associated with increased risk of WM. Our study expands on the previous analysis of HCV and risk of WM by demonstrating that hepatitis B was also associated with WM, supporting the hypothesis that infection with hepatitis viruses may cause chronic immune stimulation leading to the development of WM.20
To our knowledge, we are the first to find that HIV was associated with increased WM risk. This observation is consistent with the large body of literature showing HIV to be associated with highly elevated risks of B-cell NHLs.30
The association with rickettsiosis is unexpected, especially since rickettsiosis is rare. Patients with rickettsial pathogens can show symptoms of lymphadenopathy,31
which may indicate activation of the immune system leading to chronic immune stimulation. Alternatively, hospitalization due to rickettsiosis may suggest the presence of an underlying immune deficit, leading to the diagnosis of WM.
This study is also the first to evaluate effect of race on the association between chronic immune stimulatory conditions and WM. The risk of WM associated with infections was consistently higher in blacks than in whites, which is surprising given that the incidence of WM is lower in blacks than in whites. If true, some other risk factor must be driving the risk in whites. It is possible that the pattern of elevated RRs for infections in blacks might reflect racial differences in immune responses to infectious agents.32–34
However, given the number of exposures evaluated, these findings have to be interpreted with caution since they could be due to chance.
To evaluate the possibility that WM may have been present prior to diagnosis of the chronic immune stimulatory conditions and may have actually caused these conditions (i.e., reverse causality), we stratified by latency ≤5 years and >5 years. For autoimmune disease, the increase in risk for WM was evident mainly in the 5 years prior to WM, and some conditions were diagnosed less than 1 year prior to WM diagnosis. These patterns suggest that in some cases the autoimmune disease could be a manifestation of underlying undetected WM, especially considering that WM often has a long latency period.35
ITP in particular is a recognized complication of WM.36;37
However, because the risk of WM among patients with autoimmune diseases remained elevated after 5 years, similar to the results from a population-based study of NHL in Denmark and Sweden,24
we feel that these findings are not entirely due to undetected WM. The clinical work-up for the suspicion of an autoimmune disease typically includes a complete blood count and may include protein electrophoresis, which should lead to WM diagnosis at or shortly after onset of the autoimmune disease. While some autoimmune diseases did have a relatively short median time to WM diagnosis (e.g., ITP and Sjögren’s syndrome), others did not (e.g., Crohn’s disease). Unfortunately, we do not have access to individual detailed clinical data that would allow us to evaluate the role of prior diagnosis of monoclonal gammopathy of undetermined significance or undetected early stage WM directly. Thus, future epidemiologic studies must verify our findings through medical-record validation of clinical, diagnostic, prognostic, and treatment data.
For infections, the similarity in RRs ≤5 years and >5 years argues against reverse causality for this group of chronic immune stimulatory conditions. While the data for many individual infectious conditions were too sparse to stratify by latency, the relatively short medians for some conditions suggest that interpretation requires caution. For example, the median time to WM diagnosis was approximately 1 year for both rickettsiosis and HIV, which could reflect detection bias (i.e., rickettsiosis or HIV detected due to workup for WM). On the other hand, the short time to WM diagnosis for HIV may reflect the fact that a separate ICD code for HIV was not added until 1987, resulting in a shorter amount of time available for the diagnosis of both HIV and WM.
Chronic immune stimulatory conditions may contribute to lymphomagenesis through persistent activation of lymphocytes leading to reduced antigen response, increased mutation rates, and downregulated T-cell response, potentially disrupting immune response to pathogens and malignant cells.38;39
While further studies are needed, our findings support the hypothesis that chronic immune stimulation may contribute to the development of WM.
The study has some limitations. First, these results may not be generalizable to the US population. It is, however, encouraging that the age-adjusted rates of WM in this cohort are similar to those found for males in SEER overall (0.35/100,000 person-years in the current study versus 0.35/100,000 person-years in SEER),5
in whites (0.37/100,000 person-years in the current study versus 0.36–0.56/100,000 person-years in SEER),5;6
and in blacks (0.26/100,000 person-years in the current study versus 0.17–0.25/100,000 in SEER).5;6
Because the data are based on hospital claims, it is possible that some conditions might have developed prior to the patient entering the VA system. The definition of WM is limited by the fact that the ICD-8-A code for WM was not entirely specific but also included macroglobulinemia (i.e., MGUS type IgM), by the lack of review for WM cases and immune-mediated conditions since demographic, clinical, treatment, laboratory, and biomarker information were unavailable, and by revisions in the definition of WM over time (e.g., it was not reportable as a malignancy in the US until 1988 40
). However, as mentioned above, the risk estimates were very similar when stratified by calendar-period, suggesting that these limitations have not introduced any major bias. Since we did not have treatment data, we could not evaluate potential confounding by immunosuppressive therapy, which is used to treat severe autoimmune disease and is also associated with development of lymphoma.41
Because the clinical work-up of immune-related diseases might include protein electrophoresis, it is possible that some of our results for autoimmune conditions are overestimated due to surveillance bias: patients with autoimmune disease may be more likely to have WM diagnosed than patients without autoimmune disease. Also, one has to keep in mind that all patients (WM as well as non-WM patients) in this cohort were hospitalized, which presumably led to more clinical work-up than in the general population. For this reason, we did not use external controls but instead applied a cohort study design allowing us to use internal controls. Although this cohort included over 4 million patients, the rarity of WM and of some of the chronic immune stimulatory conditions evaluated limited analyses and led to imprecision in some estimates. Multiple comparisons may result in chance findings. Further, exposures that have been discovered recently (e.g., HCV in 1989, HIV in 1983) and less severe autoimmune and infectious conditions that do not lead to hospitalization may not be well represented.
Strengths of our study include its extensive follow-up in a patient population with access to standardized medical care that does not depend on socioeconomic status. Further, there is no recall bias because the exposure information is obtained from medical records. Because of the size of this population, we were able to evaluate the incidence of WM in blacks and to provide the first analysis of risk factors for WM in blacks.
In summary, we found that WM is associated with autoimmune disease, especially those with detectable autoantibodies, in the largest study of chronic immune stimulatory conditions and WM to date. Patients with specific infectious diseases, such as hepatitis, HIV, and rickettsiosis, also appeared to be at increased of WM. These results suggest that chronic immune stimulation plays an important role in the etiology and pathogenesis of WM. Better characterization of mechanisms mediating clonal proliferation and survival will ultimately enhance our understanding of WM pathophysiology, provide clues to etiology, and allow identification of novel molecular targets.