We were intrigued that clinic-based case series have produced conflicting results regarding whether the serum globulin level, a marker of a dysregulated B-cell function, might predict NHL development among HIV-infected persons (Engels et al, submitted for).10,10a
By taking advantage of sensitive serum/plasma Ig assays (ie, protein electrophoresis confirmed with immunofixation, and κ and λ FLC assays), we tested whether AIDS lymphomas are typically preceded by a precursor state manifested in elevated markers of B-cell activation.
Notably, we found that the presence of elevated free κ and λ FLC levels strongly predicted NHL among HIV-infected individuals, and NHL risk increased directly in relation to FLC level. In contrast, although IgG levels were higher among our HIV-infected patients than in the general population,27
levels of IgG, IgA, and IgM were not associated with NHL risk. Serum FLC levels may be more sensitive indicators of B-cell activation than IgG, IgA, and IgM,26,28
and abnormally elevated levels have been reported in patients with hepatitis C virus infection, rheumatoid arthritis, and Sjögren syndrome,29,30
which are themselves associated with B-cell immune dysfunction and increased NHL risk. In addition, Breen et al31
previously reported that elevated serum levels of soluble CD30, also a marker of B-cell activation, were predictive of subsequent NHL among HIV-infected patients.
AIDS NHL risk increases with declining CD4 counts, which reflects advancing immunosuppression.5
In our investigation, we observed higher FLC levels among HIV-infected individuals with lower CD4 counts, and the association between FLC levels and NHL varied depending on the CD4 count. Specifically, for individuals with a CD4 count at or greater than 100 cells/mm3
, the association was present for FLCs measured in both prediagnostic time periods, but for individuals with CD4 counts less than 100 cells/mm3
, the association was present only for FLCs measured in the earlier 2- to 5-year period. We hypothesized that, as AIDS progresses, B-cell dysfunction becomes more common; however, because the profound effects of T-cell immunosuppression become increasingly important, the contribution of B-cell dysfunction to NHL pathogenesis becomes harder to discern. Thus, the predictive value of FLCs in relation to lymphomagenesis is most apparent at relatively preserved CD4 counts. Furthermore, we found stronger associations between FLCs and NHL when we excluded individuals on HAART therapy (). Patients on HAART had lower CD4 counts than those not receiving HAART, which likely reflects both physician choices regarding whom to treat and the selection criteria for our study (ie, we selected NHL patients and matched controls who would be expected to have had low CD4 counts even if HAART treated). HAART has profound effects on the immune system that may mitigate the utility of FLCs as a prognostic marker, although our study did not include sufficient number of patients receiving HAART to look at that group separately. Taken together, these observations suggest that abnormal B-cell activation is a risk factor for development of NHL in HIV-infected individuals, particularly those not receiving effective HIV treatment. It is unknown how such a pathway might relate to loss of immune control of EBV and other viruses implicated in lymphomagenesis and how it may have variable roles in the individual pathogenesis of different NHL subtypes. EBV replication, particularly, is poorly regulated in HIV-infected patients, and this virus is detectable in many, but not all, patients with AIDS NHLs.3,4
Importantly, we did not find that MGUS or an abnormal FLC ratio predicted NHL risk among HIV-infected persons. MGUS was uncommon and appeared to be somewhat transient (ie, some patients with MGUS in the 2- to 5-year period no longer had a detectable M-proteins in the 0- to 2-year period). The prevalence of MGUS is similar to that described in prior reports (3% to 4%),12,32
and one study likewise observed that M-proteins may be transient in HIV-infected individuals.32
Our report is the first, to our knowledge, to define the prevalence of abnormal FLC ratios in HIV-infected persons before NHL diagnosis (20.0% at 2 to 5 years, and 13.6% at 0 to 2 years). The higher prevalence of abnormal FLC ratio than for detectable M-protein reflects that this ratio is a more sensitive measure of monoclonality than protein electrophoresis.28
Nonetheless, the prevalence of abnormal FLC ratio was virtually the same in controls. These findings suggest that the generation of M-proteins and abnormal FLC ratios, presumably by dysregulated plasma cells, is not strongly driven by HIV-related immunosuppression, and that this process is not related to AIDS lymphomagenesis. HIV-infected individuals have an approximately two- to three-fold elevated risk for multiple myeloma compared with the general population,33
but this risk does not increase steeply with onset of AIDS.34
Strengths of our study include its prospective design, available prediagnostic blood samples, and the application of assays for the determination of B-cell stimulation and clonal proliferation. Limitations also should be noted. Although the size of this study was sufficient to study NHL risk overall, we had insufficient statistical power to evaluate associations with FLC levels in strata defined by NHL subtypes. Other limitations were the lack of information regarding tumor EBV status and the lack of central blinded pathology review, which was impossible to implement in a retrospective study.
We speculate that FLC measurement may have clinical utility in assessing risk for NHL and perhaps other AIDS-related outcomes. At present, decisions regarding initiation of HAART are guided mainly by the CD4 count and, to a secondary degree, the HIV viral load.35
Commonly, a threshold CD4 count of 350 cells/mm3
is used, but recent evidence suggests that earlier initiation of HAART may be beneficial to prevent HIV-related complications.36
One possibility is that clinicians could utilize FLC levels to help determine which patients might benefit most in starting HAART. Although this is a preliminary suggestion, this approach would find support from our observations that FLCs were especially predictive of NHL risk among patients not on HAART who had a relatively high CD4 count (≥ 100 cells/mm3
) and that this predictive relationship was obtained over a prolonged period of 2 to 5 years after FLC measurement.
Another possibility is that the B-cell abnormalities identified by elevated FLC levels may not be specific to the development of NHL but may instead indicate a generalized disruption of B-cell function. If that is the case, then this marker also may reflect risk for HIV-related complications other than NHL. Future studies are needed to explore these topics and to better define the biologic mechanisms underlying the observed associations.
In conclusion, we found that the presence of elevated FLC levels, a marker of polyclonal B-cell activation, is a strong risk factor for AIDS-related NHL among HIV-infected individuals. Although NHL risk has declined substantially in the HAART era, lymphoma still remains a considerably important morbidity in the setting of HIV infection.6
On the basis of our findings presented here, additional elucidation of the pathogenetic mechanisms of AIDS-related NHL should continue to be a priority in epidemiologic studies and clinical trials, and this elucidation may help in the development of improved prevention strategies and the identification of novel therapeutic targets.