The treatment of lymphoma complicating autoimmune disease: two birds with one stone?

Lymphoproliferative diseases, particularly non-Hodgkin’s lymphoma (NHL), have increased dramatically in frequency during the last three decades with a more than two-fold increase in NHL incidence from the mid-1970s to the mid-1990s alone. NHL is currently the fifth most common malignancy in the USA with 60 000 new cases diagnosed annually. Although environmental and genetic risk factors for lymphoma are not well defined, antecedent autoimmune disease has been increasingly recognized as a robust determinant of NHL risk. Rheumatoid arthritis (RA), a systemic autoimmune condition characterized by synovial inflammation and progressive joint deformity, has been associated with a twoto six-fold increase in the risk for NHL (reviewed in [1]). Relative risks for lymphoproliferative disease may be even higher in conditions such as systemic lupus erythematosus (SLE) and Sjogren’s syndrome (reviewed in [2]). Despite much needed insight provided by recent investigations, the precise etiology of NHL in the context of autoimmune disease remains poorly understood. It has long been hypothesized that disease-modifying antirheumatic drugs (DMARDs) and other immunomodulating agents used to treat these conditions are major culprits or at least play an important role in heightening the overall risk for lymphoproliferative disorders. There have been numerous reports, for instance, indicating an association of methotrexate (the gold standard DMARD for the treatment of RA) with incident NHL, particularly with tumors positive for Epstein– Barr virus (reviewed in [1]). Likewise, cyclophosphamide (a commonly used intervention in systemic vasculitis and the treatment of end organ complications of SLE) has been associated with subsequent development of lymphoproliferative diseases including NHL. Concerns regarding the role of DMARDs and immunomodulators used to treat rheumatic conditions and NHL risk have been fueled by reports indicating associations of biologic therapies (particularly those targeting tumor necrosis factor-a) with lymphoma development [3]. Taken together, reports linking both conventional and biologic DMARDs with lymphoproliferative diseases have been a major source of angst for patients suffering from autoimmune disease as well as health care providers. In this issue of the Annals of Oncology, Wohrer et al. [4] provide results from a select case series of patients with varied autoimmune conditions complicated by NHL and receiving standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). As detailed by the authors, their results—although preliminary in nature—indicate that R-CHOP has dual efficacy in the treatment of both NHL and the underlying autoimmune disease, perhaps circumventing the need for high-risk DMARDs and, in the process, alleviating patient and provider angst. While the report by Wohrer et al. [4] is intriguing, there are important limitations to this work that warrant discussion. Most notably, the heterogeneous makeup and small size of this retrospective cohort greatly limit inferences that can be drawn from this effort. Given the nuances of different autoimmune conditions and anticipated differences in responses to immunomodulating therapies, combining these cases in a single analysis may be problematic. Small sample sizes and resulting limits in statistical power are not unique to this study and are perhaps the single greatest barrier to conducting research in this area. We recently reported on our own experiences with a systematic evaluation of a large tissue registry of subjects with lymphoma [5]. Examining the records of >3000 NHL cases collected during a 20-year time span, we were able to identify only 24 cases with either definite or probable RA. In a national French study examining the association of methotrexate use with incident lymphoma, investigators identified only 18 cases of incident NHL meeting inclusion criteria during a 3-year period of follow-up [6]. In addition to problems of heterogeneity and small sample size, the accompanying retrospective report appears to rely on self-reported diagnoses for autoimmune conditions rather than validated disease classification criteria (i.e. American College of Rheumatology or ACR classification criteria for RA [7] or SLE [8]), potentially problematic given the limited predictive value of the former approach. Similarly, the efficacy analyses relevant to the underlying connective tissue diseases are based solely on serial patient global reports rather than more universally accepted and validated composite measures of disease activity that are available and widely used both as research tools and in the clinic, measures such as the disease activity score in RA that combines patient-level data (global well-being) with more objective measures including tender and swollen joint counts and values of acute-phase reactants [9]. As the authors concede, it should perhaps not be too surprising that R-CHOP would prove efficacious in the treatment of autoimmune disease, conditions characterized by the presence of autoreactive lymphocytes. Rituximab, a chimeric monoclonal anti-CD20 antibody that targets and depletes B cells, has revolutionized the treatment of NHL and has recently been approved in both Europe and the USA for the treatment of RA and is under active investigation for the treatment of SLE. There are numerous reports indicating that e d it o ri a l