B-Cell Stimulating Factors Tied to Lymphoma in Sjogren's

Genetic blood tests indicated that Bruton's tyrosine kinase (BTK) and a cytokine called APRIL were overexpressed in patients with primary Sjögren's syndrome who subsequently developed lymphoma, French researchers reported, suggesting that BTK inhibitors might be useful in this population.

Serial whole-blood gene expression analyses in a cohort of 345 Sjögren's patients showed that, in 21 later developing lymphoma, BTK was expressed at levels 20% higher on average than among those without lymphoma, according to Pierre-Marie Duret, MD, MSc, of Colmar Civilian Hospital in Colmar, France, and colleagues.

While that may seem like a rather modest difference, multivariate analysis taking other lymphoma risk factors into account yielded an odds ratio of 47.6 (95% CI 5.5-411.9) that elevated BTK expression at cohort enrollment would predict lymphoma onset, the group reported in Arthritis & Rheumatology.

The study also indicated that APRIL (proliferation-inducing ligand), a cytokine that stimulates B-cell expansion, was also overexpressed to a similar degree prior to lymphoma development in Sjögren's patients.

Non-Hodgkin lymphoma (NHL) is relatively common in primary Sjögren's syndrome. A 2014 meta-analysis found the risk was 14 times greater in these patients versus the general population, and Duret's group cited other studies indicating a lifetime lymphoma risk of 5% to 10%.

"Lymphoma can occur before, concomitantly, or after the diagnosis of" primary Sjögren's, they wrote. Moreover, they added, most NHL cases are marginal zone B-cell malignancies originating in the same tissues involved in Sjögren's, such as the salivary and lacrimal glands.

Those factors suggest a common pathology centered in B-cell activity, which in turn points a finger at factors driving B-cell activation and proliferation. For the current study, Duret and colleagues drew on a prospective cohort study called ASSESS that began in 2006 to investigate the natural history and predictive factors for Sjögren's syndrome, including "the underlying mechanisms" of lymphoma in these patients. Participants were seen regularly with periodic blood sampling.

The researchers checked expression levels of eight genes whose products are known for their involvement in B-cell activation, from which BTK and APRIL emerged as the ones most closely associated with lymphoma development. Somewhat to the group's surprise, others, such as B-cell activating factor (BAFF) and B-cell maturation antigen (BCMA), were not clearly overexpressed (numerical increases were seen relative to non-lymphoma Sjögren's patients but they did not reach statistical significance).

Duret and colleagues also performed sensitivity analyses that included Sjögren's patients who already had lymphoma at cohort entry, and with controls limited to those with relatively more active Sjögren's syndrome. These also supported the primary findings, although some also found that expression of BAFF, BCMA, and certain others were associated with lymphoma.

The study came with a number of limitations, most notably the small sample size and resultant broad confidence intervals in the gene expression analyses. As a result, Duret and colleagues emphasized that the association they found "needs confirmation in other prospective cohorts."

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