New Insights into Management of Sjögren-Related Lymphoma

Hematologists and rheumatologists may be able to adopt a more aggressive approach for managing low-grade marginal lymphoma in Sjögren disease, particularly mucosa-associated lymphoid tissue (MALT) lymphoma, based on recent findings that confirmed a key early biomarker and found that a systemic treatment strategy reduced Sjögren disease activity and the risk for lymphoma relapse.

Two European studies published in The Lancet Rheumatology — one a case-control study reporting that rheumatoid factor (RF) was an early and strong predictor of Sjögren disease–related MALT lymphoma and the other a retrospective study that found a combination of chemotherapy and anti-CD20 therapy with rituximab as a first-line treatment for lymphoma was more effective than localized treatment or watch-and-wait approach in minimizing autoimmune activity and treating the lymphoma — potentially shed new light on strategies to manage Sjögren’s disease–related lymphoma.

A commentary accompanying the studies noted that 5%-10% of patients with Sjögren disease will develop non-Hodgkin B-cell lymphoma, with marginal lymphoma the most common type of low-grade lymphoma. The commentary, led by Suzanne Arends, MD, a rheumatologist at the University of Groningen in Groningen, the Netherlands, found the studies “clinically relevant” but stated that the lack of consistent definitions between the two studies along with their retrospective nature prevent any “definitive conclusions.”

High Lymphoma Risk in Sjögren Disease

“It is the autoimmune disease in which the risk of lymphoma is the highest, a 10- to 20-fold increase of the risk of lymphoma in this disease,” Xavier Mariette, MD, PhD, co-senior author of the retrospective treatment study, said of Sjögren disease.

These lymphomas are predominantly the marginal zone type, specifically MALT occurring in the salivary glands, the same site of the autoimmune disease, said Mariette, who is the head of Rheumatology and professor at Université Paris-Saclay and Hôpital Bicêtre. Autoimmune B cells become lymphomatous. “So there is a continuity between autoimmunity and lymphoma genesis,” Mariette told Medscape Medical News. Typically, hematologists do not treat the lymphoma if it doesn’t migrate beyond the salivary glands, he said.

Mariette said his group’s findings make the case for a more aggressive treatment.

“When patients got the systemic treatment, there was a decreased risk of flare of the autoimmune disease of Sjögren’s, but there was no effect on the lymphoma formation,” Mariette said. “And when these patients have combined therapy, immunotherapy plus chemotherapy, compared to single immunotherapy, they did have improvement of the lymphoma progression-free survival.”

Their multicenter study enrolled 106 patients with Sjögren disease who developed lymphoma, 64% (n = 68) of whom had MALT, 13% (n = 14) of whom had other marginal zone subtypes and the same percentage with diffuse large B-cell lymphoma. With a median follow-up of 7 years, 32 patients with marginal zone subtypes who had combination chemotherapy and anti-CD20 therapy had a 64% greater chance of lymphoma progression-free survival than 18 of their counterparts who received anti-CD20 monotherapy. Overall, outcomes for Sjögren disease systemic activity or survival were no different between the combination therapy and monotherapy arms.

Patients who had a systemic approach had a 57% reduced risk for new Sjögren disease activity compared with those who had first-line surgery or radiation (16%, n = 13) or underwent watch and wait (23%, n = 19).

The study strengthens the argument for a systemic treatment approach over localized therapy “because patients with Sjögren’s have a higher degree of development of MALT lymphoma of the salivary glands,” Juan Pablo Alderuccio, MD, a hematologist and lymphoma clinical site disease group leader at the Sylvester Comprehensive Cancer Center at the University of Miami Health Systems, Miami, Florida, told Medscape Medical News.

“We already knew that the combination of chemotherapy with rituximab usually achieves a better outcome,” Alderuccio added, citing a 2017 clinical trial that found combined chemotherapy with chlorambucil plus rituximab improved progression-free survival compared with either therapy alone. The latest retrospective study from France reinforces that, he said.

“The study also shows it’s very important to consider treatment-related specificities — to select the most appropriate treatment for these patients,” Alderuccio added.

RF Biomarker

The case-control study by researchers in Italy and Greece included 80 patients with Sjögren-related MALT lymphoma matched to controls with Sjögren disease who did not have lymphoma.

“We showed that rheumatoid factor positivity at the time of Sjögren’s disease diagnosis serves as the most reliable and temporally distant independent predictor of MALT lymphoma development,” lead author Andreas Goules, MD, a pathophysiologist at the National and Kapodistrian University of Athens, Athens, Greece, told Medscape Medical News.

He added that the study found that specific biomarkers in addition to RF positivity were signs of a high risk for MALT lymphoma and a more advanced stage of Sjögren disease–related lymphomagenesis. They included high systemic disease activity, measured as a European Alliance of Associations for Rheumatology Sjögren’s Syndrome Disease Activity Index ≥ 5, and specific B-cell manifestations, such as cryoglobulinemia, salivary gland enlargement, hypocomplementemia, and palpable purpura.

“Ideally, all patients should be evaluated at the time of diagnosis for the presence of RF and undergo a minor salivary gland biopsy to exclude an underlying ongoing lymphoproliferative process,” Goules said.

RF-positive patients with Sjögren disease require a closer follow-up to identify an advanced stage of lymphoma development, he added.

“It is well known that Sjögren’s disease is characterized by an increased mortality rate, compared to the general population, mainly due to the related lymphomas,” Goules added. “Thus, the early diagnosis of MALT lymphoma, which is associated with a better prognosis, is expected to improve the overall clinical outcome of Sjögren’s disease patients.”

Rheumatologists and hematologists should employ a similar strategy for Sjögren disease–related large B-cell lymphomas, he said.

“The pathogenetic mechanisms of these two lymphoma types are vastly different, so it wouldn’t be surprising if an entirely different risk factor emerges,” Goules said. “However, given the rarity of diffuse large B-cell lymphomas, much larger multinational cohorts will be necessary to obtain clinically and pathogenetically meaningful results.”

Alan Baer, MD, a rheumatologist and founder of the Sjögren’s Disease Clinic at Johns Hopkins University in Baltimore, noted Goules and colleagues are not the first to identify RF, along with a host of other clinical and laboratory findings, as a risk factor for lymphoma in patients with Sjögren’s disease. “The current study validates rheumatoid factor as an independent risk factor present at a time that is temporally distant from the time of lymphoma diagnosis,” he said.

However, he cautioned that RF alone isn’t highly predictive of Sjögren-related lymphoma. Up to 60% of patients with Sjögren disease are positive for RF at the time of the diagnosis, Baer said.

“Thus, the finding of rheumatoid factor alone does not necessarily mandate closer surveillance of this group of patients, with the potential for more frequent clinical exams, imaging, and laboratory testing,” he said. “Such an approach has the risk of subjecting patients to unnecessary testing, including invasive procedures.” 

More detailed findings, such as if a certain RF level was more predictive of lymphoma or whether other features in combination with RF heightened the risk, would be helpful, he said.

What Future Studies Should Look At

The studies call for further research into biomarkers for Sjögren disease–related lymphoma and treatment of the disease, both Mariette and Goules said.

Goules said a multicenter prospective study is needed to measure RF positivity and RF titers over time and determine whether higher levels mean an increased risk for lymphoma development or a shorter time interval until lymphoma onset. “Such a study requires a large number of RF-positive Sjögren’s disease patients who would be followed up for a long period of time,” Goules said.

To further evaluate treatment approaches for Sjögren disease–related lymphoma, Mariette said a prospective study should compare the watch-and-wait approach with combination chemotherapy and anti-CD20 therapy. “It would be difficult to run because the primary endpoint would be lymphoma progression-free survival, and the secondary would be Sjögren’s relapse and mortality, but it would take a lot of time,” he said.

He added, “It’s a reason why this retrospective study is important. Maybe if we had another retrospective study reaching the same conclusion, I think it would be very, very strong evidence.”

Funding for the case-control study came from the European Commission—Horizon 2020 program. The retrospective treatment study had no outside funding. Mariette disclosed financial relationships with AstraZeneca, Bristol Myers Squibb, Galapagos, GlaxoSmithKline, Novartis, and Pfizer. Alderuccio, Goules, and Baer had no relevant relationships to disclose.

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.