Newly recognized features associated with the development of lymphoma among patients with primary Sjogren's syndrome include rheumatoid factor (RF) positivity and moderate or high disease activity, a case-control study revealed.
In a multivariate analysis, the likelihood of developing lymphoma among Sjogren's patients was tripled among those who were RF positive (OR 3.04, 95% CI 1.33-6.93, P=0.0083), according to , of Universite Paris-Sud, and colleagues.
Action Points
- Note that this case-control study among individuals with Sjogren's syndrome found that rheumatoid factor positivity was associated with a greater risk of lymphoma progression.
- Be aware that other risk factors included cryoglobulinemia and lymphopenia.
And in a model that included disease activity measurements according to the European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI), a score of 5 or higher was associated with a risk that was almost four times greater (OR 3.84, 95% CI 1.98-7.43, P<0.0001), the investigators reported online in
Sjogren's syndrome is an autoimmune disorder in which lymphocytic infiltration of lachrymal and salivary glands leads to excessive dryness. The condition is also associated with various systemic and organ manifestations, and an estimated 5% to 10% of patients eventually develop lymphoma.
Previous studies have identified a number of clinical and biologic predictors of lymphoma, including persistent salivary gland swelling, lymphadenopathy, splenomegaly, cryoglobulinemia, CD4 lymphopenia, and low complement. However, little is known about the effects of disease activity or whether the various treatments used to control the disease influence lymphoma risk.
Therefore, to explore these concerns, Mariette and colleagues undertook a study comparing a relatively large group of patients with Sjogren's syndrome who developed lymphoma and a matched group who also had the autoimmune disease but did not have the malignancy.
From French and U.K. Sjogren's syndrome registries, they identified 101 patients who developed lymphoma at least 6 months after their Sjogren's diagnosis and two matched controls for each case.
Participants' mean age was 57, and 86% were women. The average time following the diagnosis of Sjogren's syndrome and the development of lymphoma was 6 years.
The most common histologic type was B-cell non-Hodgkin's lymphoma, in 98%, with 77% being marginal zone lymphomas. Of the marginal zone subtype, 59% derived from mucosa-associated lymphoid tissue and 17% were diffuse large B-cell lymphomas.
Among those with B-cell non-Hodgkin's lymphoma, 82.8% reached complete remission with various standard treatments. In 62%, sustained remission was achieved after a first course of treatment, and in 22%, remission followed two or more treatment courses.
During a mean follow-up of 5.5 years after lymphoma diagnosis, seven patients died, including five whose deaths were attributed to progression of lymphoma.
In univariate analyses, clinical factors that were associated with lymphoma included salivary gland enlargement, splenomegaly, and purpura, but no associations were seen for the Sjogren's syndrome treatments such as hydroxychloroquine.
Biologic factors that were predictive on univariate analysis were those typical of chronic antigenic stimulation -- anti-SSA or anti-SSB antibodies, RF, cryoglobulinemia, and low C4.
Among patients for whom an RF titer was available, the mean titer for cases was 584.4 IU/mL compared with 31.2 IU/mL for controls (P<0.0001). In addition, each 10-IU increase in RF titer was associated with a 5.7% increased risk of lymphoma (OR 1.057, 95% CI 1.026-1.100).
A dose-effect on lymphoma risk also was seen for disease activity, with a 10% increase for each additional point on the ESSDAI (OR 1.10, 95% CI 1.05-1.15, P<0.0001).
The multivariate analysis confirmed the association with lymphoma for several factors other than RF positivity:
- History of salivary gland enlargement: OR 3.48 (95% CI 1.50-8.07, P=0.0037)
- Cryoglobulinemia: OR 3.68 (95% CI 1.38-9.83, P=0.0093)
- Low C4; OR 3.16 (95% CI 1.32-7.55, P=0.0098)
- Lymphopenia: OR 5.65 (95% CI 2.46-12.99, P<0.0001)
And in a multivariate model that also included disease activity, patients with the highest scores (ESSDAI ≥14) had an OR of 4.82 (95% CI 1.94-12.01) compared with those who had low disease activity (ESSDAI <5).
The steeply elevated risk associated with high disease activity supports the importance of tight disease control for the prevention of lymphoma in patients with Sjogren's syndrome, although further research will be needed to clarify the effects of the specific treatments used, according to the authors.
They also noted that the association between RF positivity and an increased risk of lymphoma had not previously been reported, although other studies have shown a link with cryoglobulinemia, a cold-precipitating type of RF.
If the association with RF itself can be confirmed, it would be "of great translational value in clinical practice since RF is much easier and cheaper to monitor than cryoglobulinemia," Mariette and colleagues wrote.
Disclosures
The study was supported by the French Ministry of Health and the French Ministry of Research.
Primary Source
Arthritis & Rheumatology
Nocturne G, et al "Rheumatoid factor and disease activity are independent predictors of lymphoma in primary Sjogren's syndrome" Arthritis Rheum 2015; DOI: 10.1002/art.39518.