SNOWMASS, COLO. (FRONTLINE MEDICAL NEWS) – A full decade after a large multicenter study identified non-Hodgkin’s lymphoma as the major cancer risk associated with SLE, it remains unclear whether the underlying explanation lies in immune dysregulation intrinsic to the disease of lupus itself or to the immunosuppresive medications prescribed for its treatment.

Regardless, the message is clear: “Non-Hodgkin’s lymphoma is the malignancy we have to think about most in our lupus patients,” Dr. Karen H. Costenbader said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“Surveillance is very important. Lupus patients develop multifocal lymphadenopathy as a manifestation of disease, but I think we should have a low threshold for biopsying. I’ve definitely sent many a lupus patient for a biopsy that came back negative, but we’re all relieved lymphoma’s not there,” said Dr. Costenbader, codirector of the lupus center at Brigham and Women’s Hospital and a rheumatologist at Harvard Medical School, Boston.

Non-Hodgkin’s lymphoma isn’t the only cancer concern, however. Patients with SLE also are at increased risk for other hematologic malignancies as well as lung cancer; hepatobiliary cancer; and cervical, vaginal, and vulvar cancers.

Women with SLE also have an increased risk of cervical dysplasia. This is believed to be attributed to decreased clearance of human papillomavirus, “possibly due to our immunosuppressive medications,” Dr. Costenbader said.

Most studies point to a possible protective effect of SLE against breast cancer, with standardized incidence ratios (SIRs) of observed cases of breast cancer significantly lower than expected based on rates in the general population.

“That’s an interesting finding that has been pursued in genetic studies that didn’t show much,” she noted.

The increased cancer risk associated with lupus was highlighted back in 2002 in a large Swedish study of hospital discharge data. It identified a modest 25% increased relative risk of cancers overall in patients with SLE, compared with the general population. Strikingly, SLE patients had a nearly threefold increased risk of non-Hodgkin’s lymphoma that was most pronounced in the first years after diagnosis of their rheumatic disease. They also had a 73% increase in the risk of lung cancer and a 53% increase in squamous cell carcinoma, both of which most often arose late, more than 15 years after diagnosis of SLE (Scand. J. Rheumatol. 2002;31:66-71).

More recently, Dr. Sasha Bernatsky of McGill University in Montreal has taken the lead in key studies aimed at further defining the risk of malignancies in lupus patients. In a study of 9,547 SLE patients in the Systemic Lupus International Collaborating Clinics cohort, the overall SIR for cancers was up only modestly, by 15%. The risk of all hematologic malignancies, however, increased 2.75-fold, compared with the expected rate in the general population.

In particular, the risk of non-Hodgkin’s lymphoma was elevated 3.64-fold. The risk of lung cancer increased by 37%, hepatobiliary cancer by 2.6-fold, and the SIR for vaginal cancer was 4.91. In contrast, the SIR for breast cancer was 0.76 (Arthritis Rheum. 2005;52:1481-90).

As in the earlier Swedish study, the SLE patients’ increased risk for non-Hodgkin’s lymphoma was noted early in the course of their disease. There also was evidence to suggest the increased risk was associated with more active lupus, but those findings weren’t confirmed in a subsequent study in which Dr. Bernatsky and Dr. Costenbader collaborated with other investigators.

This recent multicenter study compared 75 SLE patients with lymphoma to 4,961 cancer-free SLE patients. Seventy-two of the 75 lymphomas were non-Hodgkin’s lymphomas, most of which were of B-cell origin. The lymphoma risk was higher in men than in women and rose with age, just as in the general population. The lymphomas occurred a mean of 12.4 years after SLE diagnosis, which is later than in the earlier studies. No clear association was found between lupus disease activity and lymphoma risk.

Higher cyclophosphamide dosage was associated with a 1.9-fold greater risk of lymphoma than in cancer-free controls with SLE. So was a higher cumulative dose of corticosteroids, although there was no clear association between lymphoma risk and the use of azathioprine and other lupus medications (Ann. Rheum. Dis. 2014;73:138-42).

“Of course, cumulative steroids probably reflect lupus disease activity; it’s hard to distinguish between those two,” Dr. Costenbader observed.

Genetic studies aimed at untangling the link between lymphoma and SLE are planned.

Dr. Costenbader reported having no financial conflicts.


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