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Systemic lupus erythematosus (SLE) is a rare multisystem, autoimmune disease that can be difficult to diagnose because it causes many nonspecific signs and symptoms. Presentations vary significantly among patients and can range from rashes and fatigue to significant problems affecting the heart, lungs, kidneys, blood cells, and other organs.
The prevalence of SLE remains unclear because it is not a reportable disease and diagnostic criteria have varied; however, US estimates range from 20 to 150 cases per 100,000 persons, with women 10 times more likely to be affected than men.1,2
Although improved treatments and a better understanding of SLE have enabled most people with the disease to achieve a normal lifespan, it remains associated with an increased risk for many complications and morbidities, including certain kinds of cancer. Because many SLE patients are young or middle-aged adults, these risks are an important consideration for health care providers.
In an international, multicenter study conducted by Sasha Bernatsky, MD, PhD, of McGill University in Montreal, Quebec, Canada, and colleagues assessing cancer risk in more than 16,000 SLE patients, the overall risk of cancers was found to be only slightly higher than that of the general population; however, the risk of non-Hodgkin lymphoma (NHL) was higher than expected, with a standardized incidence ratio (SIR) of 4.39 vs 1.14 for all cancers combined.3 These findings supported those of earlier, smaller studies and are reflective of the overall literature. The biological mechanisms behind lymphomagenesis in patients with SLE remains unclear, but various pathways have been proposed.
Rheumatology Advisor had the opportunity to discuss SLE-related lymphoma with 2 SLE experts: Dr Bernatsky and Michelle Petri, MD, MPH, director of the Hopkins Lupus Center and professor of medicine at Johns Hopkins Medicine in Baltimore, Maryland.
Rheumatology Advisor: How well recognized is SLE-related lymphoma? Does it tend to be overlooked?
Dr Bernatsky: Many studies have been published over the years showing patients with SLE have a higher-than-normal risk of lymphoma, so physicians should be aware of this possibility. However, no one has studied whether it takes longer to detect lymphoma in patients with SLE compared with the general population. Since SLE patients tend to have regular contact with the medical system, one might think that lymphoma would be diagnosed faster in someone with SLE compared with someone without the condition. However, since some of the symptoms of SLE and lymphoma are similar, it is possible that there could be delays in the detection of cancer. Our research group is considering conducting research on this topic in the future. It should be kept in mind that while lymphoma is the most common cancer associated with SLE, it remains a rare complication in these patients, occurring in much less than 1% of SLE patients.
Rheumatology Advisor: What mechanisms might be behind lymphomagenesis in SLE?
Dr Petri: The exact mechanisms remain unclear, but a variety of complex factors — including genetic, environmental, hormonal, and pathogenic — are likely to interact and contribute to its development. Various complex biological pathways have been proposed, including an overproliferation of lymphocytes from prolonged exposure to chronic inflammation leading to a cascade of cellular events that culminate in lymphoma. Patients with SLE are also more vulnerable to viruses than the general population, which can increase their cancer risk. One such virus, Epstein-Barr, has been linked to SLE and other autoimmune diseases, as well as to B-cell lymphoma. Certain forms of lymphoma also appear to be driven by the immunosuppressive agents that are commonly used to treat SLE. More research is needed to better outline the possible pathways to lymphoma development.
Rheumatology Advisor: What are the greatest risk factors for SLE-related lymphoma?
Dr Bernatsky: As is seen in the general population, lymphoma risk in SLE appears to be higher in men than women, and risk increases with age. A study conducted by our team examined demographic factors of patients with SLE who developed non-Hodgkin lymphoma, revealing a median patient age at diagnosis of 57 years.4 An important finding of this study was that relatively aggressive histological subtypes predominated, with diffuse large B-cell lymphoma (DLBCL) being the most commonly identified (11 out of 21 cases). Interestingly, DLBCL is also the type of lymphoma most often found in patients with rheumatoid arthritis.
Additionally, some of our work suggests that SLE patients who develop lymphoma have greater exposure to the potent immunosuppressive cyclophosphamide and higher cumulative steroid use than cancer-free SLE controls. Fortunately, cyclophosphamide is not used as often as it once was and is often used in lower doses than before. However, it should be kept in mind that most SLE patients who require cyclophosphamide will never develop a lymphoma. Thus, for now, while newer treatments are in development for SLE, cyclophosphamide remains potentially useful.
Rheumatology Advisor: Because immunosuppressive agents might increase the risk of lymphoma, should they be avoided in SLE patients?
Dr Bernatsky: Although exposure to cyclophosphamide and to higher cumulative doses of steroids has been seen more often in SLE lymphoma cases than in cancer-free SLE controls, it should be kept in mind that lymphoma is a rare complication of SLE, occurring in <1% of SLE patients, as previously stated. Therefore, the vast majority of patients, even those who have received prednisone or cyclophosphamide, will not develop lymphoma. Thus, I would not recommend that SLE patients avoid these drugs if they are recommended by their health care provider.
Dr Petri: To optimize patient care, it is essential to weigh benefits against risks. In the case of immunosuppressive agents, we only use them when they are truly needed, such as when there is serious lupus activity that is damaging vital organs. As an example, if we did not use the immunosuppressant mycophenolate mofetil for SLE patients with class IV nephritis, they would end up with renal failure, which is a much more pressing threat than the very small chance that exposure to mycophenolate mofetil will cause lymphoma in the future.
Rheumatology Advisor: What laboratory indices are available to predict lymphoma development and how can they be used in clinical practice?
Dr Bernatsky: Some studies have suggested that hematologic indices, like hemoglobin and platelet counts, might be markers of lymphoma risk, but many people who have SLE will have abnormalities in their white cell counts, hemoglobin, or platelets, and almost all of those people will not develop lymphoma. Our team is studying this issue, especially trying to see if there are antibodies that might correlate with or predict cancer risk.
Rheumatology Advisor: How can the prognosis of patients with SLE-related lymphoma be improved?
Dr Petri: As with any cancer, prognosis hinges on early detection. Unexplained fever, weight loss, night sweats, and/or swollen lymph nodes should raise a high level of suspicion for lymphoma and warrant an immediate workup to assess for infection, malignancy, or any new-onset autoimmune disorders. Additionally, when lymphoma or cancer is discovered, patients should follow the therapy outlined by their oncologist. Some cancer treatments, such as rituximab, might even reduce SLE disease activity. For example, in a 14-year study, rituximab was shown to safely and effectively reduce SLE disease activity in patients who had severe or refractory SLE.5 Additionally, after the first treatment, 40% of patients had a complete response and 27% had a partial response. The treatment was well tolerated, with a low incidence of adverse events.5
Dr Bernatsky: Of additional interest, some researchers have suggested that antimalarial agents, which are commonly used to treat lupus, might prevent certain cancers, including lymphoma. One such drug is hydroxychloroquine. However, but these findings remain controversial.
An essential factor to consider is lifestyle, which applies whether a patient is dealing with SLE, SLE-related cancer, other morbidities, or just wants to maintain their general health. Lifestyle factors have a significant impact on health and should be addressed. Patients should be encouraged to attain or maintain a healthy weight by following a good nutrient-dense diet and exercising regularly, and those who smoke should be encouraged to quit. As the adage goes, “An ounce of prevention is worth a pound of cure.”
References
- Schur PH, Hahn BH. Epidemiology and pathogenesis of systemic lupus erythematosus. https://www.uptodate.com/contents/epidemiology-and-pathogenesis-of-systemic-lupus-erythematosus. Updated April 26, 2017. Accessed May 12, 2017.
- American College of Rheumatology. Lupus. https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Lupus. Updated March 2017. Accessed May 12. 2017.
- Bernatsky S, Ramsey-Goldman R, Labrecque J, et al. Cancer risk in systemic lupus: an updated international multi-centre cohort study. J Autoimmun. 2013;42:130-135. doi:10.1016/j.jaut.2012.12.009
- Bernatsky S, Ramsey-Goldman R, Rajan R, et al. Non-Hodgkin’s lymphoma in systemic lupus erythematosus. Ann Rheum Dis. 2005;64(10):1507-1509. doi:10.1136/ard.2004.034504
- Aguiar R, Araújo C, Martins-Coelho G, Isenberg D. Use of rituximab in systemic lupus erythematosus: a single center experience over 14 years. Arthritis Care Res (Hoboken). 2017;69(2):257-262. doi: 10.1002/acr.22921
