Managing Treatments

The LGL Leukemia and RA Connection Explained

Many people with LGL leukemia also have rheumatoid arthritis. The two share some genetic basis and overlapping treatment options. Find out more about the connection between LGL leukemia and RA.

Many people with LGL leukemia also have an autoimmune disorder, most commonly rheumatoid arthritis (RA). In fact, as many as between 11 and 36 percent of people with LGL leukemia may also have RA, according to research published in the Current Opinion in Hematology. But what’s the connection between the two?

Understanding the Diseases

To understand how LGL leukemia and RA are linked, let’s first review the two disorders. Large granular lymphocyte (LGL) leukemia is a rare form of blood cancer, in which a person has too many or a higher than normal ratio of large granular lymphocytes compared to other types of white blood cells. White blood cells help your body fight off infection; too many of them can lead to problems with how your immune system responds to a threat or invader. This type of leukemia is most frequently a chronic disease, requiring regular monitoring and with symptoms that come and go. Although LGL leukemia is generally chronic with patients having a normal lifespan, it is called a cancer because the high amount of white blood cells are clonal. In other words, the large population of white blood cells was copied over and over from one original cancer cell.

Rheumatoid arthritis is an autoimmune disorder in which your immune system attacks your joints rather than harmful invaders. It causes inflammation and joint damage. About 1.5 million people in the United States have been diagnosed with RA, according to the Arthritis Foundation. Yet, only about 1,000 people annually are diagnosed with LGL leukemia. In addition, a rare variant of RA known as Felty’s syndrome also exhibits low neutrophil counts and an enlarged spleen. Thus, the overlap between disease features commonly observed in Felty’s syndrome and in LGL leukemia patients with co-occurring RA suggests that these may actually be the same disorder.

Commonalities Between LGL Leukemia and RA

Published studies have identified a number of features that are commonly observed in both LGL leukemia and RA. Both are associated with an expansion of a particular subpopulation of CD8+ T cells, which is technically referred to as a “clone.” This expansion is dramatic in LGL leukemia, and the evidence of a dominant clonal population in the blood is a key diagnostic feature of this disease. In contrast, RA is associated with detection of more subtle CD8+ clonal expansion in the blood and affected joints. Both diseases are associated with increased levels of inflammatory cytokines within the serum, although the exact cytokines may vary between individual patients and between the diseases. Treatment for both diseases frequently includes immunosuppressive agents, as described below.

Uncovering a Genetic Basis

Researchers are trying to figure out the connection between LGL leukemia and RA. Many people with LGL leukemia have someone in their family who has also been diagnosed with RA, which suggests that there are common underlying genetic features.

The two diseases have a similar genetic basis, so researchers know there’s a relationship. They don’t, however, know whether one leads to the other. People with LGL leukemia plus co-occurring RA and those with Felty’s syndrome, the rare subset of RA described above, have a high frequency of the HLA-DR4 haplotype, according to an article published in Cancer Therapy Advisor. A haplotype refers to a cluster of genes. The HLA-DR4 cluster is related to how your body controls its immune system response.

This connection suggests to researchers that rather than being separate diseases, LGL leukemia, Felty’s syndrome and RA may potentially be part of the same disease process within the body. Therefore, this is an active area of research within the Loughran lab at the UVA Cancer Center and in their collaborative studies with other research groups. Having both diseases together doesn’t seem to affect how one reacts. This means that if you have RA, that disease will have the same progression and symptoms regardless of whether you also have LGL leukemia.

How RA Affects LGL Leukemia Treatment

Treatment for LGL leukemia involves suppressing the immune system response, the same treatment approach used for autoimmune disorders, according to the Arthritis Foundation. Methotrexate is most often the first medication used for LGL leukemia and is a common medication to treat RA. Cyclophosphamide and cyclosporine are also commonly used to treat LGL leukemia and may be utilized in rare situations for RA. Tofacitinib, a new medication that targets the JAK-STAT signaling pathway that plays a key role in your immune system, may also be used to treat RA. This drug has been evaluated in a small group of patients with both LGL leukemia and RA as a possible treatment when other options aren’t working. In addition, methotrexate has also been shown to inhibit the JAK-STAT pathway.

Dr. Thomas Loughran, Jr., the director of the UVA Cancer Center and the physician who discovered LGL leukemia, prescribes a treatment for LGL leukemia and works closely with a patient’s rheumatologist to manage the RA as well when both diseases co-occur. This collaborative approach between an oncologist and rheumatologist can help you get the best, safest treatment possible.

Researchers in the Loughran lab and elsewhere continue to study the genetic basis of both diseases to better understand the connection and causes. Contributing blood and tissue samples to the LGL Registry helps further efforts not only at UVA, but also around the world to uncover new treatments and possibilities for people with LGL leukemia.

UVA Cancer Center is on the cutting edge of LGL leukemia research. Find out how you can help this effort.

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Patricia Chaney
Patricia Chaney