I Have Rheumatoid Arthritis... I'Ve Heard That Something Called Cathepsin G Is Important ... What Is It?

Rheumatoid arthritis is the most common inflammatory form of arthritis. It is a chronic, systemic, autoimmune process that affects more than 2 million Americans. While it typically affects both small (hands, wrists, ankles, feet) and large joints (shoulders, elbows, knees, hips), leading to a potentially disabling and crippling situation, it also causes internal organ damage and can affect the eyes, skin, heart, and lungs and other organs as well.

The thrust of much research has been in the direction of detecting the immune abnormalities that are responsible for the damage in rheumatoid arthritis (RA). Strides in understanding how the disease starts and is perpetuated has shown that RA is a result of many complex interactions among different cells such as T lymphocytes, B lymphocytes, macrophages, plasma cells, fibroblasts, dendritic cells, and neutrophils.

This cellular interaction leads to the manufacture and release of many chemical messengers or enzymes that are responsible for the perpetuation of chronic inflammation. These chemical messengers are called cytokines.

Theoretically, blocking the effect of cytokines that promote inflammation may lead to a reduction in inflammation and subsequent damage.

To date, the most important cytokine appears to be tumor necrosis factor (TNF). Drugs such as etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade) have shown great efficacy in controlling and slowing down the progression of RA.

However, other cytokines also appear to play major roles in the perpetuation of inflammation. Among the many cytokines that have been studied in addition to TNF are interleukin 1, interleukin 6, interleukin 17, protein kinases, and most recently a substance called cathepsin G.

Scientists at Washington University School of Medicine in St. Louis have found a new role for this enzyme that may make it a target for anti-inflammatory treatments.

The finding by researchers shows that cathepsin G regulates the ability of the immune cells known as neutrophils to secrete chemicals that attract other immune cells and start the local inflammatory process. Over time, the excessive accumulation of immune cells that is a result of cytokine overactivity can lead to tissue and cartilage damage in joints, causing pain, limited mobility, and progressive crippling.

"Cathepsin G affects a very early step in this kind of immune response, so inhibiting it has attractive potential for developers of therapeutics," says senior author Christine T.N. Pham, M.D., assistant professor of medicine and a rheumatologist at Barnes-Jewish Hospital.

The study appears in the June 2005 issue of Immunity.

Cathepsin G, which is made by the neutrophils it regulates, is also an attractive target because it belongs to a class of enzymes known as proteases. Proteases are anew class of cytokines that may play a significant role in chronic inflammation and joint destruction.

(Raptis SZ, Shapiro SD, Simmons PM, Cheng AM, Pham CTN. Serine protease Cathepsin G regulates adhesion-dependent neutrophil effector functions by modulation integrin clustering. Immunity, June 7, 2005, 679-691).

RA is a heterogenous condition, meaning that it encompasses a wide spectrum of presentations and possible mechanisms that cause the disease. Because it is such a wide spectrum of diseases, it has been difficult to find a pinpoint cure. Since different cytokines may be responsible for different types of RA, it is important to better understand the complicated mechanisms of disease so that better and more specific therapies can be produced.

Author''s note: It is uncertain as to how big a "player" in RA cathepsin G will be. I can still remember the days when all we had were gold, hydroxychloroquine (Plaquenil), and de-penicillamine as drugs that would modify disease. The advent of biologic therapies has changed all that for the better. It is these observational experiments that will lead to the unlocking of the secret to an eventual cure for this most debilitating and crippling illness.

Nathan Wei, MD FACP FACR is a rheumatologist and Director of the Arthritis and Osteoporosis Center of Maryland. He is a Clinical Assistant Professor of Medicine at the University of Maryland School of Medicine. For more info: Arthritis Treatment.