Since I’m now on my second biological medicine for RA and have a degree in biology, curiosity got the best of me. I wanted to know what’s going on in my body when I inject these wild, expensive medicines. That led me to try to understand the biochemical processes involved with RA. Scientists may not know the causes for RA, but they do know a great deal about the biochemical processes.
Rheumatoid arthritis is an autoimmune disease so a primer on immunity is necessary. It’s a complex system but some basic understanding will help. When a substance gets into the body that does not belong, the immune system kicks into gear in an effort seek and destroy the invader. Special cells called lymphocytes (our “white knights” in shining armor) rush in to save the day. The T-cell lymphocytes identify the invaders via their antigens. You could think of T-cells as the intelligence gathering cells. Once the invaders are identified, the T-cells release chemicals called cytokines which trigger B-cell lymphocytes to produce antibodies. The antibodies find the invader antigens and attach to then so that various white blood cells can destroy the invaders. In RA, our “white knights” don’t work correctly. [i], [ii]
As the immune response occurs, tissues become inflamed. Inflammation, which can include heat, redness, swelling, and pain, is a good thing in the short term as it helps the body to heal. But if something is wrong and inflammation is long term, the body starts damaging itself. [iii] Thus the term autoimmunity…attacking self. RA involves chronic inflammation.
During immune responses, many signaling chemicals called cytokines are produced. Cytokines are of great interest to researchers because they are involved in many diseases. Tumor necrosis factor (TNF) is a cytokine which is involved in inflammatory responses. It can be produced by numerous sources in the body including T-cells. Many diseases are connected with TNF. [iv] As I mentioned in an earlier post, TNF was first linked with RA in the 1980s. High concentrations of TNF are found in the bone joints of active RA patients.
RANKL (Receptor Activator for Nuclear Factor κ B Ligand) is a member of the TNF family. RANKL is needed in the body as it activates cells called osteoclasts. Two types of bone cells, osteoclasts and osteoblasts, help regulate the amount of bone tissue. The ‘blasts form new bone and the ‘clasts break it down. Both are needed to keep bone tissue healthy. Osteoporosis, a common ailment primarily in elderly women, results when osteoclasts are over activated by a hormone. In rheumatoid arthritis, RANKL is overproduced resulting in overproduction of osteoclasts leading to the erosion of bone tissue.[v]
The biochemical picture of RA in simplistic terms is as follows:
- Something unknown triggers lymphocytes (T-cells, B-cells)
- Lymphocytes trigger TNF and inflammation
- TNF induces RANKL
- RANKL promotes the production of osteoclasts
- Osteoclasts erode bone tissue.
Most of the typical symptoms of RA are tied to these processes and include swelling, pain, fatigue, and bone erosion.
RA treatments (other than those only addressing pain and inflammation) include drugs like methotrexate. The exact reasons why methotrexate helps RA patients is unknown but it is linked to suppression of the immune system. A clearer understanding of the biochemical processes that emerged since the 1980s led to the development of biological treatments that target the system described above. Many of the current biological drugs target the TNF part of the system. Antibodies designed to attach to TNF, the so-called TNF Inhibitors, include Enbrel, Humira, Remicade, Simponi, and Cimzia. Other antibodies used to treat RA include Rituxan which reduces B-cells, Orencia which reduces T-cells, and Kineret which impacts cytokines. All of these biological treatments suppress the immune system making patients susceptible to infections.
I’m hopeful that researchers will continue to unravel the mysteries of RA which in turn will lead to new, more effective biological treatments. For example, researchers at the University of Rochester recently announced that they found another aspect of the system related to TNF and RANKL called the factor kappa B complex (NF-κB) which may lead to new treatments. [vi] There are a number of new medicines being tested and RA patients can participate in clinical trials. [vii]