I have just returned from my annual meeting. I have been reviewing my notes and thanks to recent technical advances, I have gone through lecture slides and science articles on the internet. Just to make it clear, I review topics like “Toll receptors” and “microRNA.” Most people are vaguely aware of genetics and gene sequencing. We have sequenced the human genome. We have found hundreds of disease related polymorphisms, SNPs. Unfortunately this has not lead to a cure for arthritis or cancer, but we know more about these diseases than ever before.
One can Google: “signal transduction images,” and see complex diagrams of cellular responses to cell surface receptor interactions with inflammatory cytokines like TNF alpha. Within this system, we now add “STAT, “ JAK pathways,” and “microRNA processing.” Google any of these terms along with “image,” and one will see even more complicated diagrams.
Why go through this? Well, it is necessary to come to grips with modern genomics and cell biology to learn why there is no simple answer to “Why did I get rheumatoid arthritis?”
It is possible that 20 to 40 small mutations or SNPs will put one at risk for autoimmune disease. These SNPs lead to small alterations in immune cell regulation leading to a prolonged chronic inflammatory response causing diseases of the joints, skin, brain, kidneys, lungs, eyes, or nerves. The diseases occur in response to know environmental stress such as tobacco use or unusual responses to common microbes in the gut or lung. There are even studies implicating gingivitis or gum disease as a cause for rheumatoid arthritis ( Porphyromonas gingivalis ).
So the simples answer is a lot of little problems in our immune cells lead to some pretty severe diseases. Because the problems are so many, it will be unlikely that we will stumble upon one perfect drug that will cure everyone with the same disease. In fact the whole idea that we define diseases by their physical, xray, and routine labs findings will one day be considered “old fashioned.” Instead we will define illness and base treatment mostly on a set of specific genetic and cell function defects. This will be amazing since treatments for multiple sclerosis may be the same as lupus. Does this sound futuristic? Well, it’s already happening.
For many years we have had a B cell targeted therapy, rituximab. This was originally used to treat a cancer, lymphoma, with great success. In 2006, it became a FDA approved therapy for rheumatoid arthritis. It is also effective for lupus, autoimmune myositis, and multiple sclerosis as well as some autoimmune skin diseases. Why is one drug effective for some many illnesses? It is because they share common genetic susceptibility single nucleotide polymorphisms as well as a similar set of aberrant immune responses.
Another example is the “B27 related diseases” or the “spondyloarthropathies.” They all share similar gene sequences at the B27 locus. Various combinations of arthritis, psoriasis, uveititis, spondylitis, and inflammatory bowel disease occur in these patients, but they all actually have the same “disease.” It is no coincidence that all respond to TNF inhibition ( Remicade or Humira ) or to a new IL-12, IL-23 inhibitor, ustekinumab.
Just Google: “understanding JAK pathways.” This will explain the science behind the latest rheumatoid arthritis drug, tofacitinib. Using detailed knowledge of intracellular signal transduction, excessive inflammation is brought under control by this drug that blocks part of the JAK pathway.
New research on the “epigenome,” will lead to the therapies based on DNA methylation or micro RNA.
What’s next?
How about true personalized medicine? Defining a patient’s disease by their own specific set of gene defects and cellular abnormalities.
We have so many therapeutic options that we will need to know which drug will be the best and safest for the individual patient.
We already have a disease activity panel for rheumatoid arthritis from Crescendo Bioscience.
Google “ batter-up rheumatoid arthritis” to find out more about predictive biomarkers.
I ran into Mary Crow, MD, Professor of Medicine Cornell Medical College, and Chief of Rheumatology at Hospital for Special Surgery in New York. Dr. Crow is working on a gene expression profile that leads to better assessment of lupus.
The “interferon gene signature” is being used to monitor new lupus drugs from Genentech and for monitoring myositis at the Mayo clinic by Ann Reed, MD.