The Autoimmune Epidemic: Bodies Gone Haywire in a World Out of Balance--and the Cutting-Edge Science that Promises Hope (No Series) (42 page)

Worldwide studies confirm:
EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet 2000 Mar 11;355(9207):873–6.

scientists may be able to develop a blood test:
Avasarala JR et al. A distinctive molecular signature of multiple sclerosis derived from MALDI-TOF/MS and serum proteomic pattern analysis: Detection of three biomarkers. J Mol Neurosci 2005 Jan;25(1):119–25.

Other breakthroughs in MS diagnostics:
Marta CB et al. Pathogenic myelin oligodendrocyte glycoprotein antibodies recognize glycosylated epitopes and perturb oligodendrocyte physiology. Proc Natl Acad Sci U S A 2005 Sep 27;102(39):13992–7. Epub 2005 Sep 19.

state-of-the-art eye exams:
Carmichael A. Eye exams detect early signs of MS. Wall Street Journal, 2007 Jan 2, D6.

Ultimately, understanding how small differences:
In one recent study that sheds light on this, researchers at the Rockefeller University found that reversing the defects in certain genes that play into the autoimmune disease lupus can restore health in animals with lupus. Although lupus clearly results from a combination of genetics that varies from person to person, nevertheless it may be that a common “gatekeeper” gene—called FCRgIIB—is critical to preventing the disease in many cases. If you can reverse the defect in that gatekeeper gene you can reverse disease in animals with lupus by preventing the accumulation of autoantibodies that are responsible for the progression of the disease. It works like this: if a mouse is deficient in this particular FCRgIIB gatekeeper gene it will produce a genetically reduced level of what are known as Fc receptors. Fc receptors are critical, because they work to inhibit the immune-system cells from becoming activated and producing the rogue autoantibodies that go on to attack the body’s own tissue. When researchers placed bone marrow in mice that expressed additional copies of the Fc receptor gene, those mice did not develop autoimmune disease. The difference between healthy immune function and autoimmune dysfunction turned out to be surprisingly small: researchers only had to increase the Fc receptor’s activity by about 40 percent. Doing so allowed the increased Fc receptors to halt the formation of the autoantibodies associated with lupus. Such a finding suggests that adjusting the level of Fc receptors could provide a promising future means of preventing and treating lupus.

For more on this see Ravetch JV et al. Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 2005 Jan 28;307(5709):590–3 and Ravetch JV et al. The inhibitory Fcgamma receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells. Nat Immunol 2005 Jan;6(1):99–106. Epub 2004 Dec 12.

Also see Ambrose SG. Dallas scientists make gains in lupus research: Genes that set off autoimmune disease in mice identified. Dallas Morning News, 2006 Jun 18;26A. Wakeland EK et al. Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc Nat Acad Sci 2006 Jun 27;103(26):9970–5. Epub 2006 June 15.

Likewise, a 2007 genome study:
International Multiple Sclerosis Genetics Consortium et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007 Aug 30;357(9):851–62. Epub 2007 Jul 29.

The idea that a gene might be protective:
An international team from the University of Montreal, Massachusetts Institute of Technology, and Harvard have just unveiled a detailed map of human genetic variation within what is known as the major histocompatibility complex, or MHC, a critical region of the human genome that encodes how we respond to infection and whether or not we develop autoimmune disease. The MHC—specifically the genes that constitute it—is associated with more diseases than any other region of the human genome, including rheumatoid arthritis, type 1 diabetes, lupus, multiple sclerosis, and Crohn’s disease. The MHC, not surprisingly, is also where our allergy genes are located. This area of the genome may provide critical clues as to why both autoimmunity and allergies are simultaneously on the rise, since they work through similar immune pathways. However, pinpointing the specific genetic differences in humans that cause these diseases is complex, given the extremely high degree of genetic diversity that exists in the MHC among different individuals.

To look at the variability of genetic patterns of the MHC, researchers analyzed its DNA sequence in more than 350 individuals from diverse geographic regions, including Africa, Europe, China, and Japan, providing data that other researchers can begin to use to identify the broader patterns that point to increased genetic risk for autoimmune diseases. Duerr RH et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006 Dec 1;314(5804):1461–3. Epub 2006 Oct 26. de Bakker PI. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 2006 Oct;38(10):1166–72. Epub 2006 Sep 24.

Women account for nearly 80 percent:
Dale E et al. A role for transcription factor NF-kappaB in autoimmunity: Possible interactions of genes, sex, and the immune response. Adv Physiol Educ 2006 Dec;30(4):152–8.

Yet the precise ways in which sex hormones:
Ibid.

Physicians can then warn patients:
In the Netherlands researchers are using a connect-the-dot approach to determine which patients who show signs of early joint pain and stiffness should be treated prophylactically for rheumatoid arthritis and which should not. Among those who seek out a doctor’s help for joint pain and stiffness, the most common diagnosis is undifferentiated arthritis (UA), or arthritic symptoms that do not add up to any specific arthritic disease. Spontaneous remission occurs in 40 to 50 percent of UA sufferers, while about 30 percent develop rheumatoid arthritis, a much more serious disease. A wealth of research supports early aggressive treatment for those with rheumatoid arthritis, or RA, showing that treatment is integral in preventing joint damage and severe disability, but the drugs of choice bring a substantial risk of liver damage and other serious complications. Physicians often face a tough choice of whether to initiate aggressive drug therapy immediately in patients presenting with early signs of arthritis or to wait and see if they are actually going to develop RA. To help inform these individual decisions to treat or not to treat, researchers at Leiden University Medical Center in the Netherlands have found a formula to help determine whether patients who present with UA are, in fact, going to progress to RA. Through a combination of questionnaires, physical examination, and blood samples, the team identified nine clinical variables that, when combined, have a strong ability to predict rheumatoid arthritis versus undifferentiated arthritis. Looking at gender, age, specific location and duration of symptoms along with specific autoantibodies and other key blood biomarkers, researchers were able to give each patient a score ranging from zero to fourteen and predict quite accurately who would develop the more debilitating of the two diseases. Using such evidence-based predictions promises to be enormously helpful to clinicians who are trying to muddle through the cost-benefit analysis of which patients should be treated with early drug intervention. Van der Helm-van Mil AH et al. A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: How to guide individual treatment decisions. Arthritis Rheum 2007 Feb;56(2):433–40.

These drugs do help to stave off joint destruction:
Enbrel (etanercept) “important information” available from http://www.enbrel.com:80/index.jsp?f=7 (accessed May 24, 2007).

Also used in the treatment of Crohn’s:
Dale E et al. A role for transcription factor NF-kappaB in autoimmunity: Possible interactions of genes, sex, and the immune response. Adv Physiol Educ 2006 Dec;30(4):152–8.

On June 5, 2006, the U.S. Food and Drug Administration:
http://www.tysabri.com/tysbProject/tysb.portal (accessed May 24, 2007).

Investigators suspect:
Johannes L. Where drug’s setback leaves patients: Withdrawal of Tysabri reshapes options for those with multiple sclerosis, Crohn’s, severe arthritis. Wall Street Journal, 2005 Mar 1;D1.

Rituxan works by preventing signals:
Rituxan works by altering the body’s production of B cells. B cells, or B lymphocytes, normally respond only to foreign antigens such as bacteria and viruses. But in people with autoimmune disease the cells react to the body’s own molecules, generating antibodies that bind to those “self-antigens” and then accumulate—in lupus for example—in their tissue, where they create tissue damage. Rituxan aids autoimmune-disease patients by blocking one of the molecular interactions that lead to antibody production and tissue injury. It works like this: T cells peruse different foreign antigens to decide whether or not they’re harmful to the body. If T cells decide that the antigen is a foreign agent that the body needs to fight against, they then send out signals that cause T cells to proliferate—and to also produce B cells. The idea is that if we can prevent these signals from being transmitted, we can prevent B cells from attacking tissue. The train will never leave the station, much less reach its target destination. Rituxan stops the train by targeting a specific protein, known as CD20, on the surface of B cells. Rituxan binds to CD20 and is believed to work with the body’s own immune system to attack and kill the marked B cells, although the exact mechanism by which this happens is still unclear. Typical treatments for those with MS, for example, involve one infusion, followed by a second infusion two weeks later and infusions every six months thereafter, a happy improvement over drugs that require daily or even monthly injections.

Rituxan not only helps to stop MS:
http://www.utsouthwestern.edu/utsw/cda/dept37389/files/219222.html (accessed May 24, 2007). Stuve O et al. Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis. Arch Neurol 2005 Oct;62(10):1620–3.

their disease went into remission:
Data presented at the 2006 American College of Rheumatology Congress show that patients receiving repeat treatment with MabThera/Rituxan (rituximab) achieved continued improvement in both physical and mental aspects of quality of life measures. A press release detailing these findings, “Repeat treatment with MabThera provides continuous improvement in quality of life in RA patients: Benefit of B cell therapy confirmed in patients who respond inadequately to one or more TNF inhibitors,” is available from http://www.eurekalert.org/pub_releases/2006-11/cwl-rtw111006.php (accessed May 24, 2007).

Doctors and analysts are unsure:
Won Tesoriero H. Drugs in testing show promise for lupus: New treatments target disease, not just symptoms; first big advances in 50 Years. Wall Street Journal, 2007 Jan 23;D1.

These include Orencia:
Ibid.

Over time, such technology:
American Autoimmune Related Diseases Association. Who we are. Press release; 1. Available through the American Autoimmune Related Diseases Association, 22100 Gratiot Avenue, East Detroit, MI 48021-2227, (586) 776-3900, [email protected].

compared to the yearly health-care burden:
http://www.cdc.gov/nccdphp/publications/factsheets/Prevention/cancer.htm (accessed May 24, 2007).

One paper in the journal
Science: Kodoma S et al. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 2003 Nov;302(5648):1223–7.

The researchers also apologized to patients with diabetes:
Based on an interview with Denise Faustman, associate professor of medicine at Harvard Medical School, October 21, 2006.

All three labs followed Dr. Faustman’s procedures:
Begley S. After initial rejection, scientists back work on cure for diabetes. Wall Street Journal, 2006 Mar 24;B1.

CHAPTER SIX: SHIELDING YOUR IMMUNE SYSTEM

He consulted several other like-minded physicians:
Gerard Mullin consulted Dr. Leo Galland in New York, Loren Marks, a holistic board-certified nutritionist in New York, and John McCorrie in the United Kingdom.

“Yet we have clear data”:
Cantorna MT. Vitamin D and its role in immunology: Multiple sclerosis and inflammatory bowel disease. Prog Biophys Mol Biol 2006 Sep;92(1):60–4. Epub 2006 Feb 28. Mark BL, Carson JA. Vitamin D and autoimmune disease—implications for practice from the multiple sclerosis literature. J Am Diet Assoc 2006 Mar;106(3):418–24. van Meeteren ME et al. Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr 2005 Dec;59(12):1347–61.

Today, 21 percent of patients:
Bensoussan M et al. Complementary and alternative medicine use by patients with inflammatory bowel disease: Results from a postal survey. Gastroenterol Clin Biol 2006 Jan;30(1):14–23.

Consumers in general in the United States:
http://dietary-supplements.info.nih.gov/pubs/fnce2005/M%20F%20Picciano-Who%20Is%20Using%20Dietary%20Supplements%20and%20What%20are%20They%20Using.pdf (accessed May 24, 2007). Also see Eisenberg DM et al. Trends in alternative medicine use in the United States, 1990–1997: Results of a follow-up national survey. JAMA 1998 Nov 11;280(18):1569–75.