WASHINGTON, D.C.—Identifying anticitrullinated protein antibodies (ACPA) as a critical marker of rheumatoid arthritis (RA) was a huge step, but deeper knowledge of how they work is crucial before therapies involving them can be used in the clinic and finely tailored for maximum benefit, a molecular medicine expert in rheumatology said in a session titled, “Prospects for Prevention and Cure of Rheumatoid Arthritis,” here at the 2012 ACR/ARHP Annual Meeting, held November 9–14 in Washington, D.C. [Editor’s Note: This session was recorded and is available via ACR SessionSelect at www.rheumatology.org.]
The Role of ACPA
The picture of ACPA and how it operates is becoming clearer all the time, said Lars Klareskog, MD, PhD, professor in the rheumatology unit and director of the Center for Molecular Medicine at the Karolinska Institute in Stockholm, Sweden. Researchers at his center and elsewhere recently have shed more light on the complexity of ACPA and its different targets, like citrullinated fibrinogen and citrullinated vimentin.
Recent work involving nearly 2,000 RA cases subdivided the disease based on different ACPA specificities and gauged how those subcategories were related to the presence of the shared epitope, HLA-DRB1, a hallmark of severe RA. The odds ratio of having the shared epitope varied widely.1
For those with ACPA specificities for both citrullinated alpha-enolase and vimentin, the likelihood of having the shared epitope was “extremely high,” Dr. Klareskog said. “This means, probably, that there are somewhat different mechanisms involved in driving the B-cell immunity against these different epitopes,” he said.
Dr. Klareskog also noted work that examined the extent to which B cells produce ACPA, which included a finding that in these patients, about 25% of all the CD19+ B cells produced antibodies against citrullinated antigens.2,3
Harnessing these kinds of new insights will require a smarter approach in surveillance and modification of the immune process, he added. Approaches might include using existing, more conventional therapies in very specific contexts and therapies directly aimed at T-cell “tolerization” and at interference with specific antibody functions, he noted.
“We are in a new situation, and then we can begin to use these things,” Dr. Klareskog said. “We are doing these things, of course, in parallel in people with diabetes, with multiple sclerosis, and I would argue that we are in a much better situation with rheumatoid arthritis.”
Early Detection Is Key
V. Michael Holers, MD, professor in the integrated department of immunology at the University of Colorado (UC) in Denver, said that RA is, “in principle, a preventable disease.” By looking at the patterns of biomarkers including ACPA and cytokines linked with imminent onset of the disease, researchers might be able to draw closer to therapies preventing RA, he said.
At UC, researchers have been defining high-risk patients as those with anticyclic citrullinated peptide 2 (antiCCP2) antibodies, or two or more rheumatoid factors, or both, which has been shown to be 95% specific for future RA. But, predicting who will get RA is one thing, and understanding how to prevent it is another, Dr. Holers said.
“We not only want to be able to predict clinical onset, we want to identify the site and the mechanisms of the onset of the disease,” he added.
For the last eight years, the Studies of the Etiologies of Rheumatoid Arthritis (SERA) project at UC has been trying to get at some of these specifics by looking at, among other things, the levels of ACPA in antiCCP2-positive subjects, and at chemokine and cytokine levels.
A possible candidate for further exploration, Dr. Holers said, is the use of a “cytokine score.” Researchers determine—for a variety of cytokines—the odds ratio that the cytokine will be linked to a high-risk RA autoimmunity status. The total of those odds ratios is the cytokine score.4
Team Approach to Research
A team approach across disease specialties will make prevention therapies more likely, Dr. Holers said. “Autoimmune diseases are really prevalent in the population and none of us, including those with type 1 diabetes, can view their diseases individually,” he continued. “They all have a very similar kind of evolution. They all have biomarkers, mostly antibodies in the preclinical phase.”
Michael Brenner, MD, professor of medicine at Harvard University in Boston, and chief of rheumatology, immunology and allergy at Brigham and Women’s Hospital in Boston, said that “nature is pointing us to something that may be useful” in developing antigen-specific treatments to replace the blunter tools now at rheumatologists’ disposal.
Studies are beginning to show antigen-specific behavior by T cells, Dr. Brenner said.5,6 “The possibility to expand or direct T-regs in vivo to relevant self antigens is what evolution has come up with to control T-cell autoreactivity,” he said. “And I think it may have an important lesson to at least point us in the direction in which we may be able to apply the self-antigen adaptive immunity that we’ve been seeking since the T-cell receptor was discovered.”
Another direction toward a possible cure might be focusing on the role of certain cadherins—adhesion molecules that effectively glue our cells together—in damage to the joints. “We focus so much on inflammation in rheumatoid arthritis, but we can also benefit from focusing on protecting the joint directly,” he added.
There is ongoing tension between discovery-driven research and the traditional hypothesis-driven research, when the goal should be to merge them, Dr. Brenner said.
A recent example of this merging can be seen in the lab of Vijray Kuchroo, DVM, PhD, professor of neurology at Harvard Medical School in Boston, where Dr. Kuchroo and collaborators have used new tools to analyze the role of genes in the differentiation of TH17 cells, which are important players in RA. That led to the discovery that serum and glucocorticoid-inducible kinase 1 (SGK-1) are closely linked to that process.
SGK-1 is a regulator of sodium channels, and researchers later found that mice on a high-salt diet showed “measurably enhanced” TH17 cell differentiation.
“The new technologies and new tools that we have really aren’t in conflict with the old, hypothesis-driven approaches that some of us know and love,” Dr. Brenner said. “But they really work together with it and allow us to discover new things.”
Thomas Collins is a freelance medical journalist based in Florida.
References
- Lundberg K, Bengtsson C, Kharlamova N, et al. Genetic and environmental determinants for disease risk in subsets of rheumatoid arthritis defined by the anticitrullinated protein/peptide antibody fine specificity profile. Ann Rheum Dis. 2012 June 1. [Epub ahead of print]
- Malmström V, Amara K, Meffre E, et al. Generation and characterization of monoclonal anti-citrullinated antibodies from single RA synovial B cells. Ann Rheum Dis. 2012;71(suppl 3):315.
- Amara K, Steen J, Murray F, et al. Monoclonal IgG antibodies (ACPAs) from synovial fluid B cells of rheumatoid arthritis patients—antigen-driven affinity maturation and cross reactivity. Arthritis Rheum. 2012;64(suppl):S1091.
- Hughes-Austin JM, Deane KD, Derber LA, et al. Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimmunity in first-degree relatives without rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA). Ann Rheum Dis. 2012 Aug 21. [Epub ahead of print]
- Wright GP, Notley CA, Xue SA, et al. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Proc Natl Acad Sci USA. 2009;106:19078-19083.
- Van Herwijnen MJ, Wieten L, van der Zee R, et al. Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis. Proc Natl Acad Sci USA. 2012;109:14134-14139.
