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Autoimmune Diseases

The AMP RA/Lupus Network studies autoimmune diseases including:

RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA) is the second most prevalent autoimmune disorder and presents clinically as a systemic autoimmune disease1.  About 1.5 million people or 0.6% of the U.S. adult population have RA2. The disease is characterized by systemic manifestations as well as local joint-based signs and symptoms that range from arthralgias (joint discomfort without tenderness) to frank swelling, pain, and inflammatory synovitis and tenosynovitis that is typically symmetric in nature. In the most severe forms of RA, loss of bone as manifest by osteopenia, and local erosions commonly occur 3. In addition to arthritis and bone loss, RA patients often show an elevated risk for cardiovascular disease and an association with various forms of pulmonary disease4.

RA is a complex disorder with several subsets of patients. For example, there are two major subsets of this disease, seropositive and seronegative RA. Seropositive and seronegative forms of RA exhibit overlapping but individually distinctive pathogenic mechanisms5.

RA is considered a prototypic polygenic disorder in which genetic risk factors interact with environmental exposures and, in the context of immune alterations, lead to the development of a severe autoimmune attack against self-tissues6. Research has shown that genetic alterations as well as genomic and epigenetic changes are associated with RA. These alterations likely reflect both environmental influences and disease-specific modifications. Treatments for RA typically have been aimed at decreasing inflammation and pain by slowing down tissue damage and reducing complications. However, most people with RA have only a partial response to available drugs, and many only respond to drugs for a limited period of time7. Therefore, scientists in the AMP RA/Lupus Network are investigating genetic and signaling pathways as potential new therapeutic targets.

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Systemic Lupus Erythematosus (SLE) is a chronic systemic autoimmune disease in which the body's immune system mistakenly attacks healthy tissue. SLE affects over 400,000 Americans, with 15-20% of patients developing the disease in childhood or adolescence.  It is estimated that 5,000-10,000 children are affected with SLE in the United States. There is a female predominance, and incidence is greater in African American, Asian, and Hispanic populations than Caucasians. SLE is characterized by the tissue deposition of autoantibodies and immune complexes that damage organ systems including kidneys, skin, blood, joints, serosa, central nervous system, and other tissues. Defects in cellular signaling and innate immunity have also been associated with lupus. The diagnostic criteria for SLE include the presence of a subset of parameters in any combination: malar rash, discoid rash, photosensitivity, oral ulcerations, arthritis, serositis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder, and antinuclear antibody 8.

Patients with SLE and other connective tissue diseases (CTDs) show production of high-titer, highly specific autoantibodies that recognize evolutionarily conserved molecules 9. Most SLE-associated autoantigens contain either the nucleic acids DNA or RNA and are often posttranslationally modified by enzymes, making the proteins immunogenic.

In SLE, anti-nuclear antibodies (ANAs) develop in the pre-disease state, epitope spreading of the ANA response is associated with progression to SLE, and titers of certain ANAs are associated with severe disease10. However, it remains unknown which specific autoantibodies are integral to the pathogenesis of SLE, and how they relate to disease manifestation and outcome. Researchers in the AMP RA/Lupus Network are working to comprehensively dissect lymphocyte responses in SLE and to identify specific ‘signatures’ associated with diagnosis, clinical subtype, disease activity, or response to therapy. 

Treatments for SLE typically have been focused on decreasing inflammation and pain by slowing down tissue damage and reducing complications. However, no effective targeted therapies exist for the most severe forms of the disease. Ongoing research in the AMP RA/Lupus Network aims to better understand the underlying disease process and identify parts of the immune system that do not function correctly. This insight will help reveal the most promising new biological targets for drug development and match existing drugs to patients with specific molecular profiles who are most likely to benefit.

REFERENCES:

1. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;358(9285):903-11. doi: 10.1016/S0140-6736(01)06075-5. PubMed PMID: 11567728.

2. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH, National Arthritis Data W. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25. doi: 10.1002/art.23177. PubMed PMID: 18163481.

3. Goldring SR. Periarticular bone changes in rheumatoid arthritis: pathophysiological implications and clinical utility. Ann Rheum Dis. 2009;68(3):297-9. doi: 10.1136/ard.2008.099408. PubMed PMID: 19213745.

4. Anaya JM, Diethelm L, Ortiz LA, Gutierrez M, Citera G, Welsh RA, Espinoza LR. Pulmonary involvement in rheumatoid arthritis. Semin Arthritis Rheum. 1995;24(4):242-54. PubMed PMID: 7740304.

5. Klareskog L, Malmstrom V, Lundberg K, Padyukov L, Alfredsson L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin Immunol. 2011;23(2):92-8. doi: 10.1016/j.smim.2011.01.014. PubMed PMID: 21376627.

6. Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, Ronnelid J, Harris HE, Ulfgren AK, Rantapaa-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54(1):38-46. doi: 10.1002/art.21575. PubMed PMID: 16385494.

7. Prince FH, Bykerk VP, Shadick NA, Lu B, Cui J, Frits M, Iannaccone CK, Weinblatt ME, Solomon DH. Sustained rheumatoid arthritis remission is uncommon in clinical practice. Arthritis Res Ther. 2012;14(2):R68. doi: 10.1186/ar3785. PubMed PMID: 22429277; PMCID: 3446437.

8. Kennish L, Labitigan M, Budoff S, Filopoulos MT, McCracken WA, Swearingen CJ, Yazici Y. Utility of the new rheumatoid arthritis 2010 ACR/EULAR classification criteria in routine clinical care. BMJ Open.2(5). PubMed PMID: 23035013.

9. Von Muhlen CA, Tan EM. Autoantibodies in the diagnosis of systemic rheumatic diseases. Semin Arthritis Rheum. 1995;24(5):323-58. PubMed PMID: 7604300.

10. Kurien BT, Scofield RH. Autoantibody determination in the diagnosis of systemic lupus erythematosus. Scand J Immunol. 2006;64(3):227-35. Epub 2006/08/22. doi: SJI1819 [pii], 10.1111/j.1365-3083.2006.01819.x. PubMed PMID: 16918691.