Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease that most commonly occurs in the proximal interphalangeal and metacarpophalangeal joints of the hand, in the wrists, and in small foot joints but can also affect shoulders, knees, elbows, and ankles. Three times more women than men develop RA, and 40- to 60-year-old individuals are most commonly diagnosed with this diease. The underlying cause of RA is not well understood, but most researchers believe that a combination of genetic and nongenetic factors are involved. Several of these risk factors and the general disease pathology are discussed below.
Risk Factors for RA
In addition to gender and age, several other genetic and nongenetic factors are associated with RA development. The largest genetic risk factor for RA is a hypervariable region of the class II major histocompatibility (MHC) antigen HLA-DR4. PAD-4, PTNP22, STAT4, and CTL4 may also be involved in a person’s susceptibility to RA, but the specific contributions and mechanisms are unclear.
Nongenetic components, especially oral bacteria and protein citrullination, have also been indicated as RA risk factors. Bacterial infections in the mouth cause signs and symptoms that are similar to those of RA, such as inflammation and bone and cartilage destruction, and may contribute to the initiation of RA pathology. In addition, some bacteria increase protein citrullination, the post-translational process by which enzymes called peptidylarginine deiminases convert arginine to citrulline, and this modification may be associated with RA progression.
Citrulline-targeted antibodies are increased in some patients with RA. Although citrullination is a natural process that occurs regularly in healthy individuals, the upregulation of anticitrulline antibodies is a dysregulated autoimmune response. Some of these antibodies can be detected fifteen years before RA symptoms appear, but not all patients with RA produce anticitrulline antibodies.
RA can be divided into four stages, with each stage exhibiting increased joint deterioration. Symptoms vary among patients, and symptom intensity may be intermittent: periods of relief may be interspersed among phases of acute pain. Early RA is characterized by synovial membrane inflammation, called synovitis, which causes joint swelling and pain with movement. As RA progresses, immune cells, specifically T and B cells, infiltrate the synovium, and angiogenesis is stimulated. Cartilage is gradually destroyed, causing the joint space to narrow and the underlying bone to be exposed. Mobility may become limited, adjacent muscles may atrophy, and mild malaise and nodules may occur. Treatment for early stage RA is focused on minimizing joint destruction and controlling inflammation.
As RA advances, patients may develop extensive muscle atrophy, extra-articular nodules and deformities. Soft tissue swelling and cartilage loss are visible with x-ray imaging. Eventually, fibrous tissue formation and/or bone ankylosis (i.e., bone fusion) impair joint function. Treatments during the final stages of RA focus on pain relief and disability prevention, and some patients undergo joint replacement surgery.
Due to the progressive nature of RA, early detection and treatment are critical to minimize joint destruction and functional impairment. Currently, over one hundred clinical studies on RA are active, and cell-based studies also produce valuable insights. These studies focus on understanding RA etiologies, identifying novel biomarkers and developing appropriate therapeutic treatments.
Folio Conversant can help with your cutting-edge research through our wide biospecimen sourcing network and ability to identify patients with specific disease criteria, such as antinuclear antibodies. How can we advance your RA research?
1. Ruffing, V and Bingham, CO. "Rheumatoid Arthritis Signs and Symptoms." Johns Hopkins Arthritis Center. https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-symptoms/. Updated August 16, 2017. Accessed May 8, 2018.
2. Ruffing, V and Bingham, CO. "RA Pathophysiology." Johns Hopkins Arthritis Center. https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-pathophysiology-2/. Updated September 24, 2013. Accessed May 8, 2018.
3. WebMD. "Progression and Stages of Rheumatoid Arthritis." https://www.webmd.com/rheumatoid-arthritis/guide/ra-progression#1. Accessed May 8, 2018.
4. Van Vollenhoven, R. Sex differences in rheumatoid arthritis: more than meets the eye... BMC Medicine, 2009;7(1). doi:10.1186/1741-7015-7-12
Revised on 6/22/18 by Rachel Lane PhD, RD