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Advances in Understanding the Pathophysiology of Rheumatoid Arthritis

Key Points

  • The immune system is the key to understanding how rheumatoid arthritis (RA) develops
    and is perpetuated.
  • Chronic synovial inflammation may be driven by interdependence between B and T cells
  • Multiple immune system targets for treatment of RA include cytokine function, T- and B-cell
    interactions, T-cell activation, or B-cell depletion
  • Like the currently available biologic agents, novel agents in development have the potential
    to significantly improve the course of RA

Insight into the pathophysiology of rheumatoid arthritis (RA) is expanding the range of available RA therapies. RA affects about 0.8% of the US population, or approximately 2 million people, with women affected 2–3 times more often than men. (1) RA exacts a significant toll; disability begins early and progresses so that by the 20th year of illness more than one-half of patients cannot work. RA also affects mortality so that patients with RA have a 2–18-year reduction in life expectancy. (1,2,3) Current aggressive therapy approaches seem to be improving the long-term outlook for these patients. (4,5) The etiologic agent for RA remains unknown, (6) despite intense study for more than a century; however, it is postulated that some environmental or microbial trigger initiates local
inflammation in the joint, leading to proliferation and activation of synovial cells and recruitment of leukocytes to the joint. (2,7,8) There is a strong association between RA and major histocompatibility complex (MHC) antigen HLA-DR4, and there is increased prevalence of RA with first-degree relatives, suggesting a genetic component to the disease. (3)

The Immune System and Rheumatoid Arthritis

Dysregulation of the immune system may result in a chronic inflammatory environment in which the production of cytokines and growth factors supports infiltration of lymphocytes and proliferation of synovial fibroblasts in the synovium. Synoviocytes along with other cells form an invasive pannus that leads to cartilage and bone damage in the joint through several mechanisms. For example, these cells can produce matrix metalloproteinases, enzymes that mediate degradation of connective tissue. (3,9,10) Synoviocytes also activate chondrocytes and osteoclasts, which, in this environment, break down cartilage and initiate bone erosion. These processes may become self-perpetuating in patients with RA, evolving into a chronic condition wherein the joint is continuously populated by synoviocytes, macrophages, and lymphocytes. The periarticular cartilage and bone are thereby damaged, leading to impaired joint function and disability. (1,3,8,10)

Autoreactive lymphocytes are common features of autoimmune conditions. In RA, CD4+ and CD8+ T cells infiltrate the synovium, possibly in recognition of some unidentified antigen(s). T cells become activated and secrete cytokines that can activate other cells, including other T cells, B cells, macrophages, and fibroblasts. Different types of T cells, including TH1, TH17, and CD4+CD25+ regulatory T cells, contribute to an imbalance of T-cell regulation and exacerbate inflammation in the RA joint. (11,12)

Advances in Understanding the Pathophysiology of Rheumatoid Arthritis

Production of autoreactive antibodies by B cells has been recognized as a feature of RA, although the role of the B cell had generally been considered a secondary consequence of ectopic T-cell activation. The precise contribution of B cells to the inflamed synovium is thought to include the following: as an antigen-presenting cell (APC) necessary for T-cell activation (13,14,15); B-cell production of proinflammatory cytokines, which contribute to inflammation and tissue damage (7,14); and B-cell autoantibody production that results in increased macrophage activity and provides paracrine signals supporting T-cell–mediated secretion of proinflammatory cytokines. (13,14)

Several autoantibodies produced by B cells may contribute to RA pathogenesis. (5,7) As part of the diagnostic criteria for RA, serologic tests for antibodies called rheumatoid factor (RF) are performed. RF is an antibody specific to the Fc portion of IgG. (16) The presence of RF is not specific to RA, as RF is also detected in other illnesses (eg, Sjögren syndrome) and is present in 5% of the population by definition, as high as 15% among certain groups such as older persons. (5,16)

More specific to RA are the presence of anticyclic citrullinated peptide (anti-CCP) antibodies. (5,16,17,18) Anti-CCP antibodies bind citrulline, a posttranslationally modified amino acid created by enzymes that are abundant in inflamed synovium. The CCP1 ELISA detects anti-CCP antibodies, with a sensitivity of 65%–75% and specificity of 95% for RA patients. Later-generation CCP ELISAs recognizing other citrullinated proteins have further increased specificity. Anti-CCP antibodies may be detected before RF is detected, thus allowing earlier, more definitive diagnosis of RA. Patients with anti-CCP antibodies early in disease may be more likely to develop erosive disease as compared with patients without anti-CCP antibodies. Patients with RA may also have other autoantibodies including antinuclear antibodies (ANA); however, their significance in patients is unknown. (5,16,17,18)

Synovial tissue from patients with RA show that most contain both B and T cells and, in some cases, B cells organized into tertiary lymphoid aggregates resembling germinal centers. (15,19,20) These organized structures require a proinflammatory environment with signals exchanged among T cells, B cells, and dendritic cells, generating autoantibodies and proinflammatory cytokines. Lymphoid infiltrates in the synovium are thus a source of B cells, autoantibodies, and proinflammatory cytokines. (15,21,22) These findings suggest that the inflammatory process in the synovium is driven to some extent by B cells, with synovial B cells acting as APCs for T cells and synovial T cells stimulating the clonal expansion of B cells and increasing autoantibody production. (23,24) These observations suggest that the inflammatory process in the synovium may be driven by interdependence between B cells and T cells.

Certain cytokines produced by T cells, B cells, and other cells in the synovium play a significant role in chronic inflammation in RA. (15,25) TNFα, a potent cytokine with diverse effects on multiple cell types, is produced by monocytes, macrophages, lymphocytes, and other cells. Aside from stimulating production of IL-1, IL-6, IL-8, and other cytokines, TNFα is known to stimulate migration of lymphocytes to inflammatory sites such as the inflamed joint. (15,26) IL-1 is produced by monocytes, macrophages, B cells, and T cells and has many functions, including the ability to stimulate fibroblasts and chondrocytes to release matrix metalloproteinases, which damage the synovium. IL-6, produced by T cells, monocytes, macrophages, and synovial fibroblasts, induces final maturation of B cells, activation of T cells, and proliferation of synovial fibroblasts, and among other activities is a potent inducer of the acute-phase response proteins, osteoclast activation, and release of matrix metalloproteinases. (15,27,28)

Therapy for Rheumatoid Arthritis

Nonsteroidal anti-inflammatory agents alleviate some of the inflammation, joint stiffness, and pain but are not effective at slowing disease progression. Corticosteroids such as prednisone are more potent agents in targeting inflammation and in slowing disease progression, but effects can diminish over time. (1,29) Traditional diseasemodifying antirheumatic drugs (DMARDs) (eg, methotrexate, sulfasalazine, leflunomide) have demonstrated clinical success in improving signs and symptoms of the disease in many patients and in slowing disease progression for some. Treatment has moved to an early institution of DMARD therapy from the time of diagnosis of disease with more aggressive dose escalation of methotrexate, which serves as the current gold standard anchoring DMARD for most patients. DMARDs also include a group of recently developed biologic agents, which target specific functions of the immune response involved in RA. (1,30) The immune-targeting biologic agents currently used in humans include agents that inhibit cytokine activities, affect T- and B-cell interactions, inhibit T-cell activation, or deplete B cells. (1,7,11,26,31,32,33,34) These agents have been most effective when combined with methotrexate or other nonbiologic DMARDs in clinical trials.

The available TNFα inhibitors etanercept, a soluble TNFR construct, and two monoclonal anti-TNFα antibodies, infliximab and adalimumab, are currently available to treat patients with RA. All of these agents demonstrate significant reduction of signs and symptoms of RA, improve quality of life, and slow or arrest radiographic progression. (35) The multiple effects of TNFα inhibitors include the reduction of other proinflammatory cytokines and matrix metalloproteinases and decreased influx of inflammatory cells into the synovium. (5,7,35,36) Two additional TNFα inhibitors are under development. Data thus far indicate that golimumab (37) and certolizumab pegol (35,38) show efficacy similar to that of other TNFα inhibitors.

IL-1 activity is normally regulated by a natural IL-1 receptor antagonist (IL-1Ra). (39) In RA, treatment with a recombinant IL-1ra (anakinra) has a modest effect on signs and symptoms of RA and radiologic progression. (7,40) Tocilizumab, a humanized anti–IL-6 receptor monoclonal antibody, has also shown efficacy and decreased radiographic damage. (41) Other cytokines found in RA are the targets of therapeutics in development, including IL-12, IL-15, IL-17, lymphotoxin-β, and others. (7,25,27,32)

The presence of T cells in inflamed synovium and the recognition of an antigen-driven immune response mediated by T cells led to attempts to treat RA by T-cell depletion strategies. Clinically, these approaches were initially disappointing, resulting in long-lasting lymphopenia with persistence of T cells in synovial tissue. (32) Strategies to more specifically target activated T cells have received renewed interest with the advent of therapeutics affecting costimulatory pathways and with discovery of another TH subpopulation, TH17 cells, which look to play an important role in RA. (12,42)

Costimulatory molecules required for T-cell activation are targets for RA therapy. Normally T cells require two signals from APCs for activation: an antigen-specific signal through the T-cell receptor binding to the MHC complex, and a costimulatory signal between CD80/86 on the APC and CD28 on the T-cell surface. (12,43) Abatacept (CTLA-4-Ig) is a genetically engineered fusion protein that contains a portion of human CTLA4 fused to a constant IgG1 region. (44) This molecule binds to CD80/86 on the APC and prevents binding to CD28, thereby inhibiting T-cell activation. Clinical trials of abatacept have shown significant improvement in RA symptoms and in slowing radiographic damage. (32,33,44)

Rituximab, a chimeric anti-CD20 monoclonal antibody, selectively depletes B cells expressing CD20, but not progenitors or plasma cells. Rituximab reduces the signs and symptoms of RA and slows radiographic damage. (14,26,45) Different B-cell–targeting agents under investigation include ocrelizumab (46) and ofatumumab, (47) both monoclonal antibodies to CD20+ B cells. (14,26,45) In addition, TRU-015, a truncated antibody, targets and depletes CD20+ B cells, (48) while atacicept blocks the action of key regulatory cytokines BLyS and APRIL necessary for B cell maturation and survival. (49)

Bone marrow transplantation has rarely been used as a treatment option of last resort in the most severe cases of RA that are refractory to other treatment protocols. (50)

Fortunately the rich pipeline of promising agents in development will hopefully lead to additional therapeutic options for patients. Better understanding of the immunopathogenesis of RA with individuals characterized according to their unique phenotype by biomarkers, genomic markers, and clinical characteristics is needed to better define the most appropriate medications or strategy for individual patients.

Summary

Chronic joint inflammation characteristic of RA is mediated by infiltration of synoviocytes, macrophages, T cells, and B cells into the synovium of affected joints. Over time, activated T cells and B cells and other cells together perpetuate inflammation via production of cytokines, autoantibodies, proteases, and other proinflammatory mediators leading to further tissue destruction. Currently available biologic DMARDs targeting specific cytokines, T cells, and B cells are effective in reducing signs and symptoms and slowing radiographic damage. Better understanding of the immunopathogenesis of RA is leading to the recognition of new targets and development of additional selective therapies.

Post Test

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