Overview of Rheumatoid Arthritis

Introduction

Rheumatoid arthritis (RA) is a progressive inflammatory disorder characterized by proliferation of the synovial membrane and persistent uncontrolled inflammation resulting in a chronic destructive polyarthritis. Typically, RA manifests as a symmetric arthritis involving numerous small and large joints. Articular symptoms may be accompanied by systemic inflammatory symptoms such as fatigue, articular stiffness, anorexia, or fever.

Underlying the initial complaint of pain and limited lifestyle, inflammatory events within the synovium become chronic and potentially destructive. These immune-mediated inflammatory changes give rise to many of the clinical findings and destructive articular changes that characterize this disorder. Without treatment, rheumatoid inflammation may have catastrophic consequences in the months and years to come.

This module is not only an overview of rheumatoid arthritis (RA), but where applicable, will focus on “early” RA, early diagnosis, rules for referral, treatment advances, unmet needs and an overview of how to initiate an early-arthritis effort or clinic in your practice.

The concept of early RA is not a new one. Even preceding its recognition as an autoimmune disease, clinicians observed that RA is a progressive condition, with disability and joint destruction advancing inexorably over the years. As with any chronic condition, astute clinicians wished to have effective therapies that might abrogate the damage and thereby improve the outcome of this pernicious incurable disease. With the delineation of the autoimmune nature of RA came interest in treating the condition early, based upon the realization that in animal models of autoimmune disease, therapies modulating the immune system are far more effective when given earlier in the disease course. While the lack of highly effective therapies precluded acting on this hypothesis, it did provide recourse for failed treatments. Thus in the latter part of the last century, accompanying any presentation of an ineffective treatment would be the disclaimer that “maybe this therapy would work if it were tried earlier in the disease course.”

The introduction of highly effective therapeutics, such as aggressively dosed methotrexate, combination therapy, biologics, cytokine inhibitors and the inhibitors of tumor necrosis factor-alpha (TNFα), have truly revolutionized the treatment approach to RA. Their proven efficacy in patients with refractory RA has resulted in greater hope for those with early disease.

With more effective therapies, the goal of therapy has been elevated such that complete elimination of disease activity is now sought. This goal of remission is most likely in patients with early RA. In addition to having highly effective treatment options, clinicians are now better able to stratify patients with early RA. As a result, treatment may be appropriately tailored, not only to present levels of activity but also to the anticipated severity of disease, thus optimizing outcomes. Helping support this has been progress in clinical assessment, laboratory testing (such as anti-cyclic citrullinated peptide [CCP] antibodies) and imaging. Compared with traditional roentgenographs, modalities such as magnetic resonance imaging (MRI) and ultrasound provide greater sensitivity in defining joint damage in early RA and also allow visualization of synovitis.

This is an exciting time in rheumatology, and the assessment and treatment of patients with early RA may be the most interesting and rapidly evolving area of investigation. Newer developments, such as the biomarker and microarrays analysis to assist in disease stratification and new drug development will help fulfill the promise of improved outcomes for all RA patients.

Epidemiology

Prevalence and Incidence

According to data from the 2017 Global Burden of Disease study, the worldwide age-standardized prevalence and incidence rates of RA (per 100,000 people) were 246.6 and 14.9, respectively, representing a respective increase of 7.4% and 8.2% since 1990. The global prevalence rate is higher in women than in men, and increases with age. There is also regional variation in prevalence, with the highest reported rates being in high-income North America (377.6), Western Europe (346.8), and the Caribbean (338.9), and the lowest reported rates in Southeast Asia (100.9), Oceania (135.3), and Western sub-Saharan Africa (135.7).

An analysis of 2004-2014 health insurance claim data in the United States revealed an overall age-adjusted RA prevalence rate of 0.53 to 0.55% (0.29 to 0.31% for men and 0.73 to 0.78% for women), equivalent to ~1.3 million affected individuals, with a slight increasing trend. An analysis of self-reported prevalence data from the NHANES - National Health and Nutrition Examination Survey (NHANES) survey found no increasing trend, but revealed prevalence rate disparities among people of different ethnicity/race (higher in non-Hispanic Black men and women and Hispanic women than in White individuals), educational attainment (lower in college-educated individuals) and socioeconomic status (lower in people from medium- and high-income families).

A United States population-based incidence study of adult patients with RA who fulfilled the 1987 American College of Rheumatology (ACR) criteria for RA reported that overall incidence rates remained stable in the period 1985-2014 (40, 43 and 41 cases per 100,000 people in 1985-1994, 1995-2004 and 2005-2014, respectively). Interestingly, the incidence rates for rheumatoid factor (RF) positive RA has decreased from 30 cases per 100,000 people in 1995-2004 to 21 cases per 100,000 people in 2005-2014, while the incidence of RF negative RA has risen from 13 to 20 cases per 100,000 people in the same period.

The lifetime risk of RA in the Rochester, Minnesota Mayo Clinic population was estimated as 3.6% (or 1 in 28) among women and 1.7% (or 1 in 59) among men, and the lifetime risk of developing RF positive RA was 2.4% for women and 1.1% for men.

Mortality and Comorbidities

Many studies have reported increased mortality in people with established RA compared with the general population. Seropositivity for anti–citrullinated protein antibodies (ACPAs) and RF is associated with increased mortality risk, and the risk increases with higher ACPA and RF titers. According to one estimate, about 40% of premature deaths in RA are attributable to cardiovascular disease (CVD), including ischemic heart disease, congestive heart failure (CHF), and stroke. Although traditional CVD risk factors were found to contribute to the increased risk of mortality in RA patients, they do not fully explain the increased cardiovascular (CV) mortality observed in patients with RA. One study examined coronary artery tissue from autopsied RA patients and observed increased evidence of inflammation and an increased proportion of unstable plaques. It also has been reported that among people with RA, the presence of RF and/or anti-citrullinated protein antibody (ACPA) are potential markers of premature mortality. It is becoming increasingly acknowledged that the underlying inflammation in RA plays an essential role. This may be related to the fact that atherosclerosis also has an inflammatory etiology that may be accelerated in RA. Nevertheless, it is not yet clear whether the increased CVD mortality in RA patients is due to the disease, the risk factor profile of people with RA, or the effects of the drugs used to treat the disease.

In RA research, body mass index (BMI) is frequently used as a demographic variable, but obesity, as such, has received little attention. This is surprising, in view of the associations of obesity with other arthritides, particularly osteoarthritis (OA), but also in view of the association of RA with increased CVD morbidity and mortality. The effect of BMI on cardiovascular mortality in RA patients was assessed in a longitudinal study in a population-based cohort of RA patients and a cohort of individuals without RA from the same population. RA patients with low BMI (<20 kg/m²) had a significantly higher risk of CV mortality (hazard ratio [HR]; 3.34) compared with people without RA with normal BMI.

Furthermore, individuals who had normal BMI at inception of the study who experienced low BMI during follow-up also had a higher risk of CV death (HR; 2.09) when compared with non-RA subjects who maintained normal BMI throughout follow-up. The association between BMI and radiographic joint damage (RJD) was evaluated in 499 patients with RA. Compared with normal weight, obese patients had a lower odds ratio (OR) for RJD (0.40, P = 0.0030) and underweight patients had a greater OR for RJD (3.86; P = 0.002) at baseline. Baseline associations between BMI category and RJD were greater among participants with multiple risk factors for bone loss. However, baseline BMI and change in weight did not independently predict radiographic progression (P >0.1) over 52 weeks.

Societal Impact

RA is the most common form of inflammatory arthritis in adults. Its prevalence and destructive potential exact a considerable toll from affected patients in terms of substantial morbidity, progressive disability and accelerated mortality. This has profound economic implications for the affected patients, their families and society. Without effective treatment, the expected course of RA is one of progressive disability.

Comprehensive studies from diverse countries have consistently shown progressive work disability in patients with RA. A systematic review of the literature reveals a consistent relationship between disease duration and work disability. Many studies have clearly shown that RA is a costly disease. Heterogeneity among the studies precludes meaningful averaging to a dollar assessment; total costs of a patient having RA was approximately $10,000 (US dollars [USD] in 2005) per patient in a number of studies.

Despite some variation in absolute costs, there are several consistent key themes across studies. Indirect costs (e.g., lost wages) typically, although not uniformly, exceed direct costs (e.g., medications, hospitalizations). Of note, the costs of disease are not uniformly distributed among the RA population. This skewing, readily evident considering differences in mean and median costs reported, reflects substantially higher costs from a subset of the patients. Importantly, patients with the most severe RA incurred the highest costs. The strongest predictor of cost was functional disability, typically measured with the Health Assessment Questionnaire (HAQ). Elevated HAQ scores were consistently correlated with greater cost. In a rigorous analysis from Spain, there was an increment of >$11,000 (USD in 2003) per unit of HAQ score among RA patients. Germane to pharmaco­economic analysis, worsening in the HAQ score over time resulted in higher costs, whereas improvements in the score resulted in lower costs of disease. The implication of this is that therapeutic agents capable of effecting significant improvements in functional status would be expected to lower the costs of disease. This is very relevant to discussions of early RA.

Pathology

Characteristic pathologic changes are most prominent in the peripheral joints, specifically diarthrodial joints. A diarthrodial joint is lined with a synovial membrane and lubricated by viscous synovial fluid. The juxtaposed bony surfaces are capped with hyaline cartilage.

With the onset of arthritis, the normally thin synovial membrane (typically one to three cells thick) that outlines the joint cavity undergoes proliferative change and is transformed into an expanding layer of synovial cells (synoviocytes) (Figure 1-1). The synovial membrane is composed of type A (macrophage-derived) and type B (fibroblast-derived) synoviocytes, both of which increase in number as the synovial membrane enlarges. Early on, the synovial membrane becomes edematous and enriched with new blood vessel formation (angiogenesis), developing a characteristic villous morphology with an inflamed or reddish appearance. The deposition of fibrin and increased synovial fluid production further contribute to the palpable soft tissue swelling of the joint capsule. The endothelium undergoes morphologic change and takes on the columnar appearance of high endothelial venules, indicative of endothelial cell activation; these changes facilitate the infiltration of circulating inflammatory cells into the joint tissue.

As a result of angiogenesis, endothelial cell activation, chemotactic stimuli and proinflammatory cytokines, an intense infiltration of leukocytes and other cells occurs below the synovial lining layer. Numerous mononuclear cells (e.g., T lymphocytes, B lymphocytes, macrophages, plasma cells) accumulate beneath the synovial membrane, often in nodular aggregates. In the synovium, CD4+ helper T cells predominate and are often found close to antigen-presenting cells (APCs), such as macrophages and dendritic cells. T cells within the rheumatoid synovium are primarily of the memory phenotype with an enhanced ability for transendothelial migration. These cells are characterized by the expression of cell surface antigens CD45RO, CD29^bright, CD11a/CD18 (LFA-1), VLA-1, CD49d/CD29, CD54, CD44, and CD7^dim). T cells have long been considered central to the orchestration of rheumatoid synovitis. In addition to their consistent presence in involved joints, additional evidence for the role of T cells comes from the efficacy of T-cell directed therapeutic agents (e.g., cyclosporine A, abatacept) and the association of RA with certain alleles of the class II major histocompatibility complex (MHC) molecule HLA-DR. T cells may direct downstream inflammatory events by a number of mechanisms, including the ability to stimulate numerous other cell types by direct contact or by the elaboration of various mediators. T cells can also provide efficient stimulatory help to B cells and immunoglobulin synthesis.

Three histologically distinct regions have been identified in the subsynovium. First, lymphocytes coalesce and organize to form distinct lymphoid follicles. Second, a transitional zone can be characterized by an increased number of lymphocyte blasts and lymphocytes lying in close proximity to HLA-DR+ (an activation antigen) macrophages and dendritic cells. Lastly, plasma cell–rich areas are often found and are responsible for immunoglobulin and RF production. High levels of immunoglobulin, ACPA and RF are characteristic of this disorder. ACPA are produced in the synovium, lung and periodontal tissues. Nonetheless, many arthropathies (e.g., gout, Lyme disease, reactive arthritis, septic arthritis, osteoarthritis [OA]) can exhibit histopathologic changes that are similar to rheumatoid synovium, including the presence of citrullination of synovial proteins. However, the presence within the inflamed synovium of an intense infiltrate, the presence of organized lymphoid follicles and abundant plasma cells, and the local production of large quantities of RF and anti-CCP antibodies all are suggestive of RA. While the exact role of autoantibodies in RA remains to be defined, it does suggest a role for B cells in the pathogenesis of disease. B cells may also contribute to rheumatoid synovitis by providing costimulatory signals to T cells, and by secreting cytokines and other mediators that can stimulate various cell types.

Other cell types are found within the rheumatoid joint and may contribute to the pathogenesis. Mast cells may be found in the rheumatoid synovial membrane, and their presence correlates with clinical activity and cellular infiltration. Mast cells prominently contribute to the local inflammatory process by secreting vasoactive materials (histamine, tryptase), cytokines (TNFα, interleukin [IL]-3, IL-4, transforming growth factor [TGF]β), and other chemotactic factors, as well as degradative enzymes. Mast cells also are capable of inducing platelet aggregation, endothelial cell activation, and tissue fibrosis. Dendritic cells are also abundant in the rheumatoid synovium and, like tissue macrophages, bear an activated phenotype and play an important role in antigen presentation and cytokine production. Increased numbers of fibroblasts are also found and are responsible for the increased synthesis of extracellular matrix components and the destructive/degradative mediators (eg, prostaglandins, cytokines) that contribute to the joint damage. It has been shown that synovial fibroblasts have an extended survival and fail to undergo apoptosis normally.

The articulating surface of the joint is covered with hyaline cartilage that cushions and protects underlying subchondral bone. However, the outer margins of the joint are not covered with articular cartilage, thereby leaving an unprotected or “bare” area that lies in proximity to the synovial membrane. This bare area is often the site of articular erosion in RA. Pannus (a hyperplastic form of granulation tissue) is often found encroaching upon articular cartilage, tendon sheaths, and the unprotected area of subchondral bone. This highly vascularized tissue contains a paucity of lymphocytes and is comprised of numerous cell types, including transformed mesenchymal cells, synoviocytes, histiocytes, mast cells, macrophages, and fibroblasts. Pannus is often found overlying articular erosions and, in some instances, this junction is relatively acellular. It is thought that pannus contributes to the generation of bony erosions in RA by locally producing degradative enzymes (e.g., metalloproteinases [MMPs], prostaglandins [PGs]) and cytokines (ie, IL-1, IL-6, etc).

Synovial fluid is produced in excess by type B synoviocytes in the rheumatoid joint. Locally generated cytokines IL-1, TNF, IL-6, complement factor C5a and leukotrienes promote the migration of neutrophils into the synovial fluid, thus accounting for the exudative, neutrophil-predominant response in the rheumatoid synovial fluid. Lymphocytes in the synovial fluid are predominantly CD8+ T cells, demonstrating their ability to migrate to and escape the inflamed synovium.

Rheumatoid nodules are painless nodular masses of various sizes that may be found subcutaneously, over extensor tendons and periarticular tissue, or adherent to periosteum rheumatoid nodules (see Rheumatoid Nodules section). Rheumatoid nodules may also be found in the lungs. Their presence correlates strongly with high serum titers of RF. Histologically, rheumatoid nodules are characterized by a zone of central necrosis, with a surrounding layer of palisading histiocytes, and an outer layer of infiltrating mononuclear cells. Rheumatoid inflammation may also affect vascular structures (rheumatoid vasculitis) (Rheumatoid Vasculitis section). Although not common, rheumatoid vasculitis may affect small or medium-sized vessels; histologic changes range from venulitis to obliterative endarteritis with mononuclear cells and immune complexes in the vessel wall.

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Etiology

Despite years of intensive study, the etiology of RA is still not known. The immunopathologic changes seen in RA are presumed to be the result of a persistent immunologic response in a genetically susceptible host to an as yet unidentified antigen(s), possibly an infectious agent. Over the past century, many viruses and bacteria have been implicated but not proved to be the cause of RA. Suspected pathogenic organisms have included Mycobacteria, Streptococci, Mycoplasma, Yersinia, rubella virus and Epstein-Barr virus. Despite its resemblance to infectious arthritis (e.g., Lyme disease, rheumatic fever, hepatitis B), RA has not been conclusively linked to any infection.

Risk factors for the development of RA have been suggested. Increasing age, female sex, RF and anti-CCP antibody positivity (that may antedate the onset of symptoms) are known risk factors. For example, the incidence rates for RA are lowest in men and those <30 years of age, while incidence rates increase to nearly 5% in women >60 years of age. Interestingly, current or past smoking has been repeatedly shown to increase the risk of developing RA and may also increase the risk of disease severity and extra-articular disease, especially in those who are serum-RF positive. The cause of this is unknown, but it has been hypothesized to relate to airway inflammation. Claims regarding the role of obesity, blood transfusion, coffee, tea and vitamin D have been made but not confirmed by repeated investigations.

Immunogenetics

Family studies demonstrate a definite but modest genetic predisposition to the development of RA. The concordance rate for monozygotic twins is about 25% (if one twin has RA, there is a 25% chance that RA will develop in the other twin). Fraternal twins and first-degree relatives of patients with RA have a 4-fold higher risk (2% to 5%) of having RA when compared with the risk in the general population (0.8%). The most clearly defined genetic association, which accounts for perhaps half of the overall genetic risk for RA, resides in particular alleles of the class II MHC genes.

The MHC is found on the short arm of chromosome 6 and includes class I, class II and class III MHC genes, each possessing important immunologic functions, including the binding and presentation of antigen to T cells and the discrimination of self and nonself. Class II, or HLA-DR, molecules are important in shaping T-cell receptor gene usage and the generation of antigen-specific T-cell responses. Certain HLA-DR molecules (e.g., HLA-DR4, HLA-DR1) are associated with an increased risk for RA as well as increased severity of the disease. Conversely, other HLA-DR alleles show no statistical association with RA. Comparisons of the amino acid sequence for the third hypervariable region of the β chain of MHC-susceptible alleles have demonstrated a consistency of sequences at amino acid positions 66-74, the so-called shared epitope. This region of the DR β chain borders the antigen-binding cleft and is important in antigen binding. The finding of a shared amino acid sequence among those positively correlated genotypes has led to the shared-epitope hypothesis, wherein presumed antigen(s) that initiate or drive rheumatoid inflammation do so via binding at this site.

In addition to HLA genes, at least 20 other loci have been linked to RA in genome-wide association and candidate gene studies, including PTPN22, which encodes the enzyme lymphoid protein tyrosine phosphatase, an important regulator of adaptive immune function. Alleles of PTPN22 and HLA-DRB1 together account for about half of the genetic component of RA. Finally, evidence is emerging that genetic risk may be modulated by epigenetic processes, including DNA methylation and histone modification, although the mechanistic details are not fully elucidated.

Immunopathogenesis

It appears that several components of the immune system contribute to the pathogenesis of RA. Figure 1-2 demonstrates the integral roles performed by vascular endothelium, circulating memory T cells, tissue macrophages, cytokines, plasma cells, B cells and RF in the initiation and perpetuation of articular and systemic rheumatoid inflammation. Angiogenesis and morphologic endothelial changes are among the earliest findings in RA. These alterations occur in response to injury, cytokine elaboration and a variety of angiogenic factors. The proliferation of blood vessels, the formation of high endothelial venules, and the expression of adhesion molecules on the endothelial surface promote the slowing and rolling of circulating T cells as they make contact with vascular endothelium. T cells bind to endothelium through a variety of receptor-ligand interactions. The expression of leukocyte function–associated antigen (LFA)-1 on the T cell is necessary for its binding to intercellular adhesion molecule (ICAM)-1 on the endothelial cell. Once bound, T cells will migrate through intercellular gaps to take up residence in the synovial tissues, often in a perivascular distribution.

CD4+ helper T cells appear to orchestrate the immune response in RA. This proposed mechanism is supported by the observation of numerous T cells bearing the memory T-cell phenotype (CD4+/CD45RO+). These cells are phenotypically activated and express HLA-DR and increased adhesion molecules such as LFA-1 and very late activation antigen 4 (VLA-4) on their surface. Moreover, memory T cells are capable of enhancing T-cell activation, endothelial permeability, plasma cell hyperactivity, macrophage/APC activation, and secretory products. Cells of the monocyte/macrophage lineage play an important effector role, interacting with T cells and elaborating numerous proinflammatory secretory products, especially proinflammatory cytokines, such as IL-1, IL-6, IL-8, IL-10, TNF and granulocyte-macrophage colony-stimulating factor (GM-CSF).

It has been postulated that unknown exogenous (i.e., infectious) or endogenous (self) antigens may trigger an aberrant immune response within the rheumatoid synovium. Postulated antigens include heat shock proteins, epitopes within type II collagen, MHC molecules themselves, and dna-j (residues within heat shock protein derived from Escherichia coli).

Many investigators have attempted to identify an antigen-specific response by studying cells eluted from rheumatoid synovial membrane. The identification of an expanded population of antigen-specific T-cell clones (oligoclonal T-cell expansion) would lend credence to an antigen-driven response underlying RA. However, studies seeking to show the oligoclonality have been hampered by disparate methodologies and results. The inability to identify oligoclonality in the synovial membrane can be explained by animal studies. In animal models of antigen-driven diseases, oligoclonality is most demonstrable before the onset of clinically manifest disease. Therefore, it may not be possible to identify oligoclonality in patients with established chronic disease, because the clonal proliferation of antigen-specific T cells has been diluted and lost amid the constant flux of other nonspecific inflammatory cells in the inflamed synovium. To date, the most compelling evidence of an antigen-driven response in the synovium is the identification of shared epitopes within the T-cell receptors of genetically susceptible patients with RA.

Plasma cells secrete an abundance of immunoglobulin, most of which displays RF activity. In clinical laboratory assays, RF is measured as IgM RF (an immunoglobulin M [IgM] antibody that binds to the Fc portion of immunoglobulin G [IgG]). Within the joint, numerous RFs of various isotypes are made and form immune complexes capable of complement fixation and neutrophil activation. These processes amplify the inflammation that is present as well as the erosive or destructive potential of this disease. Moreover, immune complexes containing RF have been implicated in the pathogenesis of rheumatoid nodules and rheumatoid vasculitis.

It has long been recognized that B cells are found in appreciable numbers within the rheumatoid synovium. Also, the demonstration of RA-related autoantibodies, namely RF and anti-CCP antibodies, also points to a role for B cells. The role of B cells in the pathogenesis of RA has been highlighted by the clinical experience with rituximab, a chimeric anti-CD20 (B-cell) monoclonal antibody that reduces circulating B-cell numbers and serum RF levels without altering other leukocyte counts or substantially altering total immunoglobulin levels. RA patients treated with a course of rituximab have shown significant clinical improvement, with sustained responses lasting 6 to 12 months. The mechanisms whereby a B-cell–targeted strategy may lead to the amelioration of disease is unclear, but may be due to reduced antigen presentation by B cells, reduction in RF-containing immune complexes, decreased B-cell–dependent antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, or the induction of apoptosis.

Numerous cytokines are found in the rheumatoid synovium and synovial fluid. Cytokines are the secreted peptide products of activated cells capable of mediating self, local and systemic effects. They possess multiple, and often overlapping, biologic activities and play an essential role in health and disease states. Operating in complex cascades and networks, the activities of various cytokines exhibit pleiotropy, redundancy, amplification and reciprocal inhibition. Many of the clinical features ascribed to RA can be directly attributed to specific cytokine(s). The migration of mononuclear cells can be attributed, in part, to IL-1, TNFα, interferon-gamma (IFNγ), TGFβ and IL-8. The activation of numerous cell types can be achieved by IL-1, IL-2, IFNγ, TNFα, IL-6, IL-10 and GM-CSF, to name a few. Other cytokines (e.g., IL-1, TNFα, TNFβ, IL-6) have demonstrated the ability to damage articular cartilage and bone directly. All of these proinflammatory cytokines have been identified in the synovium or synovial fluid of patients with RA.

In summary, numerous cellular and genetic mechanisms contribute to rheumatoid inflammation. The overlapping nature and intensity of these effector mechanisms are responsible for the severity and chronicity that characterize RA.

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