Introduction
Rheumatoid arthritis (RA) is a common, chronic, systemic autoimmune disease, characterized by symmetrical synovitis, inflammatory exudates in the joint cavity and erosion of articular cartilage and marginal bone. RA predominantly manifests in the synovial membrane of diarthrodial joints. It is exemplified by the infiltration of immune cells into the synovial membrane, ultimately resulting in the proliferation of cellular cytotoxic lymphocytes and synoviocytes, by the production of inflammatory cytokines and chemokines and by B cell activation with autoantibody production, all of which contribute to cartilage and bone destruction (El-Gabalawy, 1999; Firestein, 2003; Choy & Panayi, 2001).
Long-term prognosis is poor with 80 percent disability after 20 years of active disease and an average 3-18 year reduction in life expectancy (Scott et. al., 2000; Pincus & Sokka, 2003). Combined therapies with traditional disease modifying anti-rheumatic drugs (DMARDS) and a growing list of novel biological agents have enhanced outcomes and reduced the destructive course of the disease. Despite these advances, substantial disease activity persists in many patients, with accompanying progressive joint damage, functional loss, and occasionally toxicities (Fleischmann, 2002; Kalden, 2001).
Main Text
Arthritis, as the leading cause of physical disability in the United States comes with significant economic implications. While most patients need continual treatment to control flares, many others require joint replacements. With 2.1 million existing patients and 150,000 newly diagnosed RA patients every year, the disease has severe long term economic consequences, with direct and indirect costs of related care totaling up to $19 billion annually in the United States alone (Medical Economics, 1999).
This is further exaggerated by the advent of the biological era with the addition of expensive biological agents adds an estimated burden in excess of $ 10,000 per year. These high direct and indirect costs, together with substantial morbidity and mortality, emphasize the imperative need for more exhaustive investigations into the etiopathophsyiology of this chronic disease.
The prevalence of RA increases with age, is about 2.5 times higher in females than in males, and affects 1.5 % of the North American population (and 6% prevalence rates among the Native American population) (Klippel, Weyand & Wortmann, 2001, p. 209). The peak incidence is between the fourth and the sixth decade with an average age of diagnosis at the age of 41. Prevalence and incidence studies are based on a set of criteria with a sensitivity and specificity of approximately 90%.
This criterion, labeled as the American College of Rheumatology (ACR) 1987 criteria, has enabled the effective classification of RA and is also used later in this dissertation. According to the ACR criteria, to achieve a diagnosis of rheumatoid arthritis, an adult over 18 years of age needs to fulfill at least four of the following seven criteria:
- a minimum of 6 weeks of morning stiffness in and around the joints lasting for at least one hour before maximal improvement,
- a minimum of 6 weeks of soft tissue swelling or joint fluid in at least 3 joint areas of any of the proximal interphalangeal(PIPs), metacarpal phalangeal(MCPs), wrists, elbows, knees, ankles, metatarsal phalangeal(MTPs),
- a minimum of 6 weeks of one swollen area in the wrist, MCP or PIP,
- a minimum of 6 weeks of symmetrical joint involvement,
- rheumatoid nodules,
- abnormal levels of serum rheumatoid factor,
- radiographic changes on radiographs of the wrists and hands (Myers, 2004, p. 575).
Definite diagnosis of RA is difficult due to the absence of a unique solitary clinical manifestation or laboratory test. Clinical diagnosis is usually made from the exclusion of other differential diagnosis diseases and from a range of compatible features that includes the presence of symmetrical peripheral polyarthritis, morning stiffness, rheumatoid nodules and the presence of radiographic erosions (Klippel, Weyand & Wortmann, 2001, pp. 161-167). In addition, extraarticular features, including anemia, fatigue, pericarditis, granulomatous myocarditis, neuropathy, dermatoses, scleritis, episcleritis, splenomegaly, Sjogren’s syndrome, myositis, vasculitis, and glomerulonephritis may occur during the course of the disease.
Severe disease is usually distinguished in clinical practice using clinical signs and symptoms, and non-specific laboratory tests of inflammation including C-reactive protein titer (CRP) and erythrocyte sedimentation rate (ESR) (Klippel, Weyand & Wortmann, 2001, pp. 161-167).
Additionally, the presence of high-titer rheumatoid factor (RF), antibodies against cyclic citrulinated peptide (CCP), and shared epitopes in human leukocyte antigen DRBl(HLA-DRBl) alleles have been shown to be associated with severe and erosive disease and poor outcomes in RA. However, no definitive criteria have been established to identify the subset of patients likely to require combination therapy based upon any current laboratory test or clinical symptoms and signs, leaving the clinicians without a clear framework for application.
The Health Assessment Questionnaire (HAQ) and the Disease Activity Score (DAS28) (Newton, Harney, Wordsworth & Brown, 2004) are usually calculated as secondary measures of efficacy responders/nonresponders to therapeutics. Physical function is assessed using the HAQ, a disease-specific, patient-perceived questionnaire that provides a self-assessment of functional ability in daily life for patients with RA. Efficacy is also assessed by DAS28, a validated composite index of inflammation integrating in a continuous variable ESR.
Multiple factors contribute to the initiation of polyarticular synovitis and the perpetuation of the disease process in an immunosuppressive host. Although there have been many insinuations to an underlying infectious etiology, one is yet to be isolated despite exhaustive efforts. Genetics, cigarette smoking, autoantibodies to citrulline-containing peptides (anti-CCP), glucose-6-phosphoisomerase (G6PI) and to other immunoglobulins (rheumatoid factors) and, the involvement of superantigens and heat shock proteins (molecular mimicry) have been positively identified in rheumatoid arthritis (Krishnan, Sokka & Hannonen, 2003; Rantapaa-Dahlqvist, et. al., 2003 & Nell, Machold, Eberl, Stamm, Uffmann & Smolen, 2004).
Introducing appropriate therapy early in the course of the disease before permanent damage to the joints has occurred can minimize disease severity and may limit pathologic immune system changes later in the course of the disease. The optimal window for such a strategy appears to be within the first 3 months of disease onset (Nell, Machold, Eberl, Stamm, Uffmann & Smolen, 2004). Early diagnosis and monitoring of disease activity and therapeutic response is therefore important for improvement of disease outcomes.
There are 3 apparent phases involved in the rheumatoid disease process: a. an initiation phase triggered by a variety of nonspecific events that may involve multiple pathways that produce local dendritic cell differentiation and trafficking. This ultimately resulting in the release of upstream distinct cytokines into the synovium. During the initiation phase, the early rheumatoid synovium consists of major mediators and cells of the innate immune system which may be involved in the initiation of inflammation through non-antigen-specific mechanisms. It is hypothesized that the natural regulatory mechanisms of the innate immune system may not be adequate to counter the stimulatory influences and prevent the development of the active rheumatoid synovitis (Arend, 2001).
Following the propagation of a successful initiation phase, a perpetuation phase results, causing the effects of an adaptive immune response, manifested by the priming of autoreactive T cells from dendrtic cells. The effectual production and local activation of memory T cells in the joint further causes the differentiation of synovial T cells to stimulate B cells and macrophages. Finally a chronic inflammation phase results from the effects of multiple cells in a dysregulated manner primarily due to abnormal fibroblast growth and T cell responses to altered self-antigens, effectually causing pannus formation, polycellular dysregulation, deformities and erosions (Arend, 2001).
Understanding the factors responsible for the initiation and perpetuation of RA has been facilitated by the functional characterization of a number of regulators and effectors of disease activity. Cytokines are small protein mediators that bind to cognate receptors and regulate cell proliferation, activation, chemotaxis, death, and differentiation. These mediators are important both in stimulation of innate immune cells and as products of these cells in modulating inflammation and adaptive immune responses. The cytokines involved in the innate immune system include molecules that mediate the inflammatory response, such as IL-1, TNF-a, and IL-6(2).
The cytokine network in RA is a complex and dynamic system in which cellular and humoral cytokines, chemokines, and growth factors regulate initiation and perpetuation of inflammation(). In RA, these agents regulate the immune and inflammatory responses of tissue-invading leukocytes, and the activation of endothelial cells, chondrocytes, and osteocytes in a complex and coordinated manner (El-Gabalawy, 1999; Firestein, 2003; Choy & Panayi, 2001).
Numerous cytokines have been identified in the rheumatoid synovium, the network of which is tightly controlled by an imbalance between pro-inflammatory and anti-inflammatory cytokines that leaves inflammation unchecked, resulting in cellular damage, manifested by the destruction of cartilage and bone. A notable example, the role of TNF-a as an upstream regulator of disease activity is underscored by the success of “TNF-a blockade” with biologic agents such as etanercept (Enbrel®), infliximab (Remicade®), and adalimumab (Humira®) in RA treatment.
Effects of TNF-a blockade are pleiotropic including amelioration of joint inflammation, systemic aspects of disease, and erosions (Pincus, Ferraccioli, Sokka, Larsen, Rau, Kushner & Wolfe, 2002). This is explained by the fact that TNF-a directly activates cells and modulates the expression of an array of disease mediators such as IL-1, IL-6, IL-8, and IL-18, which in conjunction, regulate many aspects of cellular pathology including: T and B cell activity, neutrophil infiltration, synoviocyte, chondrocyte and osteoclast activation, and release of matrix metalloproteinases, such as MMP-1 MMP-3, and MMP-13. While extremely efficacious, TNF-blockade is only partially effective in the majority of patients.
Accordingly, key regulators such as IL-1, IL-6, and IL-8 while attenuated are not fully suppressed. Agents targeting these and other cytokines may play a useful role in mono- and combination therapy and a variety of these biologic agents are approved, in clinical trials, or in preclinical development. For example, B cell and T cell depletion agents (rituximab and abatacept respectively) and an IL-6 signaling blocker when used in combination with methotrexate(MTX), have recently demonstrated significant clinical efficacy and minimal toxicity in phase 3 RA clinical trials.
Conclusion
There are many additional biologies currently in the clinical trial pipeline including agents that target: cytokines such as IL-15 and IL-18, signaling molecules such as NF-kappaB, and MAP kinase, and leukocyte trafficking molecules such as CD2 and CD1 la. With the current development of novel biologic targeted therapies, the ability to control multiple cellular and molecular mediators will provide an unprecedented opportunity for controlling disease activity, an opportunity that will be concomitant with increased treatment design complexity.
The limits of current disease assessment tools, disease heterogeneity, increasing numbers of therapeutic options available for RA, and the chronic progressive nature of the disease make it well-suited for a more evidenced-based medical approach: an approach in which individually tailored treatments are directed by direct measurements of disease regulators and effectors.
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