Pathogenesis

While RA is classified as a form of inflammatory arthritis, synovial pathology suggests a complex process that transforms the joint into a site of persistent inflammation and tissue destruction. The normal synovial lining is ordinarily only a few cells thick and is comprised of fibroblastic cells called ‘synoviocytes’ along with macrophages. With RA, the synovial lining expands dramatically in association with disturbed synoviocyte growth to form a structure called ‘pannus’. In this setting, the synovial fibroblast in RA becomes destructive and produces mediators that degrade cartilage and joints .

In addition to synoviocyte proliferation, the joint, including the synovial fluid, displays intense inflammation that results from the interplay of B cells, T cells, macrophages and neutrophils, all operating locally to produce cytokines and other pro-inflammatory mediators. Among these mediators, the cytokine tumour necrosis factor (TNF), a product of macrophages and other immune populations, can orchestrate the activity of other cells in the joint, including stimulation of cytokines such as interleukin (IL)-1 .

Pointing to a role of autoreactivity in disease pathogenesis, two autoantibodies have major significance as markers for diagnosis and prognosis: rheumatoid factor (RF) and antibodies to citrullinated proteins (ACPAs). A RF is an immunoglobulin (Ig)M antibody to IgG. While considered an autoantibody, RFs may have a physiological function in host defence to potentiate the activity of IgG antibodies. RFs occur commonly in infectious and inflammatory diseases, likely reflecting non-specific immune activation. RFs occur in about 80% of patients with RA. Although sensitive markers for diagnosis, RFs are not specific for RA .

In contrast to RFs, ACPAs are highly specific for RA. These antibodies are directed to proteins containing citrulline, a post-translational modification of the amino acid arginine that is mediated by the enzyme peptidyl arginine deiminase (PAD). The role of citrullination is not known, although this modification may result from inflammation. While many citrullinated proteins are autoantigens, current assays involve a synthetic peptide antigen called ‘cyclic citrullinated peptide (CCP)’ whose composition can be varied to increase the sensitivity of antibody detection. The term anti-CCP is therefore commonly applied to this serological finding since most assays involve antibody binding to the CCP antigen. Depending on the assay, the sensitivity of anti-CCP in diagnosing RA approaches that of RF .

Studies on the epidemiology of RA indicate a powerful relationship between genetic and environmental factors, with anti-CCP playing an important role. Thus, these studies indicate that smoking may be a trigger for disease, perhaps leading to protein citrullination in the lung because of chronic inflammation . In the presence of certain genes (most prominently genes encoding the shared epitope in the HLA-DR molecule), citrullinated proteins may induce anti-CCP autoantibodies which form immune complexes to drive immune cell activation and cytokine production. These cytokines can in turn stimulate fibroblasts to proliferate and activate osteoclasts to degrade bone.

Diagnosis of RA

Current treatment paradigms for RA are based on early therapy to decrease inflammation; improve patient quality of life; and reduce pain, disability and joint damage. Key to this paradigm is early diagnosis which, in the clinical setting, is based on the presence of synovitis, as exemplified by joint tenderness and swelling; the presence of RF and/or anti-CCP; and non-specific measures of systemic inflammation such as increased sedimentation rate or levels of C-reactive protein. X-ray evidence of joint destruction includes erosions and/or joint space narrowing and, while these findings can be characteristic of RA, they indicate established disease.

These findings form the basis of new criteria for classification which, interestingly, do not include X-ray findings to increase applicability to early stage disease ( Table 1 ). Classification is based on a total score . Of these findings, anti-CCP is notable since, in some patients, the anti-CCP antibodies can precede the development of arthritis, sometimes by several years . Thus, while anti-CCP is an important diagnostic marker, interpretation of the finding must be made in the context of the overall clinic presentation.

Radiographs are important in documenting arthritis, with plain radiographs traditionally the main modality to evaluate joint damage in the routine clinical setting. Plain radiographs can reveal erosions, which are focal areas of bone loss, as well as joint space narrowing indicative of cartilage destruction. In early disease, however, radiographs may show only soft-tissue swelling and juxta-articular osteopenia. Two other radiographic techniques can provide information to assess arthritis. Magnetic resonance imaging (MRI) allows more complete visualisation of joint structures as well as adjacent bone marrow. Ultrasound imaging can also reveal events in soft tissue and bone and, using Doppler flow methodology, show vascularity of the synovial tissue .

Principles of RA treatment

The treatment of RA is ideally based on objective measures of disease activity with the goal of reducing, if not eliminating, inflammation to prevent tissue destruction . This approach has been termed ‘treat to target’ by analogy with other conditions where the reduction of measures such as blood pressure or cholesterol to a set level is the goal. These measures are of two kinds: measures of disease activity based on joint counts along with laboratory markers of inflammation and questionnaires to assess patient functional status.

Of measures of disease activity, the disease activity scores (DAS) provides a simple score for the intensity of inflammation. While joint involvement of RA is extensive, a commonly used DAS format involves testing of only 28 joints for tenderness and swelling . Joints in this count must allow palpation, eliminating from consideration joints such as the hip and the cervical spine. Furthermore, the 28-joint count does not include the feet, a common site of RA involvement, since swelling and pain in the lower extremity often occurs in the general population. To the joint count in the DAS are added a measure of inflammation (erythrocyte sedimentation rate or C-reactive protein) and a patient global assessment score. The values are introduced into a formula to provide a score.

In contrast to the DAS and related measures, indices such as the health assessment questionnaire (HAQ) rely rather on patient reports of functional ability for common activities of daily life . Each activity receives a score from 0 to 3, with an average calculated. The HAQ and its derivative versions are easy to complete and encourage patient participation in the process. While the HAQ can correlate with other activity measures, it can be limited with advanced disease when functional disability is fixed.

The range of anti-rheumatic drugs

The therapy of RA involves a wide variety of agents that exert either anti-inflammatory or immunomodulatory activity. These agents can be either small molecules or large molecules. The large molecules include biological agents such as monoclonal antibodies and soluble receptors. These agents can attenuate the signs and symptoms of RA and modify the course of disease as assessed by radiographic progression of bone erosion and joint space narrowing. Those agents that can slow or halt erosion are termed ‘disease-modifying anti-rheumatic drugs’ (DMARDs); sometimes, this term is used for the small molecules as opposed to the biological agents .

At present, the treatment of RA involves four classes of agents that can be used alone or in combination to reduce disease activity as indicated by the DAS (or related index) or the HAQ (or related index). In clinical trials, imaging is a key part of the assessment; in routine practice, however, imaging is less commonly used to assess treatment effects since quantitation of erosions and joint space narrowing can be difficult and requires special skill. The following are the agents used to treat RA.

• (1)
  

  Nonsteroidal anti-inflammatory agents (NSAIDs) . These agents inhibit the cyclooxygenase (COX) enzymes and can reduce pain and swelling. Most available NSAIDs inhibit both COX I and COX II. According to current models, anti-inflammatory actions relate to the inhibition of COX II while gastrointestinal side effects relate to inhibition of COX I; an increase in CVD appears common among all of these agents. Celecoxib is the only NSAID available in the United States that is selective for COX II. Because of their cardio-renal effects, NSAIDs are used cautiously for prolonged therapy especially in older patients. Furthermore, among non-selective COX inhibitors, gastrointestinal (GI) side effects (bleeding and ulceration) can be significant and require adjunctive measures such as proton pump inhibitors or H2 blockers to reduce risk .

  
  
• (2)
  

  Glucocorticoids . These agents, of which prednisone is the most commonly used, have broad anti-inflammatory and immunosuppressive activities that result from inhibition of key immune signalling systems such as nuclear factor kappa B (NF-κB). Glucocorticoids are used at widely varying doses both acutely and chronically to control disease activity. When prednisone is used chronically, doses usually are in the range of 5–7.5 mg daily. Some regimens for treating early RA prescribe much higher doses initially (up to 1 mg/kg) to achieve rapid disease control. In addition to the systemic use of glucocorticoids, intra-articular steroids can quell inflammation in single joints .

  
  
• (3)
  

  Small molecule DMARDs . These agents differ in pharmacological action although they are all orally active and have immunomodulatory effects; in general, the actual mode of action of these drugs is not known . Of the group, methotrexate (MTX) has emerged as the preferred orally active agent for initial DMARD therapy. MTX inhibits the enzyme tetrahydrofolate reductase, an essential enzyme for purine synthesis and cell growth and division, but it is used at low doses where expected side effects of cell cytotoxicity such as cytopenias are minimal. This observation has suggested that MTX reduces arthritis by another mechanism such as adenosine release from cells .

MTX has become a mainstay of RA treatment and is begun in patients with signs of persistent disease activity and evidence of poor prognosis such as the presence of erosions on radiographs. Doses used range from 7.5 mg to 25 mg each week on a single day although, for some patients, subcutaneous administration may be necessary to achieve adequate bioavailability. The major side effect of MTX is hepatic toxicity which can be associated with fibrosis and even cirrhosis. Frequent monitoring of liver function including albumin is necessary to assess hepatic toxicity and allow dose adjustment .

The other small-molecule DMARDs include leflunomide, sulphasalazine, hydroxychloroquine, azathioprine and cyclosporine. These agents can be used as adjuncts or substitutes for MTX, alone or in combination .

• (4)
  

  Biological or large-molecule DMARDs . The advent of the biological agents has had a major impact on the treatment RA, with TNF blockers achieving widespread use frequently in combination with MTX. The TNF blockers include monoclonal antibodies (infliximab, adalimumab, certolizumab and golimumab) as well as a soluble receptor (etanercept). These proteins can all bind TNF, a potent pro-inflammatory mediator, and block its downstream effects. While these agents are ‘targeted’, the effects of TNF are broad and the step in pathogenesis that is blocked is not clear .

Well-performed clinical trials indicate that TNF blockers can improve the signs and symptoms of RA and can retard radiographic progression. In some studies, these effects are similar to those of MTX although the effects on radiographic progression appear to be greater and, depending on the agent, benefits can be achieved more rapidly. Importantly, the combination of a TNF blocker and MTX produces benefits greater than either alone, with this combination able to block radiographic progression almost entirely .

Since many patients with RA can respond well to MTX alone, this agent is still commonly used before a TNF blocker, reflecting cost considerations and greater experience. The major side effects of TNF blockers relate to susceptibility to infection, with tuberculosis (TB) a major concern. Screening for TB is necessary before institution of TNF blockade; for patients who show skin reactivity indicative of TB infection, evaluation for extent of disease and treatment with anti-TB therapy is required before beginning a TNF blocker.

At present, four other biological agents have been approved for the treatment of RA. Two act on cytokines. Anikinra or IL-Ra is a molecularly cloned form of a naturally occurring inhibitor of the pro-inflammatory cytokine IL-1. While blocking IL-1 should be effective in RA, the pharmacologic properties of IL-1Ra as a receptor blocker and the necessity for daily administration of high doses of protein have limited anikinra use; this agent, however, can be very effective in the treatment of autoinflammatory syndromes and possibly gout. Tocilizumab is an antibody to the IL-6 receptor and can block the effects of IL-6, another potent pro-inflammatory mediator that plays a key role in the acute-phase response .

Abatacept is a molecularly cloned product which is a fusion protein of the cytotoxic T lymphocyte-associated (CTLA)-4 molecule with the Fc portion of IgG. Abatacept can block the interaction of the surface molecule CD28 on T cells with the surface molecules B7-1/B7-2, preventing an interaction of T cell with antigen-presenting cells called ‘co-stimulation’. By contrast, rituximab is a monoclonal antibody that can deplete B cells. Despite their different modes of action, both abatacept and rituximab are effective DMARDs and are usually used in patients who have not had an adequate response to other therapies including a TNF blocker, especially in combination with MTX .

Treatment paradigm of RA

Given the armamentarium of effective agents to treat RA and the ability to use multi-drug combinations, the number of possible treatments of RA is virtually limitless. In the face of this variety, head-to-head trials of adequate size have not been accomplished and treatment remains empiric. Nevertheless, the effectiveness of reducing disease activity by ‘treating to target’ appears well established . In the application of these approaches, two key issues remain. The first concerns the relative merits of switching drugs as opposed to adding drugs in face of an inadequate response to a single agent (or even a combination). While combination therapy can work better than single agents in large clinical trials, this effect could relate to the benefits gained by the administration of effective agents to a greater number of patients as opposed to additive or synergistic effects of the combination in individual patients.

A second question relates to the continuation of therapy once remission is achieved. This situation is new but has become possible with the availability of so many effective agents. While in established disease (years duration), continued therapy may be needed to maintain a treatment response, early disease (less than a year or two) may have a different pattern of response. There has long been interest in the idea of a ‘window of opportunity’; this theoretical window represents a time in which therapy can inhibit or even terminate pathogenetic pathways in RA such that continued therapy is no longer necessary or entails fewer agents or much lower doses. Perhaps, with early treatment, RA will show long-term disease quiescence following an initial intensive therapy .

Pathogenesis

While RA is classified as a form of inflammatory arthritis, synovial pathology suggests a complex process that transforms the joint into a site of persistent inflammation and tissue destruction. The normal synovial lining is ordinarily only a few cells thick and is comprised of fibroblastic cells called ‘synoviocytes’ along with macrophages. With RA, the synovial lining expands dramatically in association with disturbed synoviocyte growth to form a structure called ‘pannus’. In this setting, the synovial fibroblast in RA becomes destructive and produces mediators that degrade cartilage and joints .

In addition to synoviocyte proliferation, the joint, including the synovial fluid, displays intense inflammation that results from the interplay of B cells, T cells, macrophages and neutrophils, all operating locally to produce cytokines and other pro-inflammatory mediators. Among these mediators, the cytokine tumour necrosis factor (TNF), a product of macrophages and other immune populations, can orchestrate the activity of other cells in the joint, including stimulation of cytokines such as interleukin (IL)-1 .

Pointing to a role of autoreactivity in disease pathogenesis, two autoantibodies have major significance as markers for diagnosis and prognosis: rheumatoid factor (RF) and antibodies to citrullinated proteins (ACPAs). A RF is an immunoglobulin (Ig)M antibody to IgG. While considered an autoantibody, RFs may have a physiological function in host defence to potentiate the activity of IgG antibodies. RFs occur commonly in infectious and inflammatory diseases, likely reflecting non-specific immune activation. RFs occur in about 80% of patients with RA. Although sensitive markers for diagnosis, RFs are not specific for RA .

In contrast to RFs, ACPAs are highly specific for RA. These antibodies are directed to proteins containing citrulline, a post-translational modification of the amino acid arginine that is mediated by the enzyme peptidyl arginine deiminase (PAD). The role of citrullination is not known, although this modification may result from inflammation. While many citrullinated proteins are autoantigens, current assays involve a synthetic peptide antigen called ‘cyclic citrullinated peptide (CCP)’ whose composition can be varied to increase the sensitivity of antibody detection. The term anti-CCP is therefore commonly applied to this serological finding since most assays involve antibody binding to the CCP antigen. Depending on the assay, the sensitivity of anti-CCP in diagnosing RA approaches that of RF .

Studies on the epidemiology of RA indicate a powerful relationship between genetic and environmental factors, with anti-CCP playing an important role. Thus, these studies indicate that smoking may be a trigger for disease, perhaps leading to protein citrullination in the lung because of chronic inflammation . In the presence of certain genes (most prominently genes encoding the shared epitope in the HLA-DR molecule), citrullinated proteins may induce anti-CCP autoantibodies which form immune complexes to drive immune cell activation and cytokine production. These cytokines can in turn stimulate fibroblasts to proliferate and activate osteoclasts to degrade bone.

Diagnosis of RA

Current treatment paradigms for RA are based on early therapy to decrease inflammation; improve patient quality of life; and reduce pain, disability and joint damage. Key to this paradigm is early diagnosis which, in the clinical setting, is based on the presence of synovitis, as exemplified by joint tenderness and swelling; the presence of RF and/or anti-CCP; and non-specific measures of systemic inflammation such as increased sedimentation rate or levels of C-reactive protein. X-ray evidence of joint destruction includes erosions and/or joint space narrowing and, while these findings can be characteristic of RA, they indicate established disease.

These findings form the basis of new criteria for classification which, interestingly, do not include X-ray findings to increase applicability to early stage disease ( Table 1 ). Classification is based on a total score . Of these findings, anti-CCP is notable since, in some patients, the anti-CCP antibodies can precede the development of arthritis, sometimes by several years . Thus, while anti-CCP is an important diagnostic marker, interpretation of the finding must be made in the context of the overall clinic presentation.

Table 1

The 2010 American College of Rheumatology/European league against rheumatism classification criteria for rheumatoid arthritis. ^a

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