In 2011, the outcome of rheumatoid arthritis (RA) is better than ever before in part due to changes in the natural history of the disease and also a reflection of improved treatments. The average age of patients at disease onset is rising. With an increasing repertoire of therapeutic agents available for treating RA, selecting the right treatment is one of the most important predictors of prognosis. It is important to consider the impact of RA and age on the presence and management of co-morbidities.
RA is the most-researched and best-understood rheumatic disease. As a consequence, its diagnosis and management are refined and sophisticated. This short book will bring you up-to-date with regard to all facets of our current appreciation of pathogenesis, diagnosis and management, in 11 chapters written by internationally acclaimed researchers.
RA is an inflammatory disease typified by chronic inflammation in the synovial tissue in multiple joints. It was originally described in the 19th century, but classification criteria were only developed in the last 50 years . The clinical syndrome spans several disease subsets which are associated with a number of inflammatory pathways . The final common pathway culminates in the development of persistent synovial inflammation and associated damage to underlying articular cartilage and bone ( Table 1 ).
| • Genetics and gender |
| • Activation of B lymphocytes |
| –Auto-antibody production |
| –Complement activation and immune complex (IC) formation |
| • Activation of T lymphocytes |
| • Activation and proliferation of synovial lining and endothelial cells |
| • Activation of macrophages and secretion of cytokines and proteases by both macrophages and fibroblasts |
| • Recruitment and activation of additional pro-inflammatory cells from the bone marrow and circulation |
| • New synovial blood vessel formation |
One of the most important pro-inflammatory cascades is the overproduction and overexpression of tumour necrosis factor (TNF) . This pathway is pivotal in driving synovial inflammation and joint destruction. The overproduction of TNF can be caused by several factors including interaction between T and B lymphocytes, synovial-like fibroblasts and macrophages. These processes lead to the activation of several cytokine subsets including interleukin 1 and interleukin 6.
There is a complex interplay between auto-antibody overproduction and genetics which form the background to the development of RA. Rheumatoid factor (RhF) is the classic auto-antibody in RA, where immunoglobulin M (IgM) and immunoglobulin A (IgA) RhFs are key pathogenic markers directed against the Fc fragment of IgG. More recently, antibodies directed against citrullinated antigens (ACPAs) in RA have been found to be more sensitive and specific than RhF and appear to be better predictors of more aggressive and erosive joint disease .
Genetic factors have been estimated to contribute up to 50% of the risk of developing RA . Much has been learnt using identification of genetic regions tagged by structural variation (single-nucleotide polymorphisms) with more than 30 regions identified as being associated with RA . The main pathogenic insights have come from associations with PTPN22 and HLA genes. Genetic risk factors are thought to be specifically associated with ACPA-positive or ACPA-negative disease. Smoking, which is one of the most prominent environmental risk factors for RA, has been reported to be a risk factor for ACPA-positive disease, especially in the context of positivity for HLA-DRB1 shared epitope alleles . The precipitating and perpetuating factors of RA immunopathology are discussed further in this issue by Scott et al. in Chapter 1.
The clinical presentation of RA is characterised by symmetrical pain and swelling, particularly in the small joints of the hand, and is often accompanied by stiffness and fatigue. The prevalence of RA is estimated to be around 0.5–1% in populations worldwide . The disease is three times more common in women than in men and particularly above the age of 65, suggesting that hormonal factors play a role . The refinement of diagnostic criteria for RA following the initial 1987 criteria culminated in the publication of the joint American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) collaborative initiative providing updated ACR/EULAR classification criteria for RA in 2010 ( Fig. 1 ). The revised 2010 criteria took into account the advent of ACPA testing and emphasise the site and duration of joint symptoms as the main focus of diagnosis . In 2011, the diagnosis of RA is based on clinical picture, including the number and pattern of affected joints, the presence of elevated inflammatory markers (including Erythrocyte sedimentation rate (ESR) and C reactive protein (CRP)), the presence of auto-antibodies including antibodies to citrullinated peptide antigens (ACPA) and/or RhF and the presence of erosions on radiographs. Together with such revised criteria and the advent of musculoskeletal imaging including ultrasound (US) in particular to detect early synovial hypertrophy and neovascularisation, the clinical presentation of RA has changed dramatically over the last two decades to a generally earlier diagnosis and therapeutic pathway. The term ‘established RA’ is generally taken to describe patients with disease duration of 2 years or more. In clinical practice, we are now treating patients at a much earlier stage in whom treatment with disease-modifying anti-rheumatic drugs (DMARDs) has largely been more effective than previous regimes of sequential monotherapy. However, chronic management also includes treating patients with long-standing disease which may be associated with the consequences of established chronic inflammation, including irreversible joint deformity, and co-morbidities such as cardiovascular disease (CVD), osteoporosis (OP) and depression which are discussed further in Chapter 2 by Gullick and Scott. Other features which require attention and management include infection in patients on immunomodulatory drugs, modification of risk factors including smoking, management of RA pregnancies, malignancy and extra-articular involvement, for example, pulmonary and eye disease.
Clinical assessments in RA are an important part of assessing joint inflammation and disease activity. Standard joint counts focus on tenderness and swelling in 28 joints in the hands, upper limbs and knees, which together with ESR/CRP and patient global activity measurements form the DAS28 disease activity index . Some clinicians prefer to use extended 66 and 68 joint counts which include the feet. Patient-based measures include appraisal of pain, global assessment and disability . In Chapter 3, Verstappen and Symmons discuss the need to identify the best predictors of treatment and to appreciate that a number of outcome measures are required to predict low activity/remission in various aspects of RA activity, for example, inflammatory markers, physical function and radiographic progression. Salomen-Escoto et al. describe which assessments are being used to evaluate disease control and their relative merits in Chapter 4.
In addition to clinical measures, imaging modalities form part of assessment criteria and include evaluation of plain radiographs for juxta-articular erosions, which characterise progressive established RA and are usually reversible. The most common imaging modality used clinically is plain radiographs, with scoring systems such as Sharp’s scores being used mainly as research tools . A great deal of interest has arisen in new imaging modalities, including US and magnetic resonance imaging (MRI) which can be used to assess reversible and irreversible structural changes. Numerous studies have now shown that early subclinical synovial hypertrophy and neovascularisation measured by power Doppler signal are visualised clearly on US scan and more recently by MRI that are modifiable and potentially reversible in response to DMARD therapies . It is now well appreciated that synovial angiogenesis is one of the earliest signs of inflammatory arthritis. Angiogenic cytokines mediate increased synovial permeability and recruitment of inflammatory cells into the joint. Since US has been demonstrated to be more sensitive than clinical assessment, it has been argued that there may be a rationale to commence DMARDs earlier based on US changes to achieve rapid remission . Some groups have gone as far as suggesting that there is an argument for imaging, for example, US, to be part of the RA remission criteria . With such considerations in mind, the best frequencies for clinical and imaging assessments are unknown. It is generally recommended that in early disease assessments may need to be relatively frequent, for example, every 6 weeks in order to perform rapid assessments and treatment to achieve disease remission. Both US and MRI have been used as outcome measures in RA therapeutic trials. One issue for future development is using standardised criteria for assessment. The OMERACT RAMRIS system (i.e., Outcome Measures in Rheumatoid Arthritis Clinical Trials rheumatoid arthritis MRI scoring system) has been introduced for MRI and assessment of cartilage via joint space narrowing. For US, OMERACT is developing a global synovitis score for monitoring and remission assessment. Tan and Conaghan discuss the pros and cons of different imaging modalities in Chapter 9 and suggest that, if used appropriately, such imaging tools can add value to clinical rheumatology practice.
While much recent work has focussed on monitoring disease activity in the joint, RA is a multisystem disease and therefore extra-articular manifestations should always be screened for and monitored. Extra-articular manifestations of RA can be classified into the following:
- •
Nodules
- •
Pulmonary: nodules, pleural effusion, fibrosing alveolitis
- •
Cardiac: pericarditis, pericardial effusion, valvular heart disease, conduction defects
- •
Neurological: mononeuritis multiplex, peripheral neuropathy, cervical myelopathy, nerve entrapment
- •
Vasculitis: systemic, nailfold
- •
Ocular: scleritis, episcleritis, keratoconjunctivitis sicca
- •
Cutaneous: leg ulceration, vasculitic rashes, pyoderma gangrenosum, palmar erythema
- •
Amyloidosis
Recent work has shown that vasculitis is particularly associated with neuropathy, rheumatoid lung disease and nodules . Rheumatoid nodules are associated with all other extra-articular RA manifestations, and often precede the onset of severe extra-articular RA. Such findings suggest shared disease mechanisms in systemic manifestations of RA.
RA is associated with a number of important co-morbidities or complications including CVD, malignancy, infection, depression and OP. These issues will be evaluated further in the following sections.
Management of established RA
The development and use of new and existing agents for RA have been informed by a number of clinical trials including Behandel Strategieen Study (BeSt), Combination therapy in early rheumatoid arthritis (COBRA), Treatment strategy of tight control for rheumatoid arthritis (TICORA) and Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) . Attaining the set remission criteria of recent clinical guidelines may not always be feasible in clinical practice; however, achieving low disease activity should at least be a target. It is also accepted that optimal patient management involves a multi-disciplinary approach to reduce disease activity, minimise pain and maximise functional ability. Kingsley and Scott discuss the relative pros and cons of various outcome measures in RA in the context of modern medical practice in Chapter 10 of this book and stress the importance of the patient perspective with the development of patient-related outcome measures (PROMs) in recent years.
The ultimate goal of therapy in RA is clinical and radiographic remission which is sustained after withdrawal of therapy. The main studies, which have informed practice, are discussed by Horton, Walsh, and Emery in Chapter 5. There are now data for combination conventional therapy and biologic therapy commenced in early RA as being more effective in achieving rapid disease remission . In Chapter 8, Thalayasingam and Isaacs discuss the relative merits of individual tumour necrosis factor alpha inhibitor (TNFi) therapies while Leandro and Becera-Fernandez discuss specific aspects of B-cell depletion therapy in Chapter 7. Another key question in the conventional DMARD and biologics era is to establish when it is safest for therapies to be stepped up or stepped down and which parameters should be used to decide on such changes. Considerations on modification of therapy are discussed by Jurgens, Jacobs, and Bijlsma in Chapter 6, where they stress that low disease activity achieved on DMARD therapy and drug-free remission are distinct entities, but that clinicians need to consider the target that they are aiming for by instituting specific treatment(s).
In the UK, the National Institute for Health and Clinical Excellence (NICE) has outlined best practice advice on the care of adults with RA . As with many chronic diseases, treatment should take into account patients’ needs and preferences. People with RA should be provided with adequate information and given the opportunity to make informed decisions about their care and treatment in partnership with health-care professionals. Such considerations play a role in direct and indirect costs for patient care and impact on time taken off work for disability. Fautrel, Verstappen, and Boonen discuss such considerations in Chapter 11 in this issue and also consider the impact of the use of biologic therapies on health economics in our societies where health costs continue to rise. Further themes which have arisen for patient care include the need for early specialist referral and treatment, especially in patients with suspected persistent synovitis of undetermined cause. Urgent referral should be performed if the small joints of the hands or feet are affected, more than one joint is affected or there has been a delay of 3 months or longer between onset of symptoms and seeking medical advice. A key aspect of RA management in 2011 is disease monitoring with regular assessments of: disease activity using DAS28 scores, Health Assessment Questionnaire (HAQ) scores, inflammatory markers; co-morbidities (including hypertension, ischaemic heart disease, osteoporosis (OP), malignancy and depression); complications (cervical spine involvement, lung or eye involvement and need for referral to surgery); and the impact on a patient’s life. A summary of pertinent issues is described below.
Management of cardiovascular risk
RA and other chronic inflammatory disorders are associated with an increased incidence of CVD, which is a major cause of death . RA patients have a significantly increased risk of CVD and a cardiovascular mortality rate of approximately 2 times that of the general population . It is thought that systemic inflammation causes an acceleration of the atherosclerotic state by a number of processes:
- 1.
Nitric oxide (NO): In RA, systemic inflammation induces endothelial dysfunction, an imbalance of prostanoids and the production of excessive amounts of NO. These are thought to be early events in the atherosclerotic disease process .
- 2.
Dyslipidaemia: RA systemic inflammation induces a secondary atherogenic dyslipidaemia .
- 3.
Coagulation cascade: Systemic inflammation activates the coagulation cascade resulting in thrombin generation and activation of platelets , which leads to atherosclerosis. Activated platelets also express P selectin, which enables them to bind to monocytes to form platelet monocytes complexes (PMCs). PMCs play a causal role in plaque instability, thrombosis and inflammation .
- 4.
T lymphocytes: CD4 + CD28 − T cells are pro-inflammatory. They are increased in patients with unstable atherosclerotic plaques and correlate with pre-clinical atherosclerotic disease in RA .
- 5.
Genetic risk factors: MHC2TA is a transcription factor regulating genes required for class II MHC-restricted antigen presentation . The −168G SNP in the promoter region of MHC2TA leads to decreased MHC class II expression, which in turn is thought to reduce protection against RA and atherosclerosis. However, recent studies have yielded conflicting results, underscoring the importance of including shared epitope allele carrier status, secondary phenotypes and more complete characterisation of gene variation in future studies .
EULAR has proposed evidence-based recommendations for cardiovascular risk management in subjects with RA . The mechanism for increased rates of premature CVD seen with chronic inflammation is incompletely understood; systemic inflammation is likely to have multiple effects such as platelet activation, disease-related dyslipidaemia and the presence of pro-inflammatory cytokines such as TNFα may play a role in triggering or perpetuating atherosclerosis . A reduced risk of cardiovascular events is seen in RA patients treated with DMARDs such as methotrexate (MTX) . EULAR guidelines have recommended CV risk assessment for all patients with RA. The same recommendations suggested that risk score models should be adapted for patients with RA by introducing a 1.5 multiplication factor . The authors propose that this multiplication factor should be used when the RA patient meets two of the following three criteria: disease duration of more than 10 years, RhF or anti-CCP positivity and the presence of certain extra-articular manifestations . It has also been proposed that dyslipidaemia, and in particular total cholesterol (TC)/high density lipoprotein (HDL-c) ratio, is an important prognostic factor for future CVD . Patients with inflammatory arthritis, particularly those with active disease, have low HDL-c levels, resulting in higher TC/HDL-c ratios, which are associated with worse prognosis in terms of cardiovascular risk . The recent EULAR recommendations for cardiovascular risk management in subjects with RA recommended that intervention should be carried out according to national guidelines since cardiovascular risk assessment varies from country to country. Some of the most commonly used models include the SCORE (Systematic Coronary Risk Evaluation) model, Framingham or locally agreed treatment thresholds for initiation of cardioprotective agents.
With respect to intervention, a randomised controlled trial of atorvastatin in RA demonstrated a moderate decrease in disease activity compared with placebo, together with a modification of vascular risk factors . In a similar fashion to statins, angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II blockers may also have a favourable effect on inflammatory markers and endothelial function in RA . With respect to non-steroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk, it is acknowledged that NSAIDs and cyclooxygenase-2 inhibitors (coxibs) are associated with an increased CV risk . Such drugs should therefore be used with due care in subjects with RA who have documented CVD or cardiovascular risk factors.
In considering the use of corticosteroids in RA, ongoing use may enhance cardiovascular risk due to deleterious effects on blood pressure, obesity, lipids, glucose tolerance, insulin production and resistance .
Tobacco smoking is an independent risk factor for CVD and can predict development of RA . It has recently been shown that smoking can increase disease activity during the first 24 months and is also associated with IgA positivity . Smoking and RF predict the development of severe extra-articular RA . Cigarette smoke condensate induces cytokines at protein levels and augments the effects of TNFα on induction of these cytokines at both messenger RNA (mRNA) and protein levels. These results support epidemiological studies which have indicated a strong association between heavy cigarette smoking and pathogenesis of RA . Based on such overwhelming evidence of harm, smoking cessation is to be recommended for all RA patients.
Management of cardiovascular risk
RA and other chronic inflammatory disorders are associated with an increased incidence of CVD, which is a major cause of death . RA patients have a significantly increased risk of CVD and a cardiovascular mortality rate of approximately 2 times that of the general population . It is thought that systemic inflammation causes an acceleration of the atherosclerotic state by a number of processes:
- 1.
Nitric oxide (NO): In RA, systemic inflammation induces endothelial dysfunction, an imbalance of prostanoids and the production of excessive amounts of NO. These are thought to be early events in the atherosclerotic disease process .
- 2.
Dyslipidaemia: RA systemic inflammation induces a secondary atherogenic dyslipidaemia .
- 3.
Coagulation cascade: Systemic inflammation activates the coagulation cascade resulting in thrombin generation and activation of platelets , which leads to atherosclerosis. Activated platelets also express P selectin, which enables them to bind to monocytes to form platelet monocytes complexes (PMCs). PMCs play a causal role in plaque instability, thrombosis and inflammation .
- 4.
T lymphocytes: CD4 + CD28 − T cells are pro-inflammatory. They are increased in patients with unstable atherosclerotic plaques and correlate with pre-clinical atherosclerotic disease in RA .
- 5.
Genetic risk factors: MHC2TA is a transcription factor regulating genes required for class II MHC-restricted antigen presentation . The −168G SNP in the promoter region of MHC2TA leads to decreased MHC class II expression, which in turn is thought to reduce protection against RA and atherosclerosis. However, recent studies have yielded conflicting results, underscoring the importance of including shared epitope allele carrier status, secondary phenotypes and more complete characterisation of gene variation in future studies .
EULAR has proposed evidence-based recommendations for cardiovascular risk management in subjects with RA . The mechanism for increased rates of premature CVD seen with chronic inflammation is incompletely understood; systemic inflammation is likely to have multiple effects such as platelet activation, disease-related dyslipidaemia and the presence of pro-inflammatory cytokines such as TNFα may play a role in triggering or perpetuating atherosclerosis . A reduced risk of cardiovascular events is seen in RA patients treated with DMARDs such as methotrexate (MTX) . EULAR guidelines have recommended CV risk assessment for all patients with RA. The same recommendations suggested that risk score models should be adapted for patients with RA by introducing a 1.5 multiplication factor . The authors propose that this multiplication factor should be used when the RA patient meets two of the following three criteria: disease duration of more than 10 years, RhF or anti-CCP positivity and the presence of certain extra-articular manifestations . It has also been proposed that dyslipidaemia, and in particular total cholesterol (TC)/high density lipoprotein (HDL-c) ratio, is an important prognostic factor for future CVD . Patients with inflammatory arthritis, particularly those with active disease, have low HDL-c levels, resulting in higher TC/HDL-c ratios, which are associated with worse prognosis in terms of cardiovascular risk . The recent EULAR recommendations for cardiovascular risk management in subjects with RA recommended that intervention should be carried out according to national guidelines since cardiovascular risk assessment varies from country to country. Some of the most commonly used models include the SCORE (Systematic Coronary Risk Evaluation) model, Framingham or locally agreed treatment thresholds for initiation of cardioprotective agents.
With respect to intervention, a randomised controlled trial of atorvastatin in RA demonstrated a moderate decrease in disease activity compared with placebo, together with a modification of vascular risk factors . In a similar fashion to statins, angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II blockers may also have a favourable effect on inflammatory markers and endothelial function in RA . With respect to non-steroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk, it is acknowledged that NSAIDs and cyclooxygenase-2 inhibitors (coxibs) are associated with an increased CV risk . Such drugs should therefore be used with due care in subjects with RA who have documented CVD or cardiovascular risk factors.
In considering the use of corticosteroids in RA, ongoing use may enhance cardiovascular risk due to deleterious effects on blood pressure, obesity, lipids, glucose tolerance, insulin production and resistance .
Tobacco smoking is an independent risk factor for CVD and can predict development of RA . It has recently been shown that smoking can increase disease activity during the first 24 months and is also associated with IgA positivity . Smoking and RF predict the development of severe extra-articular RA . Cigarette smoke condensate induces cytokines at protein levels and augments the effects of TNFα on induction of these cytokines at both messenger RNA (mRNA) and protein levels. These results support epidemiological studies which have indicated a strong association between heavy cigarette smoking and pathogenesis of RA . Based on such overwhelming evidence of harm, smoking cessation is to be recommended for all RA patients.
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