The remarkable advances in understanding the pathogenesis and therapeutic options for rheumatoid arthritis over the last 10 years are a leap forward in the treatment of this disease. This has led to a shift in focus from established disease to early identification and treatment. Actualisation of treatment guidelines aiming for remission, and a vastly growing arsenal of new synthetic and biological agents have been major achievements. An area of ongoing research is the discovery and development of additional and improved biomarkers for (early) disease with the goal of designing a more personalised treatment regimen to prevent structural tissue damage. Developing valid tools to predict response and outcome for the individual patient remains, however, a great challenge. We will herein summarise some of the major achievements in diagnostic and therapeutic discoveries in rheumatoid arthritis of the past decade.
Introduction
Over the past decade, insights into the pathogenesis and treatment of rheumatoid arthritis (RA) have accelerated at an unprecedented pace. Not only has it become evident that RA is a chronic inflammatory disease requiring active treatment in an early stage of the disease, but great advances have also been made with regard to understanding comorbidities, especially those involving the cardiovascular system. Based on these insights, targeted strategies have emerged with a substantially better prognosis for a considerable number of RA patients, although constant and stable remission is still not achieved in the majority. The next challenges include unravelling the role of the individual contributors to the development of early disease, translation to more effective treatments for individual patients and elucidating RA’s etiopathogenesis.
Advances in understanding the etiopathogenesis of RA
Novel translational methods, including analysis of synovial biopsies, and applied molecular, cellular and genetic technologies, have increased our understanding of the pathogenesis of RA. It has become apparent that years before clinical onset of RA increased levels of autoantibodies, cytokines and chemokines can already be detected, suggesting the advancement of disease long before joint destruction is evident , although the primary target of RA, the synovium, is not affected in the earliest stages of preclinical RA .
Genetic factors
In 2000, it was estimated that the relative contribution of genetic factors to RA is about 50%, based on twin studies . In 2010 a meta-analysis of genome wide association studies has identified seven new RA risk loci, totalling the known risk alleles to 16% of the estimated 50% of disease variance due to genetic factors . From all genetic data, the risk associations with human leukocyte antigen (HLA)-DRB1-shared epitope alleles and, secondly, PTPN22 alleles are the strongest . The next step would be to translate the findings of genome wide association studies to epidemiological and pathogenetic studies.
Anti-citrullinated protein antibodies
Since the beginning of the century anti-citrullinated protein antibodies (ACPAs) have been recognised as a hallmark of RA . ACPAs can be detected years before onset of disease and play a role in the pathogenesis of RA . Citrullination is a biochemical event in which arginine is changed into citrulline by deimination. The basic charge conferred by arginine is then turned into a neutral site in the peptide by citrulline, an event that may alter the tridimensional conformation of the protein. The enzymes catalysing this biochemical reaction are the peptidylarginine deiminases (PADIs). The upregulated expression of PADI enzymes provoked by smoking may promote the citrullination of proteins in the lung, leading to autoimmunity against citrullinated antigens in RA . ACPA-positive disease is associated with unfavourable outcome, and there is an association between ACPA positivity and the presence of the specific genotype encoding the shared epitope, smoking , and periodontal disease . Porphyromonas gingivalis is one of the bacteria causing periodontal disease and may express PADI, allowing the generation of citrullinated peptides. In genetically susceptible (shared epitope-positive) individuals, such citrullinated peptides may interrupt tolerance to endogenous citrullinated antigens, resulting in the generation of ACPA .
The notion that RA should be viewed as a syndrome consisting of more than one pathogenetic entity is strongly supported by the differences between patients with detectable ACPA and those who are ACPA negative . Taken together, the available data suggest that after initiation of the immune response in, for instance, the lung or the periodontium, leading to production of ACPA, a second ‘hit’ like a trauma or a viral infection, leading to inflammation and citrullination in the synovium, may result in epitope spreading, and autonomous disease progression, finally resulting in full-blown RA .
Insights into synovial inflammation
In established RA, the inflamed synovium is characterised by infiltration with macrophages, plasma cells, T-cells and other cells such as mast cells, B cells, dendritic cells, natural killer cells and neutrophils . Because of their production of matrix degrading enzymes as well their role in attracting and activating immune cells, synovial fibroblasts have gained increased focus. They are stably activated and can produce high levels of mediators of inflammation and destruction, even without stimulation by immune cells . Recent work has shown that in addition to a critical role for synovial fibroblasts, other systems may influence the inflammatory process, such as the neuroendocrine system . Neuroinflammatory mechanisms control synovial inflammation, including the cholinergic anti-inflammatory pathway. The activity of cytokine producing innate immune cells expressing the nicotinic acetylcholine receptor subunit α7 (α7nAChR) may be (indirectly) reduced by acetylcholine released from the peripheral branches of the vagus nerve. In animal models administration of 7nAChR agonists or electrical stimulation of the vagus nerve resulted in a decrease of 50–75% of pro-inflammatory cytokine production . These insights may lead to exciting advances in our understanding and ultimately the development of new therapies for RA.
Cardiovascular disease
There has also been an upsurge of research on comorbidity associated with RA, for instance, osteoporosis and cardiovascular disease. The increased cardiovascular co-morbidity seen in RA is associated with the chronic inflammatory state of this disease. Factors such as tumour necrosis factor alpha (TNFα) and the acute phase reactant C-reactive protein (CRP) play a pivotal role; TNFα may for instance induce potent atherogenic effects on the arterial wall, involving cell apoptosis and upregulation of adhesion molecules. Statin treatment, a cornerstone in preventing cardiovascular disease, also exerts immunomodulatory properties and could help dampen the inflammation in RA; a hard endpoint statin trial is still ongoing (TRACE RA; http://www.dgoh.nhs.uk/tracera/ ) .
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Systemic autoimmunity precedes the development of synovitis
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ACPA-positive and ACPA-negative diseases are two distinct entities
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Smoking and periodontitis are important risk factors for the development of ACPA-positive RA in genetically susceptible subjects
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In addition to immunity, other mechanisms are critically involved in RA, including a role for synovial fibroblasts and neurological mechanisms.
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RA is a systemic disease with significant co-morbidity including cardiovascular disease.
Advances in understanding the etiopathogenesis of RA
Novel translational methods, including analysis of synovial biopsies, and applied molecular, cellular and genetic technologies, have increased our understanding of the pathogenesis of RA. It has become apparent that years before clinical onset of RA increased levels of autoantibodies, cytokines and chemokines can already be detected, suggesting the advancement of disease long before joint destruction is evident , although the primary target of RA, the synovium, is not affected in the earliest stages of preclinical RA .
Genetic factors
In 2000, it was estimated that the relative contribution of genetic factors to RA is about 50%, based on twin studies . In 2010 a meta-analysis of genome wide association studies has identified seven new RA risk loci, totalling the known risk alleles to 16% of the estimated 50% of disease variance due to genetic factors . From all genetic data, the risk associations with human leukocyte antigen (HLA)-DRB1-shared epitope alleles and, secondly, PTPN22 alleles are the strongest . The next step would be to translate the findings of genome wide association studies to epidemiological and pathogenetic studies.
Anti-citrullinated protein antibodies
Since the beginning of the century anti-citrullinated protein antibodies (ACPAs) have been recognised as a hallmark of RA . ACPAs can be detected years before onset of disease and play a role in the pathogenesis of RA . Citrullination is a biochemical event in which arginine is changed into citrulline by deimination. The basic charge conferred by arginine is then turned into a neutral site in the peptide by citrulline, an event that may alter the tridimensional conformation of the protein. The enzymes catalysing this biochemical reaction are the peptidylarginine deiminases (PADIs). The upregulated expression of PADI enzymes provoked by smoking may promote the citrullination of proteins in the lung, leading to autoimmunity against citrullinated antigens in RA . ACPA-positive disease is associated with unfavourable outcome, and there is an association between ACPA positivity and the presence of the specific genotype encoding the shared epitope, smoking , and periodontal disease . Porphyromonas gingivalis is one of the bacteria causing periodontal disease and may express PADI, allowing the generation of citrullinated peptides. In genetically susceptible (shared epitope-positive) individuals, such citrullinated peptides may interrupt tolerance to endogenous citrullinated antigens, resulting in the generation of ACPA .
The notion that RA should be viewed as a syndrome consisting of more than one pathogenetic entity is strongly supported by the differences between patients with detectable ACPA and those who are ACPA negative . Taken together, the available data suggest that after initiation of the immune response in, for instance, the lung or the periodontium, leading to production of ACPA, a second ‘hit’ like a trauma or a viral infection, leading to inflammation and citrullination in the synovium, may result in epitope spreading, and autonomous disease progression, finally resulting in full-blown RA .
Insights into synovial inflammation
In established RA, the inflamed synovium is characterised by infiltration with macrophages, plasma cells, T-cells and other cells such as mast cells, B cells, dendritic cells, natural killer cells and neutrophils . Because of their production of matrix degrading enzymes as well their role in attracting and activating immune cells, synovial fibroblasts have gained increased focus. They are stably activated and can produce high levels of mediators of inflammation and destruction, even without stimulation by immune cells . Recent work has shown that in addition to a critical role for synovial fibroblasts, other systems may influence the inflammatory process, such as the neuroendocrine system . Neuroinflammatory mechanisms control synovial inflammation, including the cholinergic anti-inflammatory pathway. The activity of cytokine producing innate immune cells expressing the nicotinic acetylcholine receptor subunit α7 (α7nAChR) may be (indirectly) reduced by acetylcholine released from the peripheral branches of the vagus nerve. In animal models administration of 7nAChR agonists or electrical stimulation of the vagus nerve resulted in a decrease of 50–75% of pro-inflammatory cytokine production . These insights may lead to exciting advances in our understanding and ultimately the development of new therapies for RA.
Cardiovascular disease
There has also been an upsurge of research on comorbidity associated with RA, for instance, osteoporosis and cardiovascular disease. The increased cardiovascular co-morbidity seen in RA is associated with the chronic inflammatory state of this disease. Factors such as tumour necrosis factor alpha (TNFα) and the acute phase reactant C-reactive protein (CRP) play a pivotal role; TNFα may for instance induce potent atherogenic effects on the arterial wall, involving cell apoptosis and upregulation of adhesion molecules. Statin treatment, a cornerstone in preventing cardiovascular disease, also exerts immunomodulatory properties and could help dampen the inflammation in RA; a hard endpoint statin trial is still ongoing (TRACE RA; http://www.dgoh.nhs.uk/tracera/ ) .
- •
Systemic autoimmunity precedes the development of synovitis
- •
ACPA-positive and ACPA-negative diseases are two distinct entities
- •
Smoking and periodontitis are important risk factors for the development of ACPA-positive RA in genetically susceptible subjects
- •
In addition to immunity, other mechanisms are critically involved in RA, including a role for synovial fibroblasts and neurological mechanisms.
- •
RA is a systemic disease with significant co-morbidity including cardiovascular disease.
Early diagnosis: which tools are available?
Early therapeutic intervention dramatically improves clinical outcome, and can result in less joint damage and disability . Consequently, a timely diagnosis is crucial. The diagnosis is primarily based on the clinical signs and symptoms of RA. The new American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria set , published in 2010, allows diagnosis in an earlier stage of the disease, although the clinical picture is slightly different on the group level, and some patients with self-limiting disease may be falsely diagnosed with RA .
Imaging technologies
Previously, changes in bone could only be visualised by plain X-ray. Technical advances during the last decade have led to the improvement of several new imaging techniques that allow detection of erosions and signs of inflammation earlier and with greater sensitivity, such as ultrasonography and magnetic resonance imaging (MRI) . Developing (and implementing) less time-intensive techniques, which can detect and define early synovitis and joint destruction, remains an important research priority. For the near future, there will be increasing interest in the identification of molecular biomarkers that could perhaps replace joint imaging, but this is still on the research agenda.
Detection of autoantibodies
Measurement of autoantibodies has a place in early detection of RA. The identification and implementation of serum ACPA assessment is one of the great achievements of the last decade. ACPA (and rheumatoid factor) can be detected in arthralgia patients long before RA becomes clinically manifest . In about 33% of patients with an established RA diagnosis, however, ACPA or rheumatoid factor cannot be detected and recent findings suggest that in about half of them novel autoantibodies may be present . Autoantibodies play an important role not only during the initial development but also in the course of disease .
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The new ACR/EULAR classification criteria set allows diagnosis in an earlier stage of the disease.
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Measurement of ACPA and rheumatoid factor may assist in early detection of RA, and the presence of ACPA is associated with an unfavourable outcome.
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Role of imaging in an early disease may become increasingly important.
Therapeutic principles
The widespread recognition of the importance of early treatment, systematic evaluation of disease activity and targeting treatment towards remission of RA is one of the great paradigm shifts of the past decade.
Initiation of antirheumatic treatment in an early stage of RA
Early antirheumatic treatment is indicated, as early DMARD treatment can protect against progressive joint destruction, which is critical to maintain function and quality of life over time. It has also become evident that abrogation of inflammation in an early stage of RA maximises the chance of achieving remission of the disease . The benefit of early intervention has been shown not only for conventional disease-modifying antirheumatic drug (DMARD) treatment but also for treatment with for instance etanercept , tocilizumab , abatacept , and rituximab . Therefore, early initiation of treatment, aimed at remission, with frequent treatment adjustment if necessary, at least every 3 months until the desired target is reached, is recommended to maximise long-term health related quality of life .
Systematic evaluation of disease activity
Several disease activity-scoring systems, consisting of both objective and subjective assessments, have been developed . The disease activity score (DAS) comprises a composite score based on tender and swollen joint counts, patient assessment of global health and erythrocyte sedimentation rate (ESR); it also proved to be valid when a reduced number of joints is evaluated (28 joints (DAS28)). Next, a simplified disease activity index (SDAI) was developed with CRP level instead of ESR, and both physician’s and patient’s global assessments of disease activity . In the clinical disease activity index (CDAI), acute phase reactants are also omitted. In most clinical trials, the DAS28 or DAS44 instead of the original DAS are included in the assessments, in conjunction with relative response measures, such as the ACR or EULAR response criteria. The relative response criteria are less useful in clinical practice, although they can show a favourable response to a specific mechanism of action. It has been suggested that the SDAI might be better in predicting radiographic progression than the DAS28, but more data are needed . The omission of the ankle and feet in the reduced joint count score remains a potential weakness of the newer indices .
Treat-to-target
The recent treat-to-target initiative by an international task force has resulted in 10 recommendations to achieve optimal outcomes in RA . Remission, that is, absence of disease activity, is the primary goal and requires a regular stringent evaluation and adjustment of therapy, at least every 3 months until the desired treatment target is achieved. In established long-standing disease, a state of low disease activity instead of remission may be an acceptable therapeutic goal . The tight control for RA (TICORA) study, published in 2004, showed that patients undergoing such an intensive, outpatient treatment strategy (including frequent objective assessments and synthetic DMARDs, but no TNF inhibitors), which was aimed at a good response of DAS <2.4, had a larger decrease in DAS, less radiographic progression, and a better physical function and quality of life at no extra cost compared to routine outpatient care . The benefit of tight disease control by adjusting medication depending on disease activity was firmly established by the BeSt (Dutch acronym for BehandelStrategieën, Treatment Strategies) study, which compared treatment with DMARDs, glucocorticoids (GCs) and the TNF antagonist infliximab over four different regimens ranging from sequential monotherapy to combination therapy in early RA . After 2 years, 79% of patients in all groups achieved the predefined goal of low disease activity (defined as a DAS ≤ 2.4), while 38–46% of patients achieved remission (DAS < 1.6) . Although the best method to measure and predict disease activity and progression in clinical practice is still under debate, the principle of treating to target remission is key even as the definition of remission may change over time.
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Treatment needs to be initiated as soon as the diagnosis can be made.
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Treat-to-target, aimed at remission in RA, is the current state of the art treatment goal.
Antirheumatic drugs
Non-steroidal anti-inflammatory drugs
The role for non-steroidal anti-inflammatory drugs (NSAIDs) has changed in the last decade from first-line treatment to a more supportive one, but their use remains quite prevalent . The selective COX-2 inhibitors have less gastrointestinal side effects, but have been associated with an increased cardiovascular risk profile. This is most clear for rofecoxib, which was taken off the mark in 2004 . However, the increased cardiovascular risk is probably not only associated with selective COX-2 inhibitors. More likely, it is substrate dependent as suggested by a meta-analysis . Combined with the inability to improve long-term outcome and prevent structural joint damage, and their possible renal adverse effects, there is a need to limit the use of NSAIDs and COX-2 inhibitors, in particular in individual patients at risk of developing side effects.
Glucocorticoids
GCs are used for rapid reduction of synovitis in early disease, during a flare-up or as local treatment of isolated, actively inflamed joints. GCs have distinct disease-modifying properties, in part via an effect on macrophages in the synovial tissue and it has become clear that GC can inhibit radiographic joint damage . From the newly developed GC compounds, modified-released prednisolone has become available. When administered in the late evening, supplementing endogenous cortisol and inhibiting pro-inflammatory cytokines such as IL-6, this may lead to reduced duration of morning stiffness compared to standard prednisolone . Numerous GC analogues have been tested to reduce the adverse events; however, there has not been a major breakthrough so far .
Conventional DMARDs
Methotrexate (MTX) became available during the early 1950s and although its long-term safety profile has been well established , the mechanism of action is still not completely understood. It has been widely studied and shown to be effective, both as monotherapy and in combination with biological agents . Although several new biological agents became available during the last decade, most are still used in combination with MTX or other conventional DMARDs, such as hydroxychloroquine, leflunomide or sulfasalazine.
Biological agents
Early, aggressive treatment of RA gained momentum after the introduction of biologicals in the late 1990s . The fast-acting properties and ability to slow down progressive joint damage in patients with insufficient response to synthetic agents are reasons for their success. Although initially exhibiting only few side effects, long-term follow-up revealed increased risk of reactivation of infections, particularly tuberculosis . The biological agents are relatively expensive, but their costs should be viewed in light of their effects on morbidity, mortality, quality of life, as well as the economic impact on society .
TNF inhibition
In RA, TNF inhibitors have been approved since more than 10 years. They represent one of the most successful examples in rheumatology of the bench to bedside approach. Efficacy of the five currently available TNF inhibitors (etanercept (soluble TNF receptor)) ; infliximab ; adalimumab ; certolizumab and golimumab (all monoclonal anti-TNF antibodies) shows on the group level similarity. Although some agents have been registered for use as monotherapy, there is no convincing evidence that they are more effective in terms of reducing signs and symptoms than MTX monotherapy; the combination with MTX is however superior . As TNF inhibitors dampen the immune system, reactivation of latent viral and bacterial infections may occur. Therefore, patients are screened for previous exposure to Mycobacterium tuberculosis prior to initiation of treatment, according to local guidelines . According to a large meta-analysis, patients receiving two to three times the recommended doses of anti-TNF were associated with a two-fold increased risk of serious infection, but the incidence of lymphoma or congestive heart failure did not seem to be raised . Generally, most investigators consider at present TNF inhibitors the first choice biological in patients with an inadequate response to conventional DMARD treatment, based on the vast experience with these drugs, but there may be reasons in individual patients to make another choice .
Biologicals with a mechanism of action other than TNF blockade
Over the last decade, biologicals with a mechanism of action other than TNF blockade have become available. If a patient has failed a first TNF inhibitor, there is the choice to switch to a second TNF antagonist, or to treatment with rituximab, tocilizumab or abatacept . The success of switching to a second TNF inhibitor appears to be dependent on the reason for discontinuation of the first one . If the first TNF inhibitor was discontinued because of adverse events, the cumulative rate of discontinuation of the second TNF antagonist was 9% compared with 16% in patients who stopped the first agent because of inefficacy . Within the non-responders, primary non-responders can be distinguished from initial responders who lost response (secondary non-responders) . Primary non-responders have on average less TNF-dependent disease and are less likely to respond to a second TNF inhibitor. In these patients, biologicals with a different mechanism of action may be preferable over trying a second TNF inhibitor .
B cell-targeted therapy with rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, has been shown to be effective in RA who previously failed anti-TNF therapy, as well other RA populations . Treatment is in particular effective in patients with a marked decrease in synovial plasma cells after administration of RTX . As plasma cells are mainly involved in the production of immunoglobulins, including autoantibodies in RA, these data supported the hypothesis that the indirect effect of rituximab on plasma cells with a consequent effect on autoantibodies (rheumatoid factor and ACPA) is crucial for clinical effectiveness. Accordingly, rheumatoid and/or ACPA positive patients respond better than seronegative patients, both in terms of reducing signs and symptoms and in protecting against progressive joint destruction . RTX is currently approved for patients failing TNF blocking therapy.
The effectiveness of tocilizumab, a humanised anti-interleukin (IL)-6 receptor antibody, has also been shown in different RA populations, including anti-TNF inadequate responders . IL-6 does play a role not only in synovial inflammation, but also in the systemic features of RA, like fatigue and anaemia. Tocilizumab has been approved for RA patients who have responded either inadequately to previous therapy with one or more conventional DMARDs or TNF antagonists. It can be prescribed as monotherapy, or in combination with MTX or other DMARDs. There are as yet no biomarkers that identify subsets of patients who are more likely to respond.
Abatacept (CTLA4-Ig), a fusion protein that prevents delivery of the costimulatory signal to T cells, has also been shown to be effective in MTX-naïve patients as well as patients failing MTX or anti-TNF treatment . The induction of T cell anergy by interfering with costimulatory signals while the T cell receptor is being stimulated leaves the T cell in a hyporesponsive state . Taken together, there are currently three biologicals available with a mechanism of action other than TNF inhibition. Whereas the response to rituximab treatment is enriched in rheumatoid factor and/or ACPA-positive patients, biomarkers’ prediction of the response to either tocilizumab or abatacept, which can be used in the context of personalised health care, remain to be identified.
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MTX is still the anchor drug in RA treatment
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If synthetic DMARD therapy fails to achieve remission, TNF inhibitors are often used as the first biological
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The treatment algorithm may be further refined based on ongoing research focussed on personalised health care.
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