Review
Remission in rheumatoid arthritis: is it all the same? Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
Expert Rev. Clin. Pharmacol. Early online, 1–12 (2015)
Hanna L Gul*1, Joana F Ferreira2 and Paul Emery3 1 Leeds Institute of Rheumatology & Musculoskeletal Medicine, 2nd Floor, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA UK 2 Leeds Institute of Rheumatology & Musculoskeletal Medicine, Rheumatology, 2nd Floor, Chapel Allerton Hospital, Chapeltown Road, West Yorkshire, Leeds, LS7 4SA UK 3 Leeds Institute of Molecular Medicine, Leeds Institute of Rheumatic & Musculoskeletal Medicine, 2nd Floor, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA UK *Author for correspondence: [email protected]
Remission is the key treatment goal in rheumatoid arthritis and should provide the optimal state for patients. Clinical remission criteria are based on composite scores of disease activity and are widely used in clinical practice and trials. With the use of biologic therapies and treat to target strategies, rates of clinical remission have significantly improved. Despite achieving this target, many patients demonstrate structural and functional deterioration. This raises the question regarding the validity of clinical criteria, although they have evolved significantly over the years. Imaging modalities such as ultrasound have been described as more accurate methods of assessing the remission state compared with clinical assessment alone. Furthermore, immuno-pathological assessments are gaining significant interest as this would enable assessment of disease activity at the primary site of pathology. Further research is required to develop accurate biomarkers of remission. We aimed to review the evolution of remission criteria in rheumatoid arthritis to date and to evaluate novel concepts in and the future of defining remission. KEYWORDS: biomarkers . classification criteria . comprehensive disease control . disease-modifying anti-rheumatic drugs
.
remission . rheumatoid arthritis . T-cell immunology
Rheumatoid arthritis (RA) is a chronic immune-mediated systemic disease characterized by a symmetrical inflammatory polyarthropathy and increased morbidity and mortality. Inflammation of the synovial lining (synovitis) appears to be the primary abnormality responsible for triggering structural joint damage which, if untreated leads to significant physical disability and reduced quality of life (QoL) [1,2]. There is no cure for RA, therefore, the key therapeutic target is to suppress inflammation and prevent any deterioration in joint damage and function, thus achieving a state of remission. With the advent of biologic therapies and treat to target strategies, rates of clinically defined remission have significantly improved, making it an achievable goal [3–5]. However, it has been observed that achieving clinical remission may not always be associated with good outcomes, specifically with regard to structural progression and functional deterioration [6]. This nonsystematic literature review explores the changing face of the concept remission in RA. Defining remission – why is it important?
Remission is the optimum treatment target in RA and should represent the absence of all
informahealthcare.com
10.1586/17512433.2015.1061429
.
ultrasound
articular and extra-articular inflammation (and immunologic activity) and the best possible structural and functional outcomes. It is important in preventing physical disability, psychosocial morbidity and co-morbidities associated with prolonged systemic inflammation, for example, cardiovascular disease [6]. The importance of remission as an outcome has recently been highlighted by the European League Against Rheumatism (EULAR) recommendations [7]. Treat to target strategies are currently employed to achieve and maintain remission through adaptation and titration of pharmacological treatments [3–5]. Although clinical remission is becoming an increasingly attainable goal, many patients demonstrate progressive structural and functional deterioration despite being in clinical remission. One possible explanation is that current remission criteria/composite disease activity scores are largely subjective and do not consider sub-clinical inflammation. Thus, the validity of these criteria remains questionable [6]. There is an evolving debate questioning how we can be sure that an optimum disease target/true remission state has been achieved and is associated with the best possible
2015 Informa UK Ltd
ISSN 1751-2433
1
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
Review
Gul, Ferreira & Emery
outcomes [8]. Are there different levels or depths of remission which can be achieved, for example, clinical, functional, radiological and immunological? Furthermore, which combination constitutes true remission and can predict the best outcomes, for example, sustainability of remission? There have been multiple attempts to re-define the concept of remission in RA. In addition to clinical definitions, the role of imaging in the detection of sub-clinical synovitis for patients in clinical remission has been of considerable interest however, the definition of what constitutes imaging remission still remains a challenge [1,9,10]. Furthermore, in recent years immunological status has been shown to predict the likelihood of sustained remission [11]. This adds another potential dimension to consider when defining the remission state in RA. With the achievement of sustained remission, optimization of treatment through either dose tapering or discontinuation of biological agents has emerged as an important consideration, which has gained significant interest. Although the adverse effects of biologic therapy reported in clinical trials is generally low, these drugs can be associated with unintended effects, for example, increased risk of malignancy, infection (dose-dependent) and rare severe adverse events [12]. Biologic diseasemodifying therapy (bDMARDs) is also associated with high costs, being more expensive than conventional synthetic disease-modifying therapy (csDMARDs) [13]. If clinical response can be maintained with more targeted and shorter durations of therapy (achieving the minimum effective dose), the risk of medication-induced side effects and long-term adverse outcomes could subsequently be reduced. Furthermore, this would be more financially beneficial [14]. There is a paucity of relevant data at present to guide clinicians on such a change in treatment focus [14]. Studies of biologic withdrawal in RA consist mainly of randomized controlled trials using anti-TNF agents and have demonstrated varied results. Methotrexate (MTX)-naı¨ve, early RA patients have demonstrated sustained biologic-free remission without functional or radiographic progression following combination treatment with TNF inhibitors and MTX [15]. This has been shown to be possible in some long-standing RA patients with inadequate responses to MTX [16–19], however, other studies have demonstrated high flare rates and adverse long-term outcomes [20]. It has been suggested that this difference between early and established RA patients may be as a result of them both having different immuno-inflammatory profiles, therefore, tapering/withdrawal strategies should be specifically tailored to the individual patient, based on the level of remission achieved [21]. These uncertainties highlight the need for validated remission biomarkers and have fueled the search for standardized remission criteria.
definitions have appeared. As previously mentioned, remission in RA should represent the absence of disease activity and should be measured by evaluating all forms of RA activity. This is not always possible in the clinical setting due to resource availability and time pressures, therefore, disease activity indices were created to facilitate assessment. These must be simple, feasible and correlate with or predict the three major gold standard outcomes for RA, which includes mortality, physical function and radiologic evidence of joint damage [22–24]. Despite the widespread use of these disease activity indices, the true definition of remission is still not clear. This raises the question: How can/should we measure disease activity? In the early 90s, a core set of measures that translate disease activity in RA were defined [25]. This core set should be reported in clinical trials and has become so useful that it is now commonly used in clinical practice also. They include tender (TJC) and swollen joint (SJC) counts, patient assessment of pain, patient global assessment of disease activity, physician’s global assessment of disease activity, patient assessment of physical function including the Health Assessment Questionnaire (HAQ) and measures of acute phase reactants (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]). Disease activity index definitions that have arisen subsequently include most of these variables. If we think of disease activity as a continuum, remission should represent the end of the disease continuum. Definitions of remission are ‘cut-off’ values of these indices and try to represent the end of the continuum [24,25]. Remission criteria to date (see TABLE 1) have included the domains of signs and symptoms of inflammation, whereas the other two major domains of RA, which include physical function and structural joint damage, have received less attention because they are used as outcomes to evaluate the proposed criteria [26].
Clinical remission criteria & their problems
This definition was the dominant instrument for measuring remission at the time, however, it posed several problems. First, it was established in a very different era, with less knowledge of pathology and fewer available treatments. It was based on the
In the early 80s, the American Rheumatism Association (ARA), now known as the American College of Rheumatology (ACR), proposed the first definition of remission [22]. Since then several doi: 10.1586/17512433.2015.1061429
ARA definition
In 1981, the ARA published the first definition of remission based on a study of 344 patients, of which 175 patients were in complete remission. The study evaluated a large number of variables in order to find discriminants between the remission and disease activity groups. Multivariate analysis resulted in proposed criteria for complete clinical remission in RA: 5 or more domains must be fulfilled for at least 2 consecutive months [22]: 1. 2. 3. 4. 5. 6.
Morning stiffness not exceeding 15 min; No fatigue; No joint pain (by history); No joint tenderness or pain on motion; No soft tissue swelling in joints or tendon sheaths; ESR (W)
Remission in rheumatoid arthritis: is it all the same? Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
Expert Rev. Clin. Pharmacol. Early online, 1–12 (2015)
Hanna L Gul*1, Joana F Ferreira2 and Paul Emery3 1 Leeds Institute of Rheumatology & Musculoskeletal Medicine, 2nd Floor, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA UK 2 Leeds Institute of Rheumatology & Musculoskeletal Medicine, Rheumatology, 2nd Floor, Chapel Allerton Hospital, Chapeltown Road, West Yorkshire, Leeds, LS7 4SA UK 3 Leeds Institute of Molecular Medicine, Leeds Institute of Rheumatic & Musculoskeletal Medicine, 2nd Floor, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA UK *Author for correspondence: [email protected]
Remission is the key treatment goal in rheumatoid arthritis and should provide the optimal state for patients. Clinical remission criteria are based on composite scores of disease activity and are widely used in clinical practice and trials. With the use of biologic therapies and treat to target strategies, rates of clinical remission have significantly improved. Despite achieving this target, many patients demonstrate structural and functional deterioration. This raises the question regarding the validity of clinical criteria, although they have evolved significantly over the years. Imaging modalities such as ultrasound have been described as more accurate methods of assessing the remission state compared with clinical assessment alone. Furthermore, immuno-pathological assessments are gaining significant interest as this would enable assessment of disease activity at the primary site of pathology. Further research is required to develop accurate biomarkers of remission. We aimed to review the evolution of remission criteria in rheumatoid arthritis to date and to evaluate novel concepts in and the future of defining remission. KEYWORDS: biomarkers . classification criteria . comprehensive disease control . disease-modifying anti-rheumatic drugs
.
remission . rheumatoid arthritis . T-cell immunology
Rheumatoid arthritis (RA) is a chronic immune-mediated systemic disease characterized by a symmetrical inflammatory polyarthropathy and increased morbidity and mortality. Inflammation of the synovial lining (synovitis) appears to be the primary abnormality responsible for triggering structural joint damage which, if untreated leads to significant physical disability and reduced quality of life (QoL) [1,2]. There is no cure for RA, therefore, the key therapeutic target is to suppress inflammation and prevent any deterioration in joint damage and function, thus achieving a state of remission. With the advent of biologic therapies and treat to target strategies, rates of clinically defined remission have significantly improved, making it an achievable goal [3–5]. However, it has been observed that achieving clinical remission may not always be associated with good outcomes, specifically with regard to structural progression and functional deterioration [6]. This nonsystematic literature review explores the changing face of the concept remission in RA. Defining remission – why is it important?
Remission is the optimum treatment target in RA and should represent the absence of all
informahealthcare.com
10.1586/17512433.2015.1061429
.
ultrasound
articular and extra-articular inflammation (and immunologic activity) and the best possible structural and functional outcomes. It is important in preventing physical disability, psychosocial morbidity and co-morbidities associated with prolonged systemic inflammation, for example, cardiovascular disease [6]. The importance of remission as an outcome has recently been highlighted by the European League Against Rheumatism (EULAR) recommendations [7]. Treat to target strategies are currently employed to achieve and maintain remission through adaptation and titration of pharmacological treatments [3–5]. Although clinical remission is becoming an increasingly attainable goal, many patients demonstrate progressive structural and functional deterioration despite being in clinical remission. One possible explanation is that current remission criteria/composite disease activity scores are largely subjective and do not consider sub-clinical inflammation. Thus, the validity of these criteria remains questionable [6]. There is an evolving debate questioning how we can be sure that an optimum disease target/true remission state has been achieved and is associated with the best possible
2015 Informa UK Ltd
ISSN 1751-2433
1
Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 07/03/15 For personal use only.
Review
Gul, Ferreira & Emery
outcomes [8]. Are there different levels or depths of remission which can be achieved, for example, clinical, functional, radiological and immunological? Furthermore, which combination constitutes true remission and can predict the best outcomes, for example, sustainability of remission? There have been multiple attempts to re-define the concept of remission in RA. In addition to clinical definitions, the role of imaging in the detection of sub-clinical synovitis for patients in clinical remission has been of considerable interest however, the definition of what constitutes imaging remission still remains a challenge [1,9,10]. Furthermore, in recent years immunological status has been shown to predict the likelihood of sustained remission [11]. This adds another potential dimension to consider when defining the remission state in RA. With the achievement of sustained remission, optimization of treatment through either dose tapering or discontinuation of biological agents has emerged as an important consideration, which has gained significant interest. Although the adverse effects of biologic therapy reported in clinical trials is generally low, these drugs can be associated with unintended effects, for example, increased risk of malignancy, infection (dose-dependent) and rare severe adverse events [12]. Biologic diseasemodifying therapy (bDMARDs) is also associated with high costs, being more expensive than conventional synthetic disease-modifying therapy (csDMARDs) [13]. If clinical response can be maintained with more targeted and shorter durations of therapy (achieving the minimum effective dose), the risk of medication-induced side effects and long-term adverse outcomes could subsequently be reduced. Furthermore, this would be more financially beneficial [14]. There is a paucity of relevant data at present to guide clinicians on such a change in treatment focus [14]. Studies of biologic withdrawal in RA consist mainly of randomized controlled trials using anti-TNF agents and have demonstrated varied results. Methotrexate (MTX)-naı¨ve, early RA patients have demonstrated sustained biologic-free remission without functional or radiographic progression following combination treatment with TNF inhibitors and MTX [15]. This has been shown to be possible in some long-standing RA patients with inadequate responses to MTX [16–19], however, other studies have demonstrated high flare rates and adverse long-term outcomes [20]. It has been suggested that this difference between early and established RA patients may be as a result of them both having different immuno-inflammatory profiles, therefore, tapering/withdrawal strategies should be specifically tailored to the individual patient, based on the level of remission achieved [21]. These uncertainties highlight the need for validated remission biomarkers and have fueled the search for standardized remission criteria.
definitions have appeared. As previously mentioned, remission in RA should represent the absence of disease activity and should be measured by evaluating all forms of RA activity. This is not always possible in the clinical setting due to resource availability and time pressures, therefore, disease activity indices were created to facilitate assessment. These must be simple, feasible and correlate with or predict the three major gold standard outcomes for RA, which includes mortality, physical function and radiologic evidence of joint damage [22–24]. Despite the widespread use of these disease activity indices, the true definition of remission is still not clear. This raises the question: How can/should we measure disease activity? In the early 90s, a core set of measures that translate disease activity in RA were defined [25]. This core set should be reported in clinical trials and has become so useful that it is now commonly used in clinical practice also. They include tender (TJC) and swollen joint (SJC) counts, patient assessment of pain, patient global assessment of disease activity, physician’s global assessment of disease activity, patient assessment of physical function including the Health Assessment Questionnaire (HAQ) and measures of acute phase reactants (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]). Disease activity index definitions that have arisen subsequently include most of these variables. If we think of disease activity as a continuum, remission should represent the end of the disease continuum. Definitions of remission are ‘cut-off’ values of these indices and try to represent the end of the continuum [24,25]. Remission criteria to date (see TABLE 1) have included the domains of signs and symptoms of inflammation, whereas the other two major domains of RA, which include physical function and structural joint damage, have received less attention because they are used as outcomes to evaluate the proposed criteria [26].
Clinical remission criteria & their problems
This definition was the dominant instrument for measuring remission at the time, however, it posed several problems. First, it was established in a very different era, with less knowledge of pathology and fewer available treatments. It was based on the
In the early 80s, the American Rheumatism Association (ARA), now known as the American College of Rheumatology (ACR), proposed the first definition of remission [22]. Since then several doi: 10.1586/17512433.2015.1061429
ARA definition
In 1981, the ARA published the first definition of remission based on a study of 344 patients, of which 175 patients were in complete remission. The study evaluated a large number of variables in order to find discriminants between the remission and disease activity groups. Multivariate analysis resulted in proposed criteria for complete clinical remission in RA: 5 or more domains must be fulfilled for at least 2 consecutive months [22]: 1. 2. 3. 4. 5. 6.
Morning stiffness not exceeding 15 min; No fatigue; No joint pain (by history); No joint tenderness or pain on motion; No soft tissue swelling in joints or tendon sheaths; ESR (W)
