Best Practice & Research Clinical Rheumatology 27 (2013) 555–570
Contents lists available at ScienceDirect
Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh
7
Outcomes of early rheumatoid arthritis – The WHO ICF framework Suzanne M.M. Verstappen* Arthritis Research UK Centre of Excellence for Epidemiology, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester Academic Health Science Centre, Stopford Building, Oxford Road, M13 9PT Manchester, United Kingdom
a b s t r a c t Keywords: Early rheumatoid arthritis WHO ICF framework Outcomes Contextual factors
With the establishment of the new American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 criteria for rheumatoid arthritis (RA) to diagnose patients earlier and with the introduction of early and aggressive treatment, the current aim is remission resulting in less functional disability, halting of radiographic damage, less pain, less fatigue and no loss of employment. These outcomes can be related to the World Health Organization International Classification of Functioning, Disability and Health (the WHO ICF framework). This framework includes the component body functions, body structures, activities and participation related to the disease. These components are related to each other in a bidirectional way and can be influenced by contextual factors including environmental and personal factors. This framework can be used to describe trends in RA outcomes and the impact of contextual factors on these outcomes. Despite aggressive treatment strategies, patients with RA still experience loss of function, pain and fatigue, and a relatively high proportion of patients have to take sick leave or become work disabled within the first few years of the disease. There is evidence that more stringent definitions of remission lead to greater improvement of outcomes and that the aim should be sustained remission and not just remission. There is, however, a need for a better understanding of the relation between contextual factors and activity and participation outcomes to better guide therapy decisions by rheumatologists and provide information to patients, families and policymakers about the impact of RA on their lives
* Tel.: þ44 01612755663. E-mail address: [email protected]. 1521-6942/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.berh.2013.09.004
556
S.M.M. Verstappen / Best Practice & Research Clinical Rheumatology 27 (2013) 555–570
and to the society. The overall aim of this overview is to highlight the important contextual factors and consequences that relate to outcomes typically measured in RA studies and to demonstrate the additional benefits that can be achieved with remission and sustained remission. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Worldwide, the burden of musculoskeletal (MSK) conditions including rheumatoid arthritis (RA), with an estimated incidence in the Western countries of 0.3–1.0%, is a major health problem contributing to physical disability, increased health-care utilisation and reduced quality of life. [1,2] RA is a heterogeneous disease and may lead to joint damage, joint swelling, pain, fatigue and development of co-morbidities such as cardiovascular diseases (CVDs) [3]. These impairments in structures and functions of the body may result in limitations in physical activities and restrictions in participation. In order to help reduce the difficulties encountered when describing the complex relations between disease and outcome, and to facilitate the understanding between health professionals, researchers, policymakers and patients, the World Health Organization (WHO) introduced the International Classification of Functioning, Disability and Health (ICF) framework in 2001 [4]. The ICF has two parts, each with two components. The first part comprises functioning and disability and includes the components ‘body functions and structures’ and ‘activities and participation’. The second part includes the contextual factors. The ICF framework is based on a ‘biopsychosocial model’ and is useful in understanding the effects and influences of RA on body structures and body functions and the patient’s participation and activities in daily life in the assessment of the disease and the consequences of the disease. The process is bidirectional and can be influenced by contextual factors which are factors describing the background of an individual’s life or living, both personal and environmental (Fig. 1). Personal factors refer to individual factors and include, for example, age, gender, lifestyle, education, ability to cope, socio-economic status or role expectations. Personal factors are not part of a health condition or health status and are not classified in ICF, but they may have an impact on the outcome. The environmental factors, which can either facilitate or worsen activities and participation, may include physical, social, structural or attitudinal factors such as health policies and attitudes towards relationships and roles. The ICF framework is very extensive and many categories are not related to RA. An ICF Comprehensive Core Set for RA was therefore defined including 96 categories. This core set was based on an extensive consensus process among 17 experts from 12 countries and included patient’s perspectives on relevant ICF categories, a Delphi exercise among experts and a systematic review of outcome assessments in clinical trials [5]. These 96 categories are made up of 25 categories (26%) from the component body functions (e.g., sensation of pain (ICF code b280), mobility of joint function (b710)), 18 Health condition (disorder or disease)
Body Functions and Structures
Activities
Environmental Factors
Personal Factors
Fig. 1. WHO ICF framework.
S.M.M. Verstappen / Best Practice & Research Clinical Rheumatology 27 (2013) 555–570
557
(19%) from the component body structures (e.g., structure of the lower and upper extremity (s750 and s730)), 32 (33%) from the component activities and participation (e.g., walking (d450), remunerative employment (d850), carrying out daily routine (d230), fine hand use (d440)) and 21 (22%) from the component environmental factors (e.g., social security services, systems and policies (e570), and products and technology for personal use in daily living (e115)). Increasingly, these outcome measures, and to a lesser extent contextual factors, are included in international recommendations for the assessment of early RA and the consequences of the disease in observational studies and clinical trials. This chapter gives an overview of the impact of the disease and the relation with contextual factors using the ICF framework. First, from the component body functions and body structures, an overview of the percentage of patients in remission, rate of joint damage, change in pain and fatigue scores is given as well as causes and consequences of these outcomes. Second, the progression of functional disability is examined as part of the component activities. Third, working status in patients with early RA in observational studies and clinical trials is reviewed as part of the component participation. Remission Remission rates in early RA The current aim of treatment in patients with early RA is remission and when it is not possible to achieve remission to aim for low disease activity. Several definitions of remission are reported in clinical trials and observational studies including the American College of Rheumatology (ACR) preliminary criteria for remission [6], the Routine Assessment of Patient Index Data (RAPID-3) or those based on existing composite scores such as the Disease Activity Score (DAS), the 28-joint DAS (DAS28) [7], the Clinical Disease Activity Index (CDAI) and the Simplified Disease Activity Index (SDAI) [8]. In 2011, an international task force from the ACR and the European League Against Rheumatism (EULAR) published new remission criteria to be used in clinical trials [8]. Table 1 shows variables included in each of these indices and the cut-off used to define remission. The inclusion of different variables and the variation in definitions and cut-off levels of remission may result in categorising different patients in remission. A few studies compared the classification of patients in remission according to these different remission indices and some of these findings are summarised below. Table 1 Definitions of remission used in clinical trials and clinical practice. Remission criteria DAS-CRP: 0.54 O(RAI) þ 0.065 (SJC44) þ 0.17 ln(CRP mg/l þ 1) þ 0.00722 (VAS well-being, mm) þ 0.45 1.6 DAS-ESR: 0.54 O(RAI) þ 0.065 (SJC44) þ 0.33 ln(ESR) þ 0.00722 (VAS well-being, mm) 1.6 DAS28-CRP: 0.56 O(TJC28) þ 0.28 (SJC28) þ 0.0.36 ln(CRP mg/l þ 1) þ 0.014 (VAS well-being, mm) þ 0.96 2.6 DAS28-ESR: 0.56 O(TJC28) þ 0.28 (SJC28) þ 0.0.70 ln(ESR) þ 0.014 (VAS well-being, mm) 2.6 CDAI: TJC28 þ SJC28 þ PhGA cm þ VAS patient cm 3.3 SDAI: TJC28 þ SJC28 þ PhGA cm þ VAS patient cm þ CRP mg/dl 2.8 ACR criteria: Presence of 5 or more of the following criteria: morning stiffness 15 min, no fatigue, no pain, no joint tenderness, no joint or tendon sheath swelling, and no elevation of ESR ACR/EULAR criteria (Booelean) clinical trials: TJC28 1, SJC 1, VAS patient 1 (cm), CRP (mg/dL) 1 ACR EULAR criteria (Boolean) clinical practice: TJC28 1, SJC 1, PhGA 1 (cm) 1 ACR/EULAR criteria (CDAI): TJC28 þ SJC28 þ PhGA cm þ VAS patient cm 2.8 RAPID3R: Patient physical function cm þ patient pain cm þ patient global cm 30.0
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S.M.M. Verstappen / Best Practice & Research Clinical Rheumatology 27 (2013) 555–570
In a study by Klarenbeek et al. [9] including patients recruited to the BeSt study, a multi-centre clinical trial comparing four treatment strategies, who were followed up for 5 years, the following composite indices were evaluated: DAS, DAS28, SDAI, CDAI and three variants of the DAS score with adjustments in the tender joint count (TJC) of the score. The percentage of patients in remission on at least three occasions during the fifth year ranged from 15.4% applying the new ACR/EULAR (66-/68joint count) clinical trial definition to 47.9% when applying the less stringent DAS28 CRP definition of remission. In this study also a small variation was observed applying the same remission criteria, but including either a 28-joint count compared to a 66-joint count as observed in other studies. It should however be noted that in the BeSt study treatment decisions were guided by the DAS score, and that patients recruited to this clinical trial may not be representative of a general RA population. In one observational cohort of patients with early RA (mean standard deviation (SD) disease duration 0.3 (0.6) years), the percentage of patients in remission 1 year after inclusion using the 28-joint count vs the 38joint count was also very similar, respectively, 9% vs 7% for the ACR/EULAR Boolean and 14% vs 10% for the SDAI clinical trial criteria for remission [10]. Somewhat higher percentages of patients in remission were observed in patients with early RA 6 months after inclusion into the ESPOIR study (median [IQR] disease duration 4.8 [2.9–7.0] months) for ACR/EULAR Boolean (12.9%), SDAI (17.0%), DAS28 (32.5%), CDAI (17.9%) and RAPID3R (25.1%). Kappa agreement between the ACR/EULAR Boolean criteria and the other indices of remission ranged from good (from 0.70 for RAPID3R þ SJ0 þ D1 to 0.79 for SDAI) to low/moderate (0.46 for DAS28 to 0.67 for RAPID3R þ SJ0) [11]. In the CATCH study, measuring agreement between ACR/EULAR remission criteria (both 28- and 66-/68-joint scores), SDAI, CDAI and DAS28, the agreement between all ACR/EULAR criteria and DAS28-based criteria was fair to moderate (8 range 0.39–0.55) and substantial for SDAI and CDAI (8 range 0.73–0.81) [12]. In this study, including 369 patients with early RA, the percentage of patients achieving remission by 6 months after inclusion ranged from 14% (ACR/EULAR trial 68/66 definition) to 30% (DAS28) and patients in DAS28 remission had overall higher swollen joint count (SJC), TJC, physician and patient-reported global assessment scores. Early remission and long-term outcomes Some conflicting results have been found when comparing these remission criteria in relation to long-term outcomes such as functional disability, radiographic damage and mortality. In the BeSt study, the estimated probability for a health assessment questionnaire (HAQ) score >0.5 and annual Sharp van der Heijde score (SHS) progression of 3 units showed high agreement between the different indices ranging from, respectively, 34% (ACR/EULAR 68/66 trial) to 41% (DAS28 CRP) for HAQ and from 9% (CDAI, ACR 66/68 trial, ACR 68/66 practice) to 12% (DAS CRP, DAS28 CRP, DAS TJC53, DAS TJC 44) for SHS [9]. Similarly, comparing the ACR/EULAR remission criteria based on the 28- or 38-joint count during a 1-year follow-up study, despite a difference in remission rates and residual pain and inflammation of the joints in the feet between the indices, no statistically significant difference between the 28- and 38-joint definitions on the impact on functional disability and radiographic damage deterioration was observed [10]. In contrast, the highest positive likelihood ratios (LRþ) were found for SDAI in association with non-progression of radiographic damage (LRþ 4.0 (95% CI 1.7–9.4)) [13], for ACR/EULAR remission criteria with low functional disability (LRþ 5.67 (95% CI 1.34–24.00)) [14] and for SDAI with absence power Doppler-positive synovitis (LRþ 6.46 (95% CI 1.95–21.34)) [14] in two observational studies, while in both studies DAS28-CRP had significantly lower positive LRs for these outcomes. Thus, when a stricter definition of remission is used, less deterioration of functional disability and progression of radiographic damage are seen. Time is not included as a criterion in most definitions of remission. In general practice, it is recognised that sustained remission is related with more favourable outcomes such as less functional disability and radiographic damage over time, less synovitis and a reduced likelihood of mortality but research is limited. To date, some of the studies investigating these associations are based on small sample sizes or include patients recruited before 2000. In a small study including patients with early RA (n ¼ 147) who had responded to methotrexate (MTX) after 3–4 months, radiographic progression was not statistically significant between those who were in remission at all time points over 2 years compared to other patients (SHS 3.79 (6.68) vs 4.75 (8.20), p ¼ 0.6) [15]. By contrast, patients recruited to the Early RA Study (ERAS), an
S.M.M. Verstappen / Best Practice & Research Clinical Rheumatology 27 (2013) 555–570
559
inception cohort including patients since 1986, who were in sustained remission (DAS
Contents lists available at ScienceDirect
Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh
7
Outcomes of early rheumatoid arthritis – The WHO ICF framework Suzanne M.M. Verstappen* Arthritis Research UK Centre of Excellence for Epidemiology, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester Academic Health Science Centre, Stopford Building, Oxford Road, M13 9PT Manchester, United Kingdom
a b s t r a c t Keywords: Early rheumatoid arthritis WHO ICF framework Outcomes Contextual factors
With the establishment of the new American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 criteria for rheumatoid arthritis (RA) to diagnose patients earlier and with the introduction of early and aggressive treatment, the current aim is remission resulting in less functional disability, halting of radiographic damage, less pain, less fatigue and no loss of employment. These outcomes can be related to the World Health Organization International Classification of Functioning, Disability and Health (the WHO ICF framework). This framework includes the component body functions, body structures, activities and participation related to the disease. These components are related to each other in a bidirectional way and can be influenced by contextual factors including environmental and personal factors. This framework can be used to describe trends in RA outcomes and the impact of contextual factors on these outcomes. Despite aggressive treatment strategies, patients with RA still experience loss of function, pain and fatigue, and a relatively high proportion of patients have to take sick leave or become work disabled within the first few years of the disease. There is evidence that more stringent definitions of remission lead to greater improvement of outcomes and that the aim should be sustained remission and not just remission. There is, however, a need for a better understanding of the relation between contextual factors and activity and participation outcomes to better guide therapy decisions by rheumatologists and provide information to patients, families and policymakers about the impact of RA on their lives
* Tel.: þ44 01612755663. E-mail address: [email protected]. 1521-6942/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.berh.2013.09.004
556
S.M.M. Verstappen / Best Practice & Research Clinical Rheumatology 27 (2013) 555–570
and to the society. The overall aim of this overview is to highlight the important contextual factors and consequences that relate to outcomes typically measured in RA studies and to demonstrate the additional benefits that can be achieved with remission and sustained remission. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Worldwide, the burden of musculoskeletal (MSK) conditions including rheumatoid arthritis (RA), with an estimated incidence in the Western countries of 0.3–1.0%, is a major health problem contributing to physical disability, increased health-care utilisation and reduced quality of life. [1,2] RA is a heterogeneous disease and may lead to joint damage, joint swelling, pain, fatigue and development of co-morbidities such as cardiovascular diseases (CVDs) [3]. These impairments in structures and functions of the body may result in limitations in physical activities and restrictions in participation. In order to help reduce the difficulties encountered when describing the complex relations between disease and outcome, and to facilitate the understanding between health professionals, researchers, policymakers and patients, the World Health Organization (WHO) introduced the International Classification of Functioning, Disability and Health (ICF) framework in 2001 [4]. The ICF has two parts, each with two components. The first part comprises functioning and disability and includes the components ‘body functions and structures’ and ‘activities and participation’. The second part includes the contextual factors. The ICF framework is based on a ‘biopsychosocial model’ and is useful in understanding the effects and influences of RA on body structures and body functions and the patient’s participation and activities in daily life in the assessment of the disease and the consequences of the disease. The process is bidirectional and can be influenced by contextual factors which are factors describing the background of an individual’s life or living, both personal and environmental (Fig. 1). Personal factors refer to individual factors and include, for example, age, gender, lifestyle, education, ability to cope, socio-economic status or role expectations. Personal factors are not part of a health condition or health status and are not classified in ICF, but they may have an impact on the outcome. The environmental factors, which can either facilitate or worsen activities and participation, may include physical, social, structural or attitudinal factors such as health policies and attitudes towards relationships and roles. The ICF framework is very extensive and many categories are not related to RA. An ICF Comprehensive Core Set for RA was therefore defined including 96 categories. This core set was based on an extensive consensus process among 17 experts from 12 countries and included patient’s perspectives on relevant ICF categories, a Delphi exercise among experts and a systematic review of outcome assessments in clinical trials [5]. These 96 categories are made up of 25 categories (26%) from the component body functions (e.g., sensation of pain (ICF code b280), mobility of joint function (b710)), 18 Health condition (disorder or disease)
Body Functions and Structures
Activities
Environmental Factors
Personal Factors
Fig. 1. WHO ICF framework.
S.M.M. Verstappen / Best Practice & Research Clinical Rheumatology 27 (2013) 555–570
557
(19%) from the component body structures (e.g., structure of the lower and upper extremity (s750 and s730)), 32 (33%) from the component activities and participation (e.g., walking (d450), remunerative employment (d850), carrying out daily routine (d230), fine hand use (d440)) and 21 (22%) from the component environmental factors (e.g., social security services, systems and policies (e570), and products and technology for personal use in daily living (e115)). Increasingly, these outcome measures, and to a lesser extent contextual factors, are included in international recommendations for the assessment of early RA and the consequences of the disease in observational studies and clinical trials. This chapter gives an overview of the impact of the disease and the relation with contextual factors using the ICF framework. First, from the component body functions and body structures, an overview of the percentage of patients in remission, rate of joint damage, change in pain and fatigue scores is given as well as causes and consequences of these outcomes. Second, the progression of functional disability is examined as part of the component activities. Third, working status in patients with early RA in observational studies and clinical trials is reviewed as part of the component participation. Remission Remission rates in early RA The current aim of treatment in patients with early RA is remission and when it is not possible to achieve remission to aim for low disease activity. Several definitions of remission are reported in clinical trials and observational studies including the American College of Rheumatology (ACR) preliminary criteria for remission [6], the Routine Assessment of Patient Index Data (RAPID-3) or those based on existing composite scores such as the Disease Activity Score (DAS), the 28-joint DAS (DAS28) [7], the Clinical Disease Activity Index (CDAI) and the Simplified Disease Activity Index (SDAI) [8]. In 2011, an international task force from the ACR and the European League Against Rheumatism (EULAR) published new remission criteria to be used in clinical trials [8]. Table 1 shows variables included in each of these indices and the cut-off used to define remission. The inclusion of different variables and the variation in definitions and cut-off levels of remission may result in categorising different patients in remission. A few studies compared the classification of patients in remission according to these different remission indices and some of these findings are summarised below. Table 1 Definitions of remission used in clinical trials and clinical practice. Remission criteria DAS-CRP: 0.54 O(RAI) þ 0.065 (SJC44) þ 0.17 ln(CRP mg/l þ 1) þ 0.00722 (VAS well-being, mm) þ 0.45 1.6 DAS-ESR: 0.54 O(RAI) þ 0.065 (SJC44) þ 0.33 ln(ESR) þ 0.00722 (VAS well-being, mm) 1.6 DAS28-CRP: 0.56 O(TJC28) þ 0.28 (SJC28) þ 0.0.36 ln(CRP mg/l þ 1) þ 0.014 (VAS well-being, mm) þ 0.96 2.6 DAS28-ESR: 0.56 O(TJC28) þ 0.28 (SJC28) þ 0.0.70 ln(ESR) þ 0.014 (VAS well-being, mm) 2.6 CDAI: TJC28 þ SJC28 þ PhGA cm þ VAS patient cm 3.3 SDAI: TJC28 þ SJC28 þ PhGA cm þ VAS patient cm þ CRP mg/dl 2.8 ACR criteria: Presence of 5 or more of the following criteria: morning stiffness 15 min, no fatigue, no pain, no joint tenderness, no joint or tendon sheath swelling, and no elevation of ESR ACR/EULAR criteria (Booelean) clinical trials: TJC28 1, SJC 1, VAS patient 1 (cm), CRP (mg/dL) 1 ACR EULAR criteria (Boolean) clinical practice: TJC28 1, SJC 1, PhGA 1 (cm) 1 ACR/EULAR criteria (CDAI): TJC28 þ SJC28 þ PhGA cm þ VAS patient cm 2.8 RAPID3R: Patient physical function cm þ patient pain cm þ patient global cm 30.0
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S.M.M. Verstappen / Best Practice & Research Clinical Rheumatology 27 (2013) 555–570
In a study by Klarenbeek et al. [9] including patients recruited to the BeSt study, a multi-centre clinical trial comparing four treatment strategies, who were followed up for 5 years, the following composite indices were evaluated: DAS, DAS28, SDAI, CDAI and three variants of the DAS score with adjustments in the tender joint count (TJC) of the score. The percentage of patients in remission on at least three occasions during the fifth year ranged from 15.4% applying the new ACR/EULAR (66-/68joint count) clinical trial definition to 47.9% when applying the less stringent DAS28 CRP definition of remission. In this study also a small variation was observed applying the same remission criteria, but including either a 28-joint count compared to a 66-joint count as observed in other studies. It should however be noted that in the BeSt study treatment decisions were guided by the DAS score, and that patients recruited to this clinical trial may not be representative of a general RA population. In one observational cohort of patients with early RA (mean standard deviation (SD) disease duration 0.3 (0.6) years), the percentage of patients in remission 1 year after inclusion using the 28-joint count vs the 38joint count was also very similar, respectively, 9% vs 7% for the ACR/EULAR Boolean and 14% vs 10% for the SDAI clinical trial criteria for remission [10]. Somewhat higher percentages of patients in remission were observed in patients with early RA 6 months after inclusion into the ESPOIR study (median [IQR] disease duration 4.8 [2.9–7.0] months) for ACR/EULAR Boolean (12.9%), SDAI (17.0%), DAS28 (32.5%), CDAI (17.9%) and RAPID3R (25.1%). Kappa agreement between the ACR/EULAR Boolean criteria and the other indices of remission ranged from good (from 0.70 for RAPID3R þ SJ0 þ D1 to 0.79 for SDAI) to low/moderate (0.46 for DAS28 to 0.67 for RAPID3R þ SJ0) [11]. In the CATCH study, measuring agreement between ACR/EULAR remission criteria (both 28- and 66-/68-joint scores), SDAI, CDAI and DAS28, the agreement between all ACR/EULAR criteria and DAS28-based criteria was fair to moderate (8 range 0.39–0.55) and substantial for SDAI and CDAI (8 range 0.73–0.81) [12]. In this study, including 369 patients with early RA, the percentage of patients achieving remission by 6 months after inclusion ranged from 14% (ACR/EULAR trial 68/66 definition) to 30% (DAS28) and patients in DAS28 remission had overall higher swollen joint count (SJC), TJC, physician and patient-reported global assessment scores. Early remission and long-term outcomes Some conflicting results have been found when comparing these remission criteria in relation to long-term outcomes such as functional disability, radiographic damage and mortality. In the BeSt study, the estimated probability for a health assessment questionnaire (HAQ) score >0.5 and annual Sharp van der Heijde score (SHS) progression of 3 units showed high agreement between the different indices ranging from, respectively, 34% (ACR/EULAR 68/66 trial) to 41% (DAS28 CRP) for HAQ and from 9% (CDAI, ACR 66/68 trial, ACR 68/66 practice) to 12% (DAS CRP, DAS28 CRP, DAS TJC53, DAS TJC 44) for SHS [9]. Similarly, comparing the ACR/EULAR remission criteria based on the 28- or 38-joint count during a 1-year follow-up study, despite a difference in remission rates and residual pain and inflammation of the joints in the feet between the indices, no statistically significant difference between the 28- and 38-joint definitions on the impact on functional disability and radiographic damage deterioration was observed [10]. In contrast, the highest positive likelihood ratios (LRþ) were found for SDAI in association with non-progression of radiographic damage (LRþ 4.0 (95% CI 1.7–9.4)) [13], for ACR/EULAR remission criteria with low functional disability (LRþ 5.67 (95% CI 1.34–24.00)) [14] and for SDAI with absence power Doppler-positive synovitis (LRþ 6.46 (95% CI 1.95–21.34)) [14] in two observational studies, while in both studies DAS28-CRP had significantly lower positive LRs for these outcomes. Thus, when a stricter definition of remission is used, less deterioration of functional disability and progression of radiographic damage are seen. Time is not included as a criterion in most definitions of remission. In general practice, it is recognised that sustained remission is related with more favourable outcomes such as less functional disability and radiographic damage over time, less synovitis and a reduced likelihood of mortality but research is limited. To date, some of the studies investigating these associations are based on small sample sizes or include patients recruited before 2000. In a small study including patients with early RA (n ¼ 147) who had responded to methotrexate (MTX) after 3–4 months, radiographic progression was not statistically significant between those who were in remission at all time points over 2 years compared to other patients (SHS 3.79 (6.68) vs 4.75 (8.20), p ¼ 0.6) [15]. By contrast, patients recruited to the Early RA Study (ERAS), an
S.M.M. Verstappen / Best Practice & Research Clinical Rheumatology 27 (2013) 555–570
559
inception cohort including patients since 1986, who were in sustained remission (DAS
