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1.  Validation of ACR/EULAR definition of remission in rheumatoid arthritis from RA practice: the ESPOIR cohort 
Arthritis Research & Therapy  2012;14(3):R156.
In development of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) remission definitions using clinical trials data, one criterion used to compare different remission definitions was whether, compared with those not in remission, those in remission had evidence of later disease stability defined by x-ray and functional status. Validation of the RA remission criteria using observational study data is necessary before recommending their use in practice.
Using data from those who met RA criteria in the ESPOIR cohort, we matched each person in remission with a person not in remission and then carried out analyses comparing later stability of x-ray and health assessment questionnaire (HAQ) between the two groups. We compared the predictive validity of the same candidate definitions of remission evaluated in the ACR/EULAR process. To minimize potential bias and produce more stable results, we used a bootstrap resampling approach to select those not in remission, repeating the sample matching analysis process 500 times.
Results were similar to those of clinical trials analyzed for the ACR/EULAR remission criteria. Specifically, the ACR/EULAR remission definitions using either an simple disease activity index (SDAI) ≤ 3.3, clinical disease activity index (CDAI) ≤ 2.8 or a definition of remission requiring tender joint count, swollen joint count, patient global assessment all ≤ 1 performed as well or better than other candidate definitions of remission in terms of predicting later x-ray and function stability.
ACR/EULAR definitions of remission developed for trials are similarly valid in observational studies in RA and could be used in practice.
PMCID: PMC3446542  PMID: 22747951
2.  Defining Remission in Rheumatoid Arthritis: Results of an Initial ACR Consensus Conference 
Arthritis and rheumatism  2009;61(5):704-710.
Due to advances in therapies for rheumatoid arthritis (RA) over the last years, an increasing proportion of patients are able to achieve a state of ‘remission’. But what exactly is remission? At the moment, randomized controlled trials around the world use different remission definitions and consequently measure different aspects of a patient’s disease state. For research findings to be correctly interpreted, the need for a uniform definition of remission is vital. The ACR constituted a committee to redefine remission in RA that included international clinical researchers, trialists and clinical epidemiologists. This group was asked to study current definitions of remission, explore the theoretical underpinning of the concept of ‘remission’, and develop a research agenda that would inform future work in the development of an ACR definition of remission.
In its first meeting, the committee preferred to develop a ‘strict’ definition, implying no or very low disease activity. Such a definition would need to be validated against long-term outcome e.g. physical function and damage. The committee decided to consider both a definition for trials and a modified version for clinical practice.
PMCID: PMC2681785  PMID: 19405006
3.  Time to achieve remission determines time to be in remission 
Though remission is currently a treatment goal in patients with rheumatoid arthritis (RA), the number of patients who achieve and sustain remission in daily practice is still small. It is suggested that early remission will be associated with sustainability of remission. The aim was to study the association between time-to-remission and sustainability of remission in a cohort of early RA patients treated according to daily practice.
For this study, three-year follow-up data were used from the Nijmegen RA Inception Cohort of patients included between 1985 and 2005 (N = 753). Patients were included upon diagnosis (ACR criteria), were systematically evaluated at three-monthly visits and treated according to daily practice. Remission was defined according to the Disease Activity Score (DAS) <1.6 and the ACR remission criteria. Remission of at least 6 months duration was regarded as sustained remission. Predictors for time-to-remission were identified by Cox-regression analyses. The relation between time-to-remission and sustained remission was analyzed using longitudinal binary regression.
N = 398 (52%) patients achieved remission with a median time-to-remission of 12 months. Male gender, younger age and low DAS at baseline were predictive to reach remission rapidly. There were n = 142 (36%) patients experiencing sustained remission, which was determined by a shorter time-to-remission only. The relationship between time-to-remission and sustained remission was described by a significant odds ratio (1.11) (1.10 to 1.12-95% CI) that was constant over the whole period 1985 to 2005. Results obtained with the ACR remission criteria were similar.
A shorter time-to-remission is related to sustainability of remission, supporting striving for early remission in patients with RA.
PMCID: PMC2911884  PMID: 20487520
4.  Adherence to a treat-to-target strategy in early rheumatoid arthritis: results of the DREAM remission induction cohort 
Arthritis Research & Therapy  2012;14(6):R254.
Clinical trials have demonstrated that treatment-to-target (T2T) is effective in achieving remission in early rheumatoid arthritis (RA). However, the concept of T2T has not been fully implemented yet and the question is whether a T2T strategy is feasible in daily clinical practice. The objective of the study was to evaluate the adherence to a T2T strategy aiming at remission (Disease Activity Score in 28 joints (DAS28) < 2.6) in early RA in daily practice. The recommendations regarding T2T included regular assessment of the DAS28 and advice regarding DAS28-driven treatment adjustments.
A medical chart review was performed among a random sample of 100 RA patients of the DREAM remission induction cohort. At all scheduled visits, it was determined whether the clinical decisions were compliant to the T2T recommendations.
The 100 patients contributed to a total of 1,115 visits. The DAS28 was available in 97.9% (1,092/1,115) of the visits, of which the DAS28 was assessed at a frequency of at least every three months in 88.3% (964/1,092). Adherence to the treatment advice was observed in 69.3% (757/1,092) of the visits. In case of non-adherence when remission was present (19.5%, 108/553), most frequently medication was tapered off or discontinued when it should have been continued (7.2%, 40/553) or treatment was continued when it should have been tapered off or discontinued (6.2%, 34/553). In case of non-adherence when remission was absent (42.1%, 227/539), most frequently medication was not intensified when an intensification step should have been taken (34.9%, 188/539). The main reason for non-adherence was discordance between disease activity status according to the rheumatologist and DAS28.
The recommendations regarding T2T were successfully implemented and high adherence was observed. This demonstrates that a T2T strategy is feasible in RA in daily clinical practice.
PMCID: PMC3674614  PMID: 23176083
5.  Sex: a major predictor of remission in early rheumatoid arthritis? 
The treatment goal of early rheumatoid arthritis is remission. This study reports remission rates in clinical practice using a cohort of patients with early rheumatoid arthritis.
698 patients with early rheumatoid arthritis were included. Mean age at inclusion was 58 years and mean disease duration was 6.4 months; 64% of the patients were women, 56% were positive for antibodies to cyclic citrullinated peptide and 60% were positive for rheumatoid factor. Remission was defined as a disease activity score <2.6, with or without ongoing treatment with drugs for rheumatoid arthritis.
After 2 years, 261 of 689 patients were in remission (37.9%), and after 5 years, the remission rate was 38.5%. However, only 26.1% were in remission at both these time points. Multiple logistic regression analyses found sex to be a main predictor for remission. Thus, significantly fewer women were in remission after 2 years (32.1% v 48%, p = 0.001) after 5 years (30.8% v 52.4%, p = 0.001) and at both these time points (19.1% v 39.3%, p = 0.001). Although disease activity was not with certainty more pronounced in women at onset of disease, the disease course became markedly worse in women. The disparity in remission frequency between women and men could not be explained by differences in disease duration, age or treatment with disease modifying antirheumatic drugs or glucocorticoids.
Early remission of rheumatoid arthritis by 28‐joint Disease Activity Score<2.6 was as frequent or more frequent in this study than in most previous reports. Importantly, women had more severe disease with a considerably lower remission rate than men, although the disease activity before treatment seemed similar.
PMCID: PMC1798403  PMID: 17158139
6.  Is DAS28 an appropriate tool to assess remission in rheumatoid arthritis? 
Annals of the Rheumatic Diseases  2005;64(10):1410-1413.
Objectives: To study which cut off point of DAS28 corresponds to fulfilment of the American Rheumatism Association (ARA) preliminary remission criteria, and clinical remission criteria in patients with rheumatoid arthritis (RA).
Methods: All adult patients diagnosed with RA at Jyväskylä Central Hospital 1997–98 were assessed for remission at 5 years. Remission was defined as (a) ARA remission; (b) clinical remission (defined as no tender or swollen joints and normal erythrocyte sedimentation rate). DAS28 was used to measure disease activity. A receiver operating characteristics curve analysis was performed to calculate a cut off point of DAS28 that best corresponds to the ARA remission criteria and the clinical remission criteria.
Results: 161 patients (mean age 57 years, 107 (66%) female, 98 (61%) with positive rheumatoid factor, and 51 (32%) with erosions) were studied. At 5 years, 19 (12%) patients met the ARA remission criteria, and 55 (34%) met the clinical remission criteria. The cut off value of DAS28 was 2.32 for the ARA remission criteria, and 2.68 for the clinical remission criteria. In patients with DAS28 <2.32, 11/57 (19%) had tender joints, 6/57 (11%) had swollen joints, and 4/57 (7%) had both tender and swollen joints (66 joint count).
Conclusion: In this study the DAS28 cut off point for the ARA remission was lower than in previous studies. The cut off point for DAS28 remission remains controversial. A substantial proportion of patients below the DAS28 cut off point for remission have tender or swollen joints, or both. DAS28 may not be an appropriate tool for assessment of remission in RA.
PMCID: PMC1755218  PMID: 15941836
7.  Systematic review: Evidence for Predictive Validity of Remission on Long Term Outcome in Rheumatoid Arthritis 
Arthritis care & research  2010;62(1):108-117.
Remission is rapidly becoming a key endpoint in rheumatoid arthritis clinical trials, but its definition is not satisfactory. Although it is generally believed that achieving a state of remission will lead to better structural outcome, this has not been studied systematically. As a part of an undertaking to redefine remission, the current review describes the relationship between remission and long term structural outcome.
A systematic literature search of PubMed,, and the Cochrane Library intersected three groups of terms: rheumatoid arthritis, remission and long term outcome. The search identified 1138 records, of which 14 were relevant to the research question.
All the studies included in this review showed a relationship between remission and long term structural damage or disability. Patients that achieved a state remission, defined in various ways, showed less deterioration of function and radiographic progression compared to patients who did not reach a state of remission.
Patients who achieve a state of remission are less likely to show deterioration of function and radiographic progression compared to patients that do not reach a state of remission.
PMCID: PMC2905735  PMID: 20191498
Rheumatoid arthritis; remission; systematic review; predictive validity
8.  The use of citrullinated peptides and proteins for the diagnosis of rheumatoid arthritis 
The presence or absence of antibodies to citrullinated peptides/proteins (ACPA) is an important parameter that helps a clinician set a diagnosis of early rheumatoid arthritis and, hence, initiate treatment. There are several commercial tests available to measure ACPA levels, although it can be difficult to decide what the best test for a given clinical question is. We analyzed literature data in which the diagnostic and other properties of various ACPA tests are compared. The results show that for diagnostic purposes the CCP2 test has the highest specificity, the highest sensitivity in stratified studies and the highest positive predictive value. For the prediction of future joint destruction the CCP2, MCV, and CCP3 tests may be used. The ability to predict the likelihood of not achieving sustained disease-modifying antirheumatic drug-free remission was highest for the CCP2 test. Finally, the levels of anti-CCP2 and anti-CCP3 (and possibly anti-mutated citrullinated vimentin) in rheumatoid arthritis patients are not significantly influenced by TNFα blocking agents.
PMCID: PMC2875630  PMID: 20236483
9.  The DAS28-ESR cutoff value necessary to achieve remission under the new Boolean-based remission criteria in patients receiving tocilizumab 
Clinical Rheumatology  2012;32(1):123-127.
To seek the cutoff value of the 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) that is necessary to achieve remission under the new Boolean-based criteria, we analyzed the data for 285 patients with rheumatoid arthritis registered between May 2008 and November 2009 by the Michinoku Tocilizumab Study Group and observed for 1 year after receiving tocilizumab (TCZ) in real clinical practice. Remission rates under the DAS28-ESR criteria and the Boolean criteria were assessed every 6 months after the first TCZ dose. The DAS28-ESR cutoff value necessary to achieve remission under the new criteria was analyzed by receiver operating characteristic (ROC) analysis. Data were analyzed using last observation carried forward. After 12 months of TCZ use, remission was achieved in 164 patients (57.5 %) by DAS28-ESR and 71 patients (24.9 %) under the new criteria for clinical trials. CRP levels scarcely affected remission rates, and the difference between remission rates defined by DAS28-ESR and by the new criteria was mainly due to patient global assessment (PGA). Improvement of PGA was inversely related to disease duration. ROC analysis revealed that the DAS28-ESR cutoff value necessary to predict remission under the new criteria for clinical trials was 1.54, with a sensitivity of 88.7 %, specificity of 85.5 %, positive predictive value of 67.0 %, and negative predictive value of 95.8 %. A DAS28-ESR cutoff value of 1.54 may be reasonable to predict achievement of remission under the new Boolean-based criteria for clinical trials in patients receiving TCZ.
PMCID: PMC3558670  PMID: 23090655
Boolean; Criteria; DAS28-ESR; Remission; Tocilizumab
10.  Sustained maintenance of clinical remission after adalimumab dose reduction in patients with early psoriatic arthritis: a long-term follow-up study 
The primary purpose of this study was to evaluate the proportion of psoriatic arthritis (PsA) patients maintaining clinical remission after adalimumab (ADA) dose reduction compared with patients with rheumatoid arthritis. Secondary purposes include evaluating the proportion of PsA patients who achieve remission, the duration of remission after ADA dose reduction, time to relapse, psoriasis course, and the frequency of adverse events at the end of follow-up.
This was a single-center, prospective, follow-up, case-control study of 76 consecutive patients (35 females, 41 males; mean age 46 ± 10.2 years) who met the classification criteria for psoriatic arthritis and required anti-tumor necrosis factor therapy according to Group for Research and Assessment of Psoriasis and Psoriatic Arthritis recommendations. The 76 patients were compared with 55 patients (40 females, 15 males; mean age 50 ± 11.6 years) who satisfied the American College of Rheumatology criteria for rheumatoid arthritis and received the same treatment. Case patients and controls were recruited from January 2008 to December 2010. At baseline, PsA patients and controls received 40 mg of ADA every other week, usually with methotrexate (10 to 20 mg/weekly). In the presence of clinical remission, ADA dose was reduced to 40 mg every 4 weeks in both groups.
Fifty-three of the 76 (69.7%) PsA patients and 17 of the 55 (30.9%) rheumatoid arthritis (P < 0.019) controls achieved remission after a mean time of 5.1 ± 1.2 and 6.3 ± 1.6 months, respectively (P = nonsignificant). After halving the dose of ADA, 47 of the 53 (88.6%) PsA patients and three of the 17 (17.6%) controls maintained remission (P = 0.016) over a mean follow-up period of 28.9 ± 8.4 and 24.2 ± 6.4 months, respectively. No significant changes in Psoriatic Arthritis Severity Index scores were observed. The mean time to relapse was 8.3 ± 3.4 months in six case patients and 7.2 ± 4.2 in 14 controls (P = not significant). No serious adverse events occurred in either group.
Clinical remission is possible in a high percentage of patients with early PsA receiving ADA. Such remission is maintained in a high proportion of subjects after ADA dose halving, with relevant advantages in terms of patient compliance, drug-exposure risk, and economic burden.
PMCID: PMC3421476  PMID: 22904612
psoriatic arthritis; anti-TNF; adalimumab; remission; dose reduction
11.  Schizophrenic: forever young? 
Genome Medicine  2010;2(5):32.
Schizophrenia is a multifactorial complex disease with a large impact on society. Many hypotheses have been proposed over the years to explain its causes, and genomics and functional genomic approaches may shed light on the reason behind these controversies and discrepancies. We give an overview of several approaches that have been used to identify the genetic causes and molecular phenotypes of the disease. We focus on a recent microarray analysis by Torkamani and colleagues on the evolution of regulatory networks in normal and schizophrenic brains. Combining the conclusion of that study with the prevalent hypotheses of schizophrenia, we suggest that the schizophrenic brain might resemble a juvenile brain.
PMCID: PMC2887076  PMID: 20497602
12.  Defining remission in rheumatoid arthritis 
Annals of the rheumatic diseases  2012;71(0 2):i86-i88.
Given the inconsistency of remission definitions in rheumatoid arthritis (RA) trials, the goal of this American College of Rheumatology/European League Against Rheumatism committee was to define remission.
The committee instructed a working group that a new remission definition, among other requirements, needed to allow for little, if any, active clinical disease and to be defined using the core set of outcome measures for RA trials and that those in remission at one time needed to have a low risk of later worsening function or radiograph progression. Remission was to be defined using trial data for use in trials but needed to anticipate use in a practice setting.
The working group started by evaluating the thresholds for core set measures compatible with remission and determined that patient-reported outcomes contributed importantly to the ability of outcome assessment to distinguish more from less effective treatments. The group created a candidate group of remission definitions to test, including Boolean versions and widely used indexes. Testing how well these candidate definitions predicted later good outcomes, the group found that Disease Activity Score 28 thresholds for remission performed worse than Simplified Disease Activity Index/Clinical Disease Activity Index or Boolean versions. Also, persons with low Disease Activity Score 28 occasionally had high joint counts, which were incompatible with remission. The parent committee chose two definitions: one Boolean (patient had to have all of the following: tender joint count, swollen joint count ≤1, C reactive protein ≤1 mg/dl) and patient global assessment ≤1 (on a 0–10 scale) and one Simplified Disease Activity Index ≤3.3.
The American College of Rheumatology/European League Against Rheumatism has promulgated two new similar definitions of remission for RA trials.
PMCID: PMC3648878  PMID: 22460146
13.  Tools for monitoring remission in rheumatoid arthritis: any will do, let's just pick one and start measuring 
Rheumatoid arthritis treatment has seen major changes in the last decade, one of which is the concept of treating to target. Various composite outcome measures have been developed, and the latest is the new American College of Rheumatology/European League Against Rheumatism remission criteria. Zhang and colleagues test the predictive validity of the new criteria in an observational cohort and show that they work as well as other definitions of remission. Our main challenge remains getting rheumatologists to use one of the outcome measures rather than developing new measures that are basically no different from already available measures in predicting functional and radiographic changes, the two most important long-term outcomes of rheumatoid arthritis.
PMCID: PMC3672754  PMID: 23374997
14.  Significance of Sex in Achieving Sustained Remission in the Consortium of Rheumatology Researchers of North America (CORRONA) Cohort of Rheumatoid Arthritis Patients 
Arthritis care & research  2012;64(12):1811-1818.
To determine whether men with rheumatoid arthritis (RA) are more likely to achieve remission compared to women.
RA patients enrolled in the CORRONA cohort between October 2001 and January 2010 were selected for the present analyses. Detailed clinical, demographic and drug utilization data were available at enrollment (baseline) and at subsequent follow up visits. We examined the influence of sex on CDAI remission (CDAI≤2.8) using sustained remission or point remission as the primary outcome measure in multivariate stepwise logistic regression models. We stratified the data by RA duration at baseline (≤2 years or >2 years) to investigate whether RA duration had differential effects on remission in men and women.
A total of 10,299 RA patients (2,406 men and 7,893 women) were available for this study. In both early and established RA, women had more severe disease at baseline with worse disease acitivity measures, modified Health Assessment Questionnaire Disability Index, pain visual analog scale and depression. Women were also more likely to have been treated with DMARDs and anti-TNF therapy compared to men. In the regression models, maleness was associated with sustained remission in early RA (OR: 1.38, 95% CI: 1.07, 1.78, p=0.01), but not in established RA. However, for point remission, an inverse association was observed with maleness in established RA (OR: 0.65, 95% CI: 0.48, 0.87, p=0.005) and not in early RA.
Within the large, real-life CORRONA cohort of RA patients, men were more likely to achieve sustained remission compared to women in early RA, although not in established RA.
PMCID: PMC3604992  PMID: 22730408
15.  Defining a role for fibroblasts in the persistence of chronic inflammatory joint disease 
Annals of the Rheumatic Diseases  2004;63(Suppl 2):ii92-ii95.
The most surprising feature of the inflammatory response in rheumatoid arthritis is not that it occurs but that it does not resolve. The persistence of the chronic inflammatory response in conjunction with ongoing joint destruction is an all too familiar finding in many patients with rheumatoid arthritis. Despite the use of effective anti-inflammatory agents and disease modifying drugs, a significant proportion of patients with rheumatoid arthritis continue to have resistant disease. Complete clinical remission is unusual for more than six months and a formal cure of the disease remains elusive. In this report we focus on how attempts to address the question of why rheumatoid arthritis persists have led to a different interpretation of the pathogenesis of rheumatoid disease; one in which alterations in stromal cells such as fibroblasts play an important role in the switch from resolving to persistent disease.
PMCID: PMC1766776  PMID: 15479882
16.  Remission in Rheumatoid Arthritis 
Current Rheumatology Reports  2010;12(5):355-362.
With advancing therapeutic options, achieving a state of remission has become the treatment goal in rheumatoid arthritis. Agreeing on what constitutes remission and what measures should be used to assess disease activity has remained a challenge. Multiple remission criteria have been devised and modified, all with different strengths and limitations. A consensus definition of remission will need to be achieved if we are to be able to evaluate outcomes of clinical trials and establish treatment targets for practice. Remission defined as the complete absence of disease currently may not be a realistic therapeutic goal.
PMCID: PMC2927687  PMID: 20697983
Rheumatoid arthritis; Remission
17.  Treatment Strategies in Early Rheumatoid Arthritis and Prevention of Rheumatoid Arthritis 
Current rheumatology reports  2012;14(5):472-480.
Data now suggest that current strategies in the treatment of rheumatoid arthritis (RA) should focus on early identification and diagnosis, followed by early initiation of DMARD therapy. Initiation of treatment in early RA—ideally, less than 3–6 months after symptom onset—improves the success of achieving disease remission and reduces joint damage and disability. While the optimal treatment regimen in early RA is unclear, use of initial DMARD mono- or combination therapy with prompt escalation to achieve low disease activity or remission is an appropriate approach. Ultimately, the goal of RA management should be the prevention of inflammatory joint disease and, thereby, prevention of disability. To date, studies have shown that pharmacologic interventions can delay progression from undifferentiated inflammatory arthritis to classifiable RA. However, further investigation is needed to identify asymptomatic individuals at high risk for future RA and to intervene early enough in the pathogenesis of RA to prevent progression to clinical disease.
PMCID: PMC3616381  PMID: 22773387
Rheumatoid arthritis; Early treatment; Prevention; Treatment; Strategies; Management; Therapy; DMARD; Joint damage; Autoimmunity
18.  Remission of Rheumatoid Arthritis in Clinical Practice: Application of the ACR/EULAR 2011 Remission Criteria 
Arthritis and rheumatism  2011;63(11):3204-3215.
To describe use of the ACR/EULAR (AE) rheumatoid arthritis (RA) remission criteria in clinical practice.
We examined remission in the US Veterans Affairs RA (VARA) registry of 1,341 patients (91% men) with 9,700 visits and a community rheumatology practice (ARCK) of 1,168 patients (28% men) with 6,362 visits. We studied cross-sectional and cumulative probabilities, agreement among various remission criteria, and aspects of reliability using Boolean definitions and CDAI and SDAI methods proposed by AE.
By AE definition for community practice (swollen and tender joints ≤1, patient global ≤1), cross-sectional remission was 7.5% (6.4, 8.7) for ARCK and 8.9% (7.9, 9.9) for VARA. Cumulative or remission at any observation was 18.0% (ARCK) and 24.4% (VARA) over a mean of 2.2 years. Addition of ESR or CRP to criteria reduced remission to 5.0-6.2%, and use of CDAI/SDAI increased proportions to 6.9-10.1%. 1.8%-4.6% of patients met remission criteria at ≥2 visits. Agreement between criteria definitions was good by Kappa and Jaccard measures. Among patients in remission, the probability of a remission lasting 2 years was 6.0%-14.1%. Among all patients the probability of a remission lasting 2 years was <3%. Remission and examination results varied substantially among physicians by multilevel analyses.
Cross-sectional remission occurs at 5.0%-10.1%, with cumulative remission 2-3 times greater. Long-term remissions are rare. Problems with reliability and agreement limit criteria usefulness in the individual patient. However, the criteria can be an effective method for measuring clinical status and treatment effect in groups of patients in the community.
PMCID: PMC3202065  PMID: 21739423
Rheumatoid arthritis; Remission; Reliability
19.  Sustained rheumatoid arthritis remission is uncommon in clinical practice 
Remission is an important goal of therapy in rheumatoid arthritis (RA), but data on duration of remission are lacking. Our objective was to describe the duration of remission in RA, assessed by different criteria.
We evaluated patients from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) not in remission at baseline with at least 2 years of follow-up. Remission was assessed according to the Disease Activity Score 28-C-reactive protein (DAS28-CRP4), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) scores, and the recently proposed American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) criteria for remission. Analyses were performed by using Kaplan-Meier survival curves.
We identified 871 subjects with ≥2 years of follow-up. Of these subjects, 394 were in remission at one or more time-points and not in remission at baseline, according to at least one of the following criteria: DAS28-CRP < 2.6 (n = 309), DAS28-CRP < 2.3 (n = 275), SDAI (n = 168), CDAI (n = 170), and 2010 ACR/EULAR (n = 158). The median age for the 394 subjects at entrance to BRASS was 56 years; median disease duration was 8 years; 81% were female patients; and 72% were seropositive. Survival analysis performed separately for each remission criterion demonstrated that < 50% of subjects remained in remission 1 year later. Median remission survival time was 1 year. Kaplan-Meier curves of the various remission criteria did not significantly differ (P = 0.29 according to the log-rank test).
This study shows that in clinical practice, a minority of RA patients are in sustained remission.
PMCID: PMC3446437  PMID: 22429277
California Medicine  1951;74(6):416-423.
The administration of cortisone acetate to patients with rheumatoid arthritis usually produces prompt and often dramatic suppression of the disease manifestations. The effects of the hormone are not lasting, however, and after withdrawal relapse ensues. For sustained improvement in a chronic disease such as rheumatoid arthritis, it appears that cortisone must be given more or less continuously. This raises the question whether administration may be continued effectively and safely for long periods.
Seventy-six patients with rheumatoid arthritis were given cortisone in the hope that treatment could be continued uninterruptedly for extended periods. For various clinical reasons it was necessary to discontinue treatment in 16 of these before six months, but the remaining 60 patients received the hormone uninterruptedly for six to 15 months. By using initial large suppressive amounts, then gradually reducing the dosage, and finally employing smaller maintenance doses, adequate degrees of rheumatic control were maintained in approximately two-thirds of the original 76 patients. The ability to sustain satisfactory improvement varied indirectly, in general, with the severity of the rheumatoid arthritis. The chief detriment to better results in the more severe cases was the intervention of adverse hormonal side effects which developed frequently when large or relatively large maintenance doses were required to support satisfactory improvement.
Unwanted signs of hormonal excess developed in 40 per cent of cases at some time during the course of treatment. Most of them were mild or transient and disappeared or lessened when the dose of cortisone was reduced, but when the dose was reduced the degree of improvement often declined also.
During prolonged cortisone therapy evidence of functional suppression of the adrenal cortices, as indicated by a decreased response of circulating eosinophils to exogenous ACTH, was present. The depression of cortical function was temporary, however. Whether irreversible damage may result when the drug is employed for longer periods cannot yet be answered.
PMCID: PMC1520676  PMID: 14848703
21.  Differential Expression of NK Receptors CD94 and NKG2A by T Cells in Rheumatoid Arthritis Patients in Remission Compared to Active Disease 
PLoS ONE  2011;6(11):e27182.
TNF inhibitors (TNFi) have revolutionised the treatment of rheumatoid arthritis (RA). Natural killer (NK) cells and Natural Killer Cell Receptor+ T (NKT) cells comprise important effector lymphocytes whose activity is tightly regulated through surface NK receptors (NKRs). Dysregulation of NKRs in patients with autoimmune diseases has been shown, however little is known regarding NKRs expression in patients with TNFi-induced remission and in those who maintain remission vs disease flare following TNFi withdrawal.
Patients with RA were recruited for this study, (i) RA patients in clinical remission following a minimum of one year of TNFi therapy (n = −15); (2) Active RA patients, not currently or ever receiving TNFi (n = 18); and healthy control volunteers (n = 15). Patients in remission were divided into two groups: those who were maintained on TNFi and those who withdrew from TNFi and maintained on DMARDS. All patients underwent full clinical assessment. Peripheral blood mononuclear cells were isolated and NKR (CD94, NKG2A, CD161, CD69, CD57, CD158a, CD158b) expression on T-(CD3+CD56−), NK-(CD3−CD56+) and NKT-(CD3+CD56+) cells was determined by flow cytometry.
Following TNFi withdrawal, percentages and numbers of circulating T cells, NK cells or NKT cell populations were unchanged in patients in remission versus active RA or HCs. Expression of the NKRs CD161, CD57, CD94 and NKG2A was significantly increased on CD3+CD56-T cells from patients in remission compared to active RA (p<0.05). CD3+CD56-T cell expression of CD94 and NKG2A was significantly increased in patients who remained in remission compared with patients whose disease flared (p<0.05), with no differences observed for CD161 and CD57. CD3+CD56− cell expression of NKG2A was inversely related to DAS28 (r = −0.612, p<0.005).
High CD94/NKG2A expression by T cells was demonstrated in remission patients following TNFi therapy compared to active RA, while low CD94/NKG2A were associated with disease flare following withdrawal of therapy.
PMCID: PMC3216944  PMID: 22102879
22.  Pain persists in DAS28 rheumatoid arthritis remission but not in ACR/EULAR remission: a longitudinal observational study 
Disease remission has become a feasible goal for most rheumatoid arthritis (RA) patients; however, patient-reported symptoms, such as pain, may persist despite remission. We assessed the prevalence of pain in RA patients in remission according to the Disease Activity Score (DAS28-CRP4) and the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria.
Data were analyzed from RA patients in the Brigham Rheumatoid Arthritis Sequential Study with data at baseline and 1 year. DAS28 remission was defined as DAS28-CRP4 <2.6. The ACR/EULAR remission criteria included (a) one or more swollen joints, (b) one or more tender joints, (c) C-reactive protein ≤1 mg/dl, and (d) patient global assessment score ≤1. Pain severity was measured by using the pain score from the Multi-Dimensional Health Assessment Questionnaire (MDHAQ). The associations between baseline clinical predictors and MDHAQ pain at baseline and 1 year were assessed by using multivariable linear regression.
Among the 865 patients with data at baseline and 1 year, 157 (18.2%) met DAS28-CRP4 remission criteria at both time points. Thirty-seven (4.3%) met the ACR/EULAR remission criteria at baseline and 1 year. The prevalence of clinically significant pain (MDHAQ pain ≥4) at baseline ranged from 11.9% among patients meeting DAS28-CRP4 remission criteria to none among patients meeting ACR/EULAR remission criteria. Patient global assessment, MDHAQ function, MDHAQ fatigue, MDHAQ sleep, and arthritis self-efficacy were significantly associated with MDHAQ pain in cross-sectional (P ≤ 0.0005) and longitudinal analyses (P ≤ 0.03). Low swollen-joint counts were associated with high MDHAQ pain in longitudinal analyses (P = 0.02) but not cross-sectional analyses. Other measures of inflammatory disease activity and joint damage were not significantly associated with MDHAQ pain at baseline or at 1 year.
Clinically significant pain continues among a substantial proportion of patients in DAS28 remission but not among those in ACR/EULAR remission. Among patients in DAS28 remission, patient global assessment, disability, fatigue, sleep problems, and self-efficacy are strongly associated with pain severity at baseline and 1 year, whereas inflammatory disease activity and joint damage are not significantly associated with elevated pain severity at either baseline or 1 year.
PMCID: PMC3218896  PMID: 21651807
23.  Don't wanna go through that madness no more: Quality of life satisfaction as predictor of sustained remission from illicit drug misuse 
Substance use & misuse  2009;44(2):227-252.
Individuals who have developed a clinical dependence on drugs and/or alcohol often report that they sought help because they were “sick and tired of being sick and tired.” Quality of life (QOL) remains the missing measurement in the addictions arena. The few studies conducted to date show that QOL is typically poor during active addiction and improves as a function of remission. An intriguing question bears on the role of quality of life in subsequent remission status. Reasoning that higher life satisfaction may `increase the price' of future use and thus enhance the likelihood of sustained remission, this exploratory study tests the hypotheses that quality of life satisfaction prospectively predicts sustained remission, and that motivational constructs mediate the association. Inner city residents (N = 289, 53.6% male, mean age 43) remitting from chronic and severe histories of dependence to crack and/or heroin were interviewed three times at yearly interval beginning in April 2003. Logistic regression findings generally support our hypotheses: Controlling for other relevant variables, baseline life satisfaction predicted remission status one and two years later and the association was partially mediated by motivation (commitment to abstinence) although the indirect effect did not reach statistical significance. Findings underline the importance of examining the role of quality of life satisfaction in remission processes. Limitations of this exploratory study are discussed including the use of a single item global life satisfaction rating; suggestions for future studies are discussed including the need to embrace QOL as a bona fide clinical outcome and to use comprehensive standardized QOL measures that speak to individual dimensions of functioning. Implications are noted, especially the need for the addiction field to continue moving away from the pathology-focused model of care toward a broader model that embraces multiple dimensions of positive health as a key outcomes.
PMCID: PMC2629650  PMID: 19142823
Quality of life; remission; recovery; motivation; addiction; processes
24.  Remission makes its way to rheumatology 
Remission was a rare event, even in the most advanced rheumatology clinics, until recent times. However, in the early 1990s, it was chosen as the treatment goal and the primary outcome measure for the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial, which can be considered the beginning of remission's way to rheumatology. In addition to remission in patients with rheumatoid arthritis, remission in patients with psoriatic arthritis is now being studied, although remission criteria for psoriatic arthritis have yet to be defined. Better treatment results with more active treatment strategies and availability of biologic agents motivate rheumatologists to monitor their patients as part of usual rheumatology care.
PMCID: PMC2945015  PMID: 20642867
25.  Radiological damage in patients with rheumatoid arthritis on sustained remission 
Annals of the Rheumatic Diseases  2006;66(3):358-363.
To assess the radiological damage progression in patients with recent rheumatoid arthritis in sustained remission.
A cohort of 191 patients with active early (<1 year) rheumatoid arthritis was prospectively assessed at baseline, 3 and 5 years by the Disease Activity Score (DAS) and the Sharp–van der Heijde Score (SHS) for radiographic damage. Patients in remission (DAS<1.6) at the 3‐year and 5‐year time points were compared with patients with a persistently active rheumatoid arthritis by Wilcoxon's signed rank test.
57 patients died, were lost to follow‐up or had incomplete data; 30 (15.7% of those who completed) patients were in remission at 3 and 5 years. The SHS in these two groups was not significantly different at baseline (p = 0.15), but was lower in the remission group at 5 years (p = 0.0047). The median (IQR) radiographic score increased from 0.5 (0–7) at baseline to 2.5 (0–14) after 5 years for the remission group (p = 0.18) and from 2 (0–7) to 13 (3–29) in the group with active rheumatoid arthritis (p<0.001). 5 (16.7%) patients in remission had relevant progression of radiographic damage (ie, progression >4.1 points) and 6 (20%) presented new erosions in a previously unaffected joint between the third and the fifth years.
Patients with early rheumatoid arthritis in sustained remission did not present statistically significant radiographic degradation at the group level; nevertheless, 16.7% of these patients did present degradation. Absence of progression should be part of the remission definition in rheumatoid arthritis.
PMCID: PMC1856000  PMID: 16935911

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