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      Goal-directed therapy for RA in routine practice is associated with improved function in patients with disease duration up to 15 years

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          Abstract

          Sir, Improved therapies have dramatically increased our ability to suppress RA disease activity. Short-term goal-directed therapy or treat-to-target, central to the management of hypertension and diabetes, may be the next step to increase effectiveness of RA therapy, although recent recommendations for treat-to-target strategies acknowledge the limited data from routine care (RC) [1]. Nevertheless, inducing remission is a logical short-term goal in RA [2, 3]. Patients receiving DMARDs and achieving low disease states have less joint damage progression [4, 5]. Patient preferences for therapy outcomes consistently identify their priorities as reduced pain and maintenance of function [6, 7]. Our RA Centre service routinely uses goal-directed therapy (GDT) strategy, short-term goal DAS-28 remission (DAS-28 < 2.6). After 2 years, we tested if this strategy improved patient function, comparing RA Centre outcomes with those of clinics in the same hospital not using this strategy. An RC group of consecutive patients recruited from clinics where treatment aimed to reduce signs and symptoms with no precise goal, was compared with a matched sample of RA Centre patients, the GDT group. The Guy's Hospital Research Ethics Committee approved the study and patients gave informed consent. Patients with RA (ACR 1987 revised criteria) [8] over the age of 18 years were recruited for assessment, with no disease- or comorbidity-related exclusion criteria. Groups were matched within disease duration ± 2 years, age ± 5 years and sex. Rheumatologists treating the RC group were not aware of the patient DAS-28 score. HAQ-Disability Index (DI) was not used to guide treatment in either clinic. RC patients were assessed on a single occasion with joint counts and global disease activity performed by a research nurse not involved in therapy decisions. Fisher's exact tests were used for categorical data, and Wilcoxon signed rank sum tests for paired continuous data, almost all non-normally distributed. Multiple logistic regression assessed clinical factor contributions to achieving remission, and multivariable linear regression assessed influences on HAQ. Analyses were performed using SPSS 15.0 and Graph Pad Prism 5. Ninety patients were recruited to the RC group and data compared with that collected contemporaneously from matched GDT patients. More GDT patients received combination DMARDs (12 vs 3%, P = 0.048) but not biologics (20 vs 13%, P = 0.32). Multiple regression analysis identified DAS-28, age, disease duration and pain VAS as independent predictors of HAQ-DI, with the highest contribution from DAS-28. Patients in the GDT group with disease duration up to 15 years showed significantly improved function compared with RC, with increasingly large differences in patients with shorter disease duration (Fig. 1A). Significantly more GDT patients achieved remission at all disease duration periods (Fig. 1B). Multiple logistic regression including all patients (disease duration up to 30 years) showed males were less likely to achieve remission [odds ratio (OR) 0.3; 95% CI 0.1, 0.8], and patients without erosions were more likely to achieve remission (OR 2.9; 95% CI 1.1, 8.2). In patients with disease duration up to 15 years, only GDT was influential in achieving remission (OR 5.7; 95% CI 1.5, 21.7). Fig . 1 Goal-directed therapy increases the numbers of patients in remission and reduces HAQ in patients up to disease duration of 15 years. (A) Median HAQ is significantly lower in the GDT group at a range of disease durations. (B) Remission was defined by DAS-28 < 2.6; increased numbers of patients were in remission at all disease durations in the GDT group. *P < 0.05, **P < 0.01. This study of outcomes in routine hospital clinics using standard medication regimens shows that a DAS-28 goal-directed strategy is associated with significantly improved function for patients with disease duration up to 15 years. DAS-28 remission achievers had significantly better HAQ scores compared with non-achievers. DAS-28 remission rates were significantly better in the GDT group with RA >15 years, but HAQ scores were not better. This may reflect clinical trial results, where patients with longer disease duration have smaller HAQ improvements despite similar DAS-28 improvements [9]. Secondly, GDT patients with disease up to 5 years, receiving 2 years of GDT, achieved much higher remission rates (39%) compared with RC patients (9%). We assessed unselected patients attending routine outpatient clinics. As such, these results are relevant to general rheumatology clinic populations. In contrast to most studies of goal-directed therapy studying early arthritis, our patients had longer disease duration. We also demonstrate the challenges of achieving remission in unselected populations. Many patients declined increases in therapy or had co-morbidities preventing intensified therapy. Our patients were not selected by consenting to a treatment protocol, and therapy decisions were the usual consensus of rheumatologist advice, assessed from the patient's perspective. The concept of patient acceptable symptom state (PASS) may explain this reluctance. A large study of RC patients, with a mean disease duration of 7.6 years, showed that the DAS-28 score cut-off for PASS status was 4.05 [10]. Additionally, in the UK, biologic therapy is only available for patients with DAS-28 > 5.1. In conclusion, a goal-directed or treat-to-target strategy can be successfully utilized in RC to achieve higher remission rates, and is associated with better function in patients with early and medium disease duration. HAQ-DI for patients in remission was significantly lower than those not in remission, suggesting that DAS-28 remission is a relevant goal to improve function.

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          Most cited references6

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          The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

          The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
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            Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade.

            To examine the association of radiographic progression and disease activity states in patients with rheumatoid arthritis (RA) treated with methotrexate with or without infliximab. Patients (n = 1049) with active RA for 3 years or less and no previous methotrexate treatment were randomly assigned (4 : 5 : 5) to receive methotrexate plus placebo or methotrexate plus infliximab 3 or 6 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter to week 46. Disease activity was classified by the simplified disease activity index as remission ( 3.3 to 11 to 26). Radiographic progression was measured as a change from baseline to week 54 in total Sharp score. At weeks 14 and 54, more patients receiving methotrexate plus infliximab than methotrexate plus placebo were in remission (10.7% versus 2.8% week 14; 21.3% versus 12.3% week 54; p<0.001 for both). Methotrexate plus placebo halted radiographic progression only if patients achieved remission within 3 months, whereas methotrexate plus infliximab also halted or minimised progression in patients with low or moderate activity, respectively. Patients with persistently high disease activity levels had much less progression of joint damage if treated with methotrexate plus infliximab versus methotrexate monotherapy. Even with infliximab plus methotrexate there was a direct relationship between disease activity and radiographic changes, although the slope was deflected when compared with methotrexate monotherapy. With methotrexate, joint damage progresses even at low and moderate disease activity levels, whereas methotrexate plus infliximab inhibits radiographic progression across all disease activity states.
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              Disconnect between inflammation and joint destruction after treatment with etanercept plus methotrexate: results from the trial of etanercept and methotrexate with radiographic and patient outcomes.

              To determine the relationship between disease activity and radiographic progression of joint destruction in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX), those treated with etanercept, and those treated with the combination of MTX plus etanercept. Baseline, 12-month, and 24-month data from the Trial of Etanercept and Methotrexate with Radiographic and Patient Outcomes database were analyzed. The dependent variable was the 1-year change in the modified Sharp/van der Heijde score (Sharp score); therefore, 2 interval changes per patient were available. Interval change in the Sharp score was modeled by time (years), treatment, disease activity, and the interaction (disease activity x treatment). Disease activity was reflected by the time-averaged Disease Activity Score (taDAS) and the time-averaged C-reactive protein (taCRP) level, which were calculated per 1-year interval. Generalized mixed linear modeling (GMLM) was used to adjust for within-patient correlation. GMLM confirmed a significant interaction between treatment and the taCRP level and taDAS with respect to the change in Sharp score (P = 0.012 and P = 0.03, respectively). In patients treated with MTX alone, radiographic progression increased with an increasing taCRP level or taDAS, although progression rates were low in patients whose disease was in remission and in those with low-to-moderate disease activity. This relationship was less clear in patients treated with etanercept and was absent in those who received combination therapy. Combination therapy with MTX plus etanercept uncouples the classic relationship between disease activity and radiographic progression in patients with RA.
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                Author and article information

                Journal
                Rheumatology (Oxford)
                brheum
                rheumatology
                Rheumatology (Oxford, England)
                Oxford University Press
                1462-0324
                1462-0332
                April 2012
                5 January 2012
                5 January 2012
                : 51
                : 4
                : 759-761
                Affiliations
                1RA Centre, Guy's and St Thomas’ NHS Foundation Trust, London, UK.
                Author notes
                Correspondence to: Bruce W. Kirkham, Department of Rheumatology, 4th Floor Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK. E-mail: bruce.kirkham@ 123456gstt.nhs.uk
                Article
                ker399
                10.1093/rheumatology/ker399
                3306167
                22223707
                470692ee-fe2a-4dea-90db-516e6a6c422e
                © The Author(s) 2012. Published by Oxford University Press on behalf of The British Society for Rheumatology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 October 2011
                Page count
                Pages: 3
                Categories
                Letters to the Editor
                Others

                Rheumatology
                Rheumatology

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