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      The association of depression and anxiety with treatment outcomes in patients with rheumatoid arthritis – a pooled analysis of five randomised controlled trials

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          Abstract

          Background:

          Rheumatoid arthritis (RA) is an inflammatory autoimmune condition associated with an increased risk of developing depression and anxiety. Depression and anxiety are associated with worse outcomes in RA, but the magnitude of the effect of each condition on RA outcomes is unclear. It is also unknown how pharmacological treatment of depression affects RA outcomes.

          Objective:

          The primary aim of this study was to investigate the association of comorbid depression and anxiety with remission in patients with RA. Secondary aims were to determine the association between comorbid depression and anxiety on patient-reported outcomes and the relationship between concomitant use of antidepressants and remission in patients with depression.

          Design:

          Data from patients with moderate to severe RA were pooled from five randomised controlled trials investigating tocilizumab and conventional synthetic disease-modifying agents.

          Methods:

          Remission was defined as a clinical disease activity index (CDAI) of ⩽2.8 and simple disease activity index (SDAI) of ⩽3.3. The association between the time to reach remission and depression and anxiety was analysed using Cox proportional hazard analysis.

          Results:

          Individual patient data were available from 5502 subjects, of whom 511 had depression, 236 had anxiety and 387 were using antidepressants. Depression was significantly associated with reduced remission [adjusted HR (95% CI): 0.62 (0.48–0.80), p < 0.001 and adjusted HR (95% CI): 0.59 (0.44–0.79), p < 0.001] using CDAI and SDAI, respectively. Depression was associated with a lower likelihood of achieving more subjective outcomes (⩽1 physician global assessment, ⩽1 patient global assessment) and ⩽1 28-swollen joint count, but not ⩽1 28-tender joint count or C-reactive protein measurement. Treatment with antidepressants did not improve outcomes for patients with depression. Anxiety was not significantly associated with RA remission.

          Conclusion:

          Comorbid depression, but not anxiety, was associated with less frequent remission. Concomitant antidepressant use was not associated with improvements in RA outcomes in patients with depression.

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          Most cited references59

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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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            American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis.

            Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials. Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement. The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved. We present a definition of improvement which we hope will be used widely in RA trials.
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              External validity of randomised controlled trials: "to whom do the results of this trial apply?".

              In making treatment decisions, doctors and patients must take into account relevant randomised controlled trials (RCTs) and systematic reviews. Relevance depends on external validity (or generalisability)--ie, whether the results can be reasonably applied to a definable group of patients in a particular clinical setting in routine practice. There is concern among clinicians that external validity is often poor, particularly for some pharmaceutical industry trials, a perception that has led to underuse of treatments that are effective. Yet researchers, funding agencies, ethics committees, the pharmaceutical industry, medical journals, and governmental regulators alike all neglect external validity, leaving clinicians to make judgments. However, reporting of the determinants of external validity in trial publications and systematic reviews is usually inadequate. This review discusses those determinants, presents a checklist for clinicians, and makes recommendations for greater consideration of external validity in the design and reporting of RCTs.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing original draft
                Role: Data curationRole: InvestigationRole: MethodologyRole: Writing review editing
                Role: MethodologyRole: Writing review editing
                Role: MethodologyRole: Writing review editing
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing review editing
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Writing review editing
                Role: InvestigationRole: MethodologyRole: SupervisionRole: Writing review editing
                Journal
                Ther Adv Musculoskelet Dis
                Ther Adv Musculoskelet Dis
                TAB
                sptab
                Therapeutic Advances in Musculoskeletal Disease
                SAGE Publications (Sage UK: London, England )
                1759-720X
                1759-7218
                22 July 2022
                2022
                : 14
                : 1759720X221111613
                Affiliations
                [1-1759720X221111613]UniSA: Clinical & Health Sciences, University of South Australia, North Terrace, Adelaide, SA 5000, Australia
                [2-1759720X221111613]Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
                [3-1759720X221111613]Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
                [4-1759720X221111613]Rheumatology Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
                [5-1759720X221111613]Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia
                [6-1759720X221111613]UniSA: Clinical & Health Sciences, University of South Australia, Adelaide, SA, Australia
                [7-1759720X221111613]Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
                [8-1759720X221111613]College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
                [9-1759720X221111613]UniSA: Clinical & Health Sciences, University of South Australia, Adelaide, SA, Australia
                Author notes
                Author information
                https://orcid.org/0000-0002-6592-5675
                Article
                10.1177_1759720X221111613
                10.1177/1759720X221111613
                9310212
                6e7bc232-7bd9-4ced-ab42-8371cae49896
                © The Author(s), 2022

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 7 March 2022
                : 17 June 2022
                Categories
                Original Research
                Custom metadata
                January-December 2022
                ts1

                anxiety,depression,rheumatoid arthritis,remission,tocilizumab

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