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

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.

[1]  Summary of the clinical practice guideline for the treatment of depression across three age cohorts. , 2021, The American psychologist.

[2]  L. Lix,et al.  Impact of Psychiatric Comorbidity on Health Care Use in Rheumatoid Arthritis: A Population‐Based Study , 2020, Arthritis care & research.

[3]  C. Edwards,et al.  Rheumatoid Arthritis: The Impact of Mental Health on Disease: A Narrative Review , 2020, Rheumatology and Therapy.

[4]  C. Dowrick,et al.  Antidepressant treatment for primary care patients with depressive symptoms: Data from the diamond longitudinal cohort study , 2020, The Australian and New Zealand journal of psychiatry.

[5]  M. Wiese,et al.  Factors associated with medication adherence in a longitudinal study of rheumatoid arthritis patients , 2019, International journal of clinical practice.

[6]  M. Aringer,et al.  New insights into the prevalence of depressive symptoms and depression in rheumatoid arthritis – Implications from the prospective multicenter VADERA II study , 2019, PloS one.

[7]  M. Ebrahimzadeh,et al.  The Relationship between Depression or Anxiety Symptoms and Objective and Subjective Symptoms of Patients with Frozen Shoulder , 2019, International journal of preventive medicine.

[8]  Nan Li,et al.  The economic burden of depression among adults with rheumatoid arthritis in the United States , 2019, Journal of medical economics.

[9]  M. Bloch,et al.  Systematic review and meta‐analysis: Dose–response curve of SSRIs and SNRIs in anxiety disorders , 2018, Depression and anxiety.

[10]  L. Lix,et al.  Psychiatric comorbidity increases mortality in immune-mediated inflammatory diseases. , 2018, General hospital psychiatry.

[11]  E. Barley,et al.  The evidence base for psychological interventions for rheumatoid arthritis: A systematic review of reviews. , 2018, International journal of nursing studies.

[12]  B. Murnion.  Neuropathic pain: current definition and review of drug treatment. , 2018, Australian prescriber.

[13]  L. Lix,et al.  Increased Burden of Psychiatric Disorders in Rheumatoid Arthritis , 2018, Arthritis care & research.

[14]  T. Huizinga,et al.  Depression and anxiety associate with less remission after 1 year in rheumatoid arthritis , 2018, Annals of the rheumatic diseases.

[15]  W. Dębowska,et al.  Effect of antidepressant treatment on peripheral inflammation markers – A meta-analysis , 2018, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[16]  H. B. Hammer,et al.  Do depression and anxiety reduce the likelihood of remission in rheumatoid arthritis and psoriatic arthritis? Data from the prospective multicentre NOR-DMARD study , 2017, Annals of the rheumatic diseases.

[17]  G. Burmester,et al.  Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naive patients with early rheumatoid arthritis: 2-year clinical and radiographic results from the randomised, placebo-controlled FUNCTION trial , 2017, Annals of the rheumatic diseases.

[18]  H. Sayles,et al.  Generalizability of Patients With Rheumatoid Arthritis in Biologic Agent Clinical Trials , 2016, Arthritis care & research.

[19]  M. Wiese,et al.  Effect of Adherence to Protocolized Targeted Intensifications of Disease-modifying Antirheumatic Drugs on Treatment Outcomes in Rheumatoid Arthritis: Results from an Australian Early Arthritis Cohort , 2016, The Journal of Rheumatology.

[20]  J. Sturgeon,et al.  Affective disturbance in rheumatoid arthritis: psychological and disease-related pathways , 2016, Nature Reviews Rheumatology.

[21]  L. Harrold,et al.  A Prospective Evaluation of the Effects of Prevalent Depressive Symptoms on Disease Activity in Rheumatoid Arthritis Patients Treated With Biologic Response Modifiers. , 2016, Clinical therapeutics.

[22]  A. Boonen,et al.  The challenging interplay between rheumatoid arthritis, ageing and comorbidities , 2016, BMC Musculoskeletal Disorders.

[23]  M. Hotopf,et al.  Are depression and anxiety associated with disease activity in rheumatoid arthritis? A prospective study , 2016, BMC Musculoskeletal Disorders.

[24]  M. Hotopf,et al.  Symptoms of depression and anxiety predict treatment response and long-term physical health outcomes in rheumatoid arthritis: secondary analysis of a randomized controlled trial , 2015, Rheumatology.

[25]  A Malizia,et al.  Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines , 2015, Journal of psychopharmacology.

[26]  M. Azeem,et al.  Frequency of ICD-10 psychiatric diagnosis in children with intellectual disability in Lahore, Pakistan & Caregivers Perspective , 2015, Pakistan journal of medical sciences.

[27]  G. Burmester,et al.  Efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA) , 2014, Annals of the rheumatic diseases.

[28]  A. Egberts,et al.  Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications , 2014, European Journal of Clinical Pharmacology.

[29]  Paul McCrone,et al.  Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: A revision of the 2005 guidelines from the British Association for Psychopharmacology , 2014, Journal of psychopharmacology.

[30]  Jonathan Kay,et al.  Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA) , 2013, Annals of the rheumatic diseases.

[31]  M. Hotopf,et al.  The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis , 2013, Rheumatology.

[32]  E. Walker,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[33]  D. Walsh,et al.  Pain in Rheumatoid Arthritis , 2012, Current Pain and Headache Reports.

[34]  D. Felson.  Defining remission in rheumatoid arthritis , 2012, Annals of the rheumatic diseases.

[35]  B. Fautrel,et al.  Evaluating disease activity in rheumatoid arthritis: which composite index is best? A systematic literature analysis of studies comparing the psychometric properties of the DAS, DAS28, SDAI and CDAI. , 2012, Joint, bone, spine : revue du rhumatisme.

[36]  Jerry L. Grenard,et al.  Depression and Medication Adherence in the Treatment of Chronic Diseases in the United States: A Meta-Analysis , 2011, Journal of General Internal Medicine.

[37]  Ricardo Blanco,et al.  Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. , 2011, Arthritis and rheumatism.

[38]  C. Mok,et al.  Prevalence and determinants of psychiatric disorders in patients with rheumatoid arthritis. , 2010, Psychosomatics.

[39]  Sami Pirkola,et al.  Treatment of major depressive disorder in the Finnish general population , 2009, Depression and anxiety.

[40]  T. Furukawa,et al.  Depression, inflammation, and pain in patients with rheumatoid arthritis. , 2009, Arthritis and rheumatism.

[41]  M. Genovese,et al.  Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study , 2009, Annals of the rheumatic diseases.

[42]  David R. Williams,et al.  Antidepressant use in black and white populations in the United States. , 2008, Psychiatric services.

[43]  M. Genovese,et al.  Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. , 2008, Arthritis and rheumatism.

[44]  A. Işık,et al.  Anxiety and depression in patients with rheumatoid arthritis , 2007, Clinical Rheumatology.

[45]  A. Eschalier,et al.  Guidelines for the use of antidepressants in painful rheumatic conditions , 2006, European journal of pain.

[46]  C. Sweep,et al.  Hypothalamic-pituitary-adrenal axis activity in patients with rheumatoid arthritis. , 2005, Clinical and experimental rheumatology.

[47]  T. Pincus,et al.  Quantitative joint assessment in rheumatoid arthritis. , 2005, Clinical and experimental rheumatology.

[48]  J. Smolen,et al.  The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. , 2005, Clinical and experimental rheumatology.

[49]  M. Uffmann,et al.  Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score , 2005, Arthritis research & therapy.

[50]  P. Rothwell.  External validity of randomised controlled trials: “To whom do the results of this trial apply?” , 2005, The Lancet.

[51]  J. Frytak,et al.  Treatment compliance and dosage administration among rheumatoid arthritis patients receiving infliximab, etanercept, or methotrexate. , 2003, The American journal of managed care.

[52]  P. Tugwell,et al.  A simplified disease activity index for rheumatoid arthritis for use in clinical practice. , 2003, Rheumatology.

[53]  Adrienne Z. Ables,et al.  Antidepressants: update on new agents and indications. , 2003, American family physician.

[54]  J J Anderson,et al.  American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. , 1995, Arthritis and rheumatism.

[55]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[56]  M. Imran,et al.  Depression in Rheumatoid Arthritis and its relation to disease activity , 1969, Pakistan journal of medical sciences.

[57]  Off-label uses of selective serotonin reuptake inhibitors (SSRIs) , 2022, Current Neuropharmacology.

[58]  M. Treadway,et al.  Inflammation Effects on Motivation and Motor Activity: Role of Dopamine , 2017, Neuropsychopharmacology.

[59]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[60]  David T Felson,et al.  UvA-DARE (Digital Academic Repository) American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials , 2011 .