Faith Matcham, Sam Norton, David L Scott, Sophia Steer, Matthew Hotopf FA I T H M AT C H A M P H D S T U D E N T,
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1 The impact of baseline and persistent symptoms of depression and anxiety on long-term physical health outcomes and response to treatment in Rheumatoid Arthritis Faith Matcham, Sam Norton, David L Scott, Sophia Steer, Matthew Hotopf FA I T H M AT C H A M P H D S T U D E N T, K I N G S C O L L E G E L O N D O N FA I T H. M AT C H A K C L. A C. U K
![Rheumatoid Arthritis (RA) RA is a chronic autoimmune disease with a worldwide adult prevalence 0.2-1.2% [1].](/docs-images/81/84703820/images/2-0.jpg "An estimated 12,000 people per year are diagnosed in the UK.")
2 Rheumatoid Arthritis (RA) RA is a chronic autoimmune disease with a worldwide adult prevalence % [1]. An estimated 12,000 people per year are diagnosed in the UK. 40% of people with RA will be unable to work within 5 years of diagnosis [2].
3 Depression in RA Depression is highly prevalent in RA [3]; prevalence estimates of 16.8% (DSM), 38.8% (PHQ-9), 48.0% (HADS) Anxiety also reported in 25% of outpatients, with 16.3% of RA outpatients experiencing depression and anxiety [4] Associated with increased pain, fatigue, disability, service usage and increased mortality [5-9]. Mental health may also impact long-term physical health outcomes (increased pain and disease activity) [10].
4 Aims 1) To examine the association between baseline symptoms of depression/anxiety and disease activity and physical disability over 2-years. 2) To examine the association between persistent depression/anxiety symptoms on disease activity and physical disability over 2-years. 3) To examine the interaction between baseline depression/anxiety and treatment type
5 Method Secondary data analysis of CARDERA1 trial [11]. 2-year randomised double-blind factorial trial in 467 patients with RA within 2 years of diagnosis. Recruited from 42 centres across England and Wales. Randomised to different medication levels (methotrexate, methotrexate + ciclosporin, methotrexate + prednisolone or Triple Therapy). EQ-5D [12] used to define symptoms of depression/anxiety: No depression/anxiety Moderate depression/anxiety Severe depression/anxiety CARDERA: COMBINATION ANTI-RHEUMATIC DRUGS IN EARLY RHEUMATOID ARTHRITIS.
6 Method Primary outcomes: Disease activity (DAS28) Physical function (HAQ) Secondary outcomes: Swollen joint count (SJC) Erythrocyte Sedimentation Rate (ESR) Tender joint count (TJC) Patient Global Assessment (PGA) Odds of reaching clinical remission (DAS28 <2.6) at study end-point Multilevel models created for each outcome, adjusted for age, gender, disease duration, baseline physical health, rheumatoid factor status, and treatment type. Logistic regression models adjusted for same covariates. Multiple regression models tested for an interaction between baseline depression/anxiety and treatment type, for first 6 months of treatment only.
7 Method Primary outcomes: Disease activity (DAS28) Physical function (HAQ) Secondary outcomes: Swollen joint count (SJC) Erythrocyte Sedimentation Rate (ESR) Tender joint count (TJC) Patient Global Assessment (PGA) Odds of reaching clinical remission (DAS28 <2.6) at study end-point Multilevel models created for each outcome, adjusted for age, gender, disease duration, baseline physical health, rheumatoid factor status, and treatment type. Logistic regression models adjusted for same covariates. Multiple regression models tested for an interaction between baseline depression/anxiety and treatment type, for first 6 months of treatment only.
8 Method Primary outcomes: Disease activity (DAS28) Physical function (HAQ) Secondary outcomes: Swollen joint count (SJC) Erythrocyte Sedimentation Rate (ESR) Tender joint count (TJC) Patient Global Assessment (PGA) Odds of reaching clinical remission (DAS28 <2.6) at study end-point Multilevel models created for each outcome, adjusted for age, gender, disease duration, baseline physical health, rheumatoid factor status, and treatment type. Logistic regression models adjusted for same covariates. Multiple regression models tested for an interaction between baseline depression/anxiety and treatment type, for first 6 months of treatment only.
9 Method Primary outcomes: Disease activity (DAS28) Physical function (HAQ) Secondary outcomes: Swollen joint count (SJC) Erythrocyte Sedimentation Rate (ESR) Tender joint count (TJC) Patient Global Assessment (PGA) Odds of reaching clinical remission (DAS28 <2.6) at study end-point Multilevel models created for each outcome, adjusted for age, gender, disease duration, baseline physical health, rheumatoid factor status, and treatment type. Logistic regression models adjusted for same covariates. Multiple regression models tested for an interaction between baseline depression/anxiety and treatment type, for first 6 months of treatment only.
10 Method Primary outcomes: Disease activity (DAS28) Physical function (HAQ) Secondary outcomes: Swollen joint count (SJC) Erythrocyte Sedimentation Rate (ESR) Tender joint count (TJC) Patient Global Assessment (PGA) Odds of reaching clinical remission (DAS28 <2.6) at study end-point Multilevel models created for each outcome, adjusted for age, gender, disease duration, baseline physical health, rheumatoid factor status, and treatment type. Logistic regression models adjusted for same covariates. Multiple regression models tested for an interaction between baseline depression/anxiety and treatment type, for first 6 months of treatment only.
11 Results Total Sample No baseline depression/anxiety Moderate baseline depression/anxiety Severe baseline depression/anxiety N = 379 N = 166 N = 180 N = 24 Mean age (SD) 54.1 (12.3) 54.1 (12.3) 54.7 (12.4) 49.1 (10.5) % Female * Mean disease duration, months (SD) (5.4) 3.8 (5.2) 4.1 (5.5) 1.5 (1.9)* Ethnicity N (%)3 Afro Caribbean 6 (1.6) 1 (0.6) 4 (2.2)* 1 (4.2) Asian 6 (1.6) 1 (0.6) 3 (1.7) 2 (8.3) White-British 364 (96.0) 164 (98.8) 172 (95.6) 20 (83.3) White-European 2 (0.5) 0 (0.0) 0 (0.0) 1 (4.2) Other 1 (0.3) 0 (0.0) 1 (0.6) 0 (0.0) Rheumatoid factor positive N (%) 254 (67.0) 114 (68.7) 117 (65.0) 18 (75.0) Median Larsen score (IQR) 7.0 (3.0, 17.0) 7.0 (2.5, 17.0) 7.0 (3.0, 16..0) 6.5 (1.5, 17.5) Mean DAS28 (SD) (1.3) 5.3 (1.3) 6.0 (1.1)*** 6.5 (1.3)*** Mean HAQ (SD) (0.7) 1.3 (0.7) 1.7 (0.6)*** 2.0 (0.6)*** Mean TJC (SD) (7.6) 9.9 (7.2) 12.2 (7.5)** 15.5 (8.6)** Mean SJC (SD) (6.2) 8.4 (5.6) 10.8 (6.4)*** 11.7 (7.4)* Mean ESR (SD) 41.4 (29.5) 38.4 (28.7) 44.5 (30.3) 40.3 (28.7) Mean PGA (SD) (26.3) 45.8 (25.4) 60.3 (24.6)*** 77.3 (22.5)***
12 Aim 1: 1) To examine the association between baseline symptoms of depression/anxiety and disease activity (DAS28) and physical disability (HAQ) over 2-years.
13 Results the relationship between baseline depression/anxiety and disease outcomes HAQ DAS-28 Mean Time (months) Mean Time (months) No Depression/Anxiety (N=166) No Depression/Anxiety (N= 166) Moderate Depression/Anxiety (N=180) Moderate Depression/Anxiety (N= 180) Extreme Depression/Anxiety (N=24) Extreme Depression/Anxiety (N= 24)
14 Results the relationship between baseline depression/anxiety and disease outcomes Unadjusted Primary Outcomes HAQ DAS-28 b (SE) d p b (SE) d p No Depression/Anxiety Moderate Depression/Anxiety 0.31 (0.07) 0.44 < (0.15) 0.34 <0.01 Extreme Baseline Depression/Anxiety Adjusted 0.72 (0.15) 1.01 < (0.30) 0.86 <0.001 No Depression/Anxiety Moderate Depression/Anxiety 0.04 (0.06) (0.14) Extreme Baseline Depression/Anxiety 0.21 (0.12) (0.29)
15 Results the relationship between baseline depression/anxiety and disease outcomes Unadjusted Primary Outcomes HAQ DAS-28 b (SE) d p b (SE) d p No Depression/Anxiety Moderate Depression/Anxiety 0.31 (0.07) 0.44 < (0.15) 0.34 <0.01 Extreme Baseline Depression/Anxiety Adjusted 0.72 (0.15) 1.01 < (0.30) 0.86 <0.001 No Depression/Anxiety Moderate Depression/Anxiety 0.04 (0.06) (0.14) Extreme Baseline Depression/Anxiety 0.21 (0.12) (0.29)
16 Results the relationship between baseline depression/anxiety and disease outcomes Unadjusted Primary Outcomes HAQ DAS-28 b (SE) d p b (SE) d p No Depression/Anxiety Moderate Depression/Anxiety 0.31 (0.07) 0.44 < (0.15) 0.34 <0.01 Extreme Baseline Depression/Anxiety Adjusted 0.72 (0.15) 1.01 < (0.30) 0.86 <0.001 No Depression/Anxiety Moderate Depression/Anxiety 0.04 (0.06) (0.14) Extreme Baseline Depression/Anxiety 0.21 (0.12) (0.29)
17 Results the relationship between baseline depression/anxiety and disease outcomes Unadjusted Secondary Outcomes- DAS-28 Components SJC ESR PGA TJC b (SE) d p b (SE) d p b (SE) d p b (SE) d p No Depression/Anxiety Moderate Depression/Anxiety Extreme Baseline Depression/Anxiety Adjusted 0.07 (0.08) (0.09) (2.24) 0.37 < (0.09) (0.15) (0.17) (4.56) 0.87 < (0.18) 0.70 <0.001 No Depression/Anxiety Moderate Depression/Anxiety (0.08) (0.07) (2.19) (0.09) Extreme Baseline Depression/Anxiety 0.06 (0.15) (0.15) (4.54) (0.17)
18 Results the relationship between baseline depression/anxiety and disease outcomes Unadjusted Secondary Outcomes- DAS-28 Components SJC ESR PGA TJC b (SE) d p b (SE) d p b (SE) d p b (SE) d p No Depression/Anxiety Moderate Depression/Anxiety Extreme Baseline Depression/Anxiety Adjusted 0.07 (0.08) (0.09) (2.24) 0.37 < (0.09) (0.15) (0.17) (4.56) 0.87 < (0.18) 0.70 <0.001 No Depression/Anxiety Moderate Depression/Anxiety (0.08) (0.07) (2.19) (0.09) Extreme Baseline Depression/Anxiety 0.06 (0.15) (0.15) (4.54) (0.17)
19 Results the relationship between baseline depression/anxiety and disease outcomes Unadjusted Secondary Outcomes- DAS-28 Components SJC ESR PGA TJC b (SE) d p b (SE) d p b (SE) d p b (SE) d p No Depression/Anxiety Moderate Depression/Anxiety Extreme Baseline Depression/Anxiety Adjusted 0.07 (0.08) (0.09) (2.24) 0.37 < (0.09) (0.15) (0.17) (4.56) 0.87 < (0.18) 0.70 <0.001 No Depression/Anxiety Moderate Depression/Anxiety (0.08) (0.07) (2.19) (0.09) Extreme Baseline Depression/Anxiety 0.06 (0.15) (0.15) (4.54) (0.17)
20 Odds of reaching clinical remission At 2-year follow-up, 80 (21.1%) patients reached clinical remission.~ Moderate baseline depression/anxiety = reduced odds of reaching remission after 2 years (OR= 0.50, SE= 0.14, p=0.02, 95%CI: ). Extreme baseline depression/anxiety symptoms = reduced odds of reaching remission after 2 years, although non-significant. (OR = 0.77, SE= 0.43, p=0.64, 95%CI: ). This may be due to the small number of patients with extreme symptoms at baseline (N=24), reducing power to find a significant effect and resulting in an imprecise estimate.
21 Aim 2: 1) To examine the association between baseline symptoms of depression/anxiety and disease activity and physical disability over 2-years. 2) To examine the association between persistent depression/anxiety symptoms on disease activity and physical disability over 2-years.
22 Results the relationship between persistent depression/anxiety and disease outcomes 2 HAQ 6.5 DAS Mean Never depressed/anxious (N=98) Time (months) Depressed <50% (N=140) Depressed >50% (N=81) Always depressed (N=60) Never depressed/anxious (N=98) Depressed/anxious <50% (N=140) Depressed/anxious >50% (N=81) Always depressed/anxious (N=60)
23 Results the relationship between persistent depression/anxiety and disease outcomes Unadjusted Primary Outcomes HAQ DAS-28 b (SE) d p b (SE) d p Never depressed/anxious <50% 0.40 (0.09) 0.56 < (0.17) 0.49 <0.001 >50% 0.67 (0.10) 0.94 < (0.19) 0.81 <0.001 Always 0.92 (0.11) 1.30 < (0.21) 1.20 <0.001 Adjusted Never depressed/anxious <50% 0.17 (0.07) 0.24 < (0.16) >50% 0.37 (0.08) 0.52 < (0.18) 0.54 <0.001 Always 0.53 (0.08) 0.73 < (0.20) 0.86 <0.001
24 Results the relationship between persistent depression/anxiety and disease outcomes Unadjusted Primary Outcomes HAQ DAS-28 b (SE) d p b (SE) d p Never depressed/anxious <50% 0.40 (0.09) 0.56 < (0.17) 0.49 <0.001 >50% 0.67 (0.10) 0.94 < (0.19) 0.81 <0.001 Always 0.92 (0.11) 1.30 < (0.21) 1.20 <0.001 Adjusted Never depressed/anxious <50% 0.17 (0.07) 0.24 < (0.16) >50% 0.37 (0.08) 0.52 < (0.18) 0.54 <0.001 Always 0.53 (0.08) 0.73 < (0.20) 0.86 <0.001
25 Results the relationship between persistent depression/anxiety and disease outcomes Unadjusted Primary Outcomes HAQ DAS-28 b (SE) d p b (SE) d p Never depressed/anxious <50% 0.40 (0.09) 0.56 < (0.17) 0.49 <0.001 >50% 0.67 (0.10) 0.94 < (0.19) 0.81 <0.001 Always 0.92 (0.11) 1.30 < (0.21) 1.20 <0.001 Adjusted Never depressed/anxious <50% 0.17 (0.07) 0.24 < (0.16) >50% 0.37 (0.08) 0.52 < (0.18) 0.54 <0.001 Always 0.53 (0.08) 0.73 < (0.20) 0.86 <0.001
26 Unadjusted Results the relationship between persistent depression/anxiety and disease outcomes Secondary Outcomes- DAS-28 Components SJC ESR PGA TJC b (SE) d p b (SE) d p b (SE) d p b (SE) d p Never depressed/anxious <50% 0.17 (0.10) (0.10) (2.50) 0.47 < (0.12) 0.38 <0.01 >50% 0.15 (0.11) (0.12) (2.85) 0.89 < (0.13) 0.56 <0.001 Always 0.20 (0.11) (0.13) (3.11) 1.43 < (0.14) 0.85 <0.001 Adjusted Never depressed/anxious <50% 0.17 (0.10) (0.09) (2.43) 0.30 < (0.11) 0.32 <0.01 >50% 0.17 (0.11) (0.10) (2.84) 0.66 < (0.12) 0.37 <0.01 Always 0.21 (0.11) (0.11) (3.13) 1.11 < (0.13) 0.60 <0.001
27 Unadjusted Results the relationship between persistent depression/anxiety and disease outcomes Secondary Outcomes- DAS-28 Components SJC ESR PGA TJC b (SE) d p b (SE) d p b (SE) d p b (SE) d p Never depressed/anxious <50% 0.17 (0.10) (0.10) (2.50) 0.47 < (0.12) 0.38 <0.01 >50% 0.15 (0.11) (0.12) (2.85) 0.89 < (0.13) 0.56 <0.001 Always 0.20 (0.11) (0.13) (3.11) 1.43 < (0.14) 0.85 <0.001 Adjusted Never depressed/anxious <50% 0.17 (0.10) (0.09) (2.43) 0.30 < (0.11) 0.32 <0.01 >50% 0.17 (0.11) (0.10) (2.84) 0.66 < (0.12) 0.37 <0.01 Always 0.21 (0.11) (0.11) (3.13) 1.11 < (0.13) 0.60 <0.001
28 Unadjusted Results the relationship between persistent depression/anxiety and disease outcomes Secondary Outcomes- DAS-28 Components SJC ESR PGA TJC b (SE) d p b (SE) d p b (SE) d p b (SE) d p Never depressed/anxious <50% 0.17 (0.10) (0.10) (2.50) 0.47 < (0.12) 0.38 <0.01 >50% 0.15 (0.11) (0.12) (2.85) 0.89 < (0.13) 0.56 <0.001 Always 0.20 (0.11) (0.13) (3.11) 1.43 < (0.14) 0.85 <0.001 Adjusted Never depressed/anxious <50% 0.17 (0.10) (0.09) (2.43) 0.30 < (0.11) 0.32 <0.01 >50% 0.17 (0.11) (0.10) (2.84) 0.66 < (0.12) 0.37 <0.01 Always 0.21 (0.11) (0.11) (3.13) 1.11 < (0.13) 0.60 <0.001
29 Unadjusted Results the relationship between persistent depression/anxiety and disease outcomes Secondary Outcomes- DAS-28 Components SJC ESR PGA TJC b (SE) d p b (SE) d p b (SE) d p b (SE) d p Never depressed/anxious <50% 0.17 (0.10) (0.10) (2.50) 0.47 < (0.12) 0.38 <0.01 >50% 0.15 (0.11) (0.12) (2.85) 0.89 < (0.13) 0.56 <0.001 Always 0.20 (0.11) (0.13) (3.11) 1.43 < (0.14) 0.85 <0.001 Adjusted Never depressed/anxious <50% 0.17 (0.10) (0.09) (2.43) 0.30 < (0.11) 0.32 <0.01 >50% 0.17 (0.11) (0.10) (2.84) 0.66 < (0.12) 0.37 <0.01 Always 0.21 (0.11) (0.11) (3.13) 1.11 < (0.13) 0.60 <0.001
30 Odds of reaching clinical remission Depression/anxiety <50% = reduced odds of reaching remission after 2 years, although non-significant (OR= 0.58, SE= 0.19, p=0.09). Depression/anxiety >50% = reduced odds of reaching remission after 2 years, although non-significant (OR= 0.39, SE= 0.17, p<0.05). Always depressed/anxious= reduced odds of reaching remission after 2 years, a. (OR = 0.10, SE= 0.08, p<0.01).
31 Aim 3: 1) To examine the association between baseline symptoms of depression/anxiety and disease activity and physical disability over 2-years. 2) To examine the association between persistent depression/anxiety symptoms on disease activity and physical disability over 2-years. 3) To examine the interaction between baseline depression/anxiety and treatment type
32 Association between baseline depression/anxiety and treatment response Patients with moderate symptoms of depression/anxiety showed a 48% (95%CI: ) reduction in prednisolone treatment effect for HAQ outcomes. Patients with severe symptoms of depression/anxiety showed a 60% (95%CI: ) reduction in prednisolone treatment effect for HAQ outcomes, although non-significant. No marked differences were found in DAS28 outcomes in patients with and without symptoms of baseline depression taking prednisolone. No marked differences were found in HAQ or DAS28 outcomes in patients with and without symptoms of baseline depression taking ciclosporin.
33 Summary Baseline and persistent symptoms of depression/anxiety at baseline predict disease activity across a 2-year follow-up period, and may reduce response to prednisolone treatment. The subjective elements of disease activity (TJC/PGA) most commonly associated with depression/anxiety, although strong effect sizes were found for SJC outcomes in relation to persistent depression/anxiety. Supports previous meta-analysis [10] results suggesting downstream association between mental health and physical health outcomes.
34 Strengths/Limitations Strengths Large sample size Consecutively recruited outpatients Adequate control for confounders Full information about randomisation process/attrition. Subjective and objective outcomes Limitations Inadequate method of identifying depression/anxiety Not representative to wider population Highly homogenous Unlikely to represent low SES patients Limited representation of non- White ethnicities
35 Next Steps: Replicate results in clinical (realistic) sample Replicate results using validated method of identifying depression/anxiety Examine mechanisms: More rigorous assessment of glucocorticoid response/inflammation Involvement of health behaviours/adherence as mediators
36 Implications Mental health should be routinely measured in clinical practice and in research cohorts. Depression is easily collected and significant psychomarker of rheumatological outcomes. Depression is also treatable in patients with coexisting physical disease [13, 14] Would treating depression/anxiety improve disease outcomes/treatment response? Essential for effective disease management.
37 References 1. Alamanos Y, Paraskevi VV, Alexandros DA. Incidence and Prevalence of Rheumatoid Arthritis, Based on the 1987 American College of Rheumatology Criteria: A Systematic Review. Sem Arth Rheum 2006;36: Young A, Dixey J, Kulinskaya E, Cox N, Davies P, Devlin J, et al. Which patients stop working because of rheumatoid arthritis? Results of five years follow up in 732 patients from the Early RA Study (ERAS). Ann Rheum Dis 2002;61: Matcham F, Rayner L, Steer S, Hotopf M. The prevalence of depression in rheumatoid arthritis: A systematic review and meta-analysis. Rheumatol 2013; 52: Rayner L, Matcham F, Hutton J, Stringer C, Dobson J, Steer S, et al. Embedding integrated mental health assessment and management in general hospital settings: Feasibility, acceptability and the prevalence of common mental disorder. Gen Hosp Psychiatry 2014; 36: Kojima M, Kojima T, Suzuki S, Oguchi T, Oba M, Tsuchiya H, et al. Depression, inflammation, and pain in patients with rheumatoid arthritis. Arthritis Care Res 2009; 61: Matcham F, Ali S, Hotopf M, Chalder T. Psychological correlates of fatigue in rheumatoid arthritis: A systematic review. Clin Psychol Rev 2015;39: Karpouzas G, Dolatabadi S, Moran R, Li N, Nicassio PM, Weisman MH. Correlates and predictors of disability in vulnerable US Hispanics with rheumatoid arthritis. Arthritis Care Res 2012; 64: Joyce AT, Smith P, Khandker R, Melin JM, Singh A. Hidden cost of rheumatoid arthritis (RA): Estimating cost of comorbid cardiovascular disease and depression among patients with RA. J Rheumatol 2009; 36: Ang DC, Choi H, Kroenke K, Wolfe F. Comorbid depression is an independent risk factor for mortality in patients with rheumatoid arthritis. J Rheumatol 2005; 32: Rathburn AM, Reed GW, Harrold LR. The temporal relationship between depression and rheumatoid arthritis disease activity, treatment persistence and response: A systematic review. Rheumatol 2013; 52: Choy EHS, Smith CM, Farewell V, Walker D, Hassell A, Chau L. Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis. Ann Rheum Dis 2008; 67: Hurst NP, Kind P, Ruta D, Hunter M, Stubbings A. Measuring health-related quality of life in rheumatoid arthritis: Validity, responsiveness and reliability of EuroQol (EQ-5D). Rheumatol 1997; 36: Rayner L, Price A, Evans A, Valsraj K, Higginson IJ, Hotopf M. Antidepressants for depression in physically ill people. Cochrane DB Syst Rev 2010; doi: / CD pub Matcham F, Rayner L, Hutton J, Monk A, Steel C, Hotopf M. Self-help interventions for symptoms of depression, anxiety and psychological distress in patients with physical illness: A systematic review and meta-analysis. Clin Psychol Rev 2014; 34:
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