Validation of Standardized Questionnaires Evaluating Symptoms of ...

Original Article

Arthritis Care & Research DOI 10.1002/acr.23002

RUNNING HEAD: Depression questionnaire validation in RA patients TITLE Validation of standardized questionnaires evaluating symptoms of depression in rheumatoid arthritis patients - approaches to screening for a frequent and yet underrated challenge AUTHORS Matthias Englbrecht PhD1, Rieke Alten MD, Martin Aringer MD, Christoph G. Baerwald MD, Harald Burkhardt MD, Nancy Eby PhD, Gerhard Fliedner MD, Bettina Gauger PhD, Ulf Henkemeier MD, Michael W. Hofmann MD, Stefan Kleinert MD, Christian Kneitz MD, Klaus Krueger MD, Christoph Pohl MD, Anne-Eve Roske MD, Georg Schett MD, Marc Schmalzing MD, Anne-Kathrin Tausche MD, Hans Peter Tony MD and Joerg Wendler MD FUNDING This work was supported by Roche Pharma AG and Chugai Pharma Europe Ltd.. Data analysis was done by AMS – Advanced Medical Services GmbH and was funded by Roche Pharma AG and Chugai Pharma Europe Ltd.. CORRESPONDING AUTHOR Address: Dr. Matthias Englbrecht Medizinische Klinik 3 - Studienambulanz Rheumatologie Universitätsklinikum Erlangen Ulmenweg 18 91054 Erlangen Tel: +49 (0)9131-85-36924 Fax: +49 (0)9131-85-35784 E-mail: [email protected] WORD COUNT: 3798

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/acr.23002 © 2016 American College of Rheumatology Received: Feb 26, 2016; Revised: Jul 08, 2016; Accepted: Jul 26, 2016 This article is protected by copyright. All rights reserved.

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Arthritis Care & Research

CONFLICT OF INTEREST STATEMENT Dr. Englbrecht reports grants from Roche Pharma AG and Chugai Pharma Europe Ltd., during the conduct of the study; personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd., outside the submitted work; Dr. Alten reports grants and personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd., during the conduct of the study; personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd., outside the submitted work; Dr. Aringer reports grants, personal fees and non-financial support from Roche Pharma AG and Chugai Pharma Europe Ltd., during the conduct of the study; Dr. Baerwald reports personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd., during the conduct of the study; personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd., outside the submitted work; Dr. Burkhardt reports grants and personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd, during the conduct of the study; grants and personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd, outside the submitted work; Dr. Eby reports fees from Roche Pharma AG for statistical analysis and manuscript preparation, during the conduct of the study; fees from Roche Pharma AG for statistical analysis and manuscript preparation outside the submitted work; Dr. Fliedner has nothing to disclose; Dr. Gauger reports to be an employee of Roche Pharma AG; Dr. Henkemeier has nothing to disclose; Dr. Hofmann reports to be an employee of Chugai Pharma Europe Ltd.; Dr. Kleinert reports grants from Chugai Pharma Europe Ltd. and Roche Pharma AG, during the conduct of the study; personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd., outside the submitted work; Dr. Kneitz reports grants from Roche Pharma AG and Chugai Pharma Europe Ltd., during the conduct of the study; personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd., consultancies for AbbVie, Celgene, Chugai, Pfizer, Roche and speakers bureau for AbbVie, Berlin Chemie, Chugai, MSD, Novartis, Pfizer, Roche, UCB, outside the submitted work; Dr. Krüger reports grants from Roche Pharma AG and Chugai Page 2

John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.


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Pharma Europe Ltd., during the conduct of the study; personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd., outside the submitted work; Dr. Pohl has nothing to disclose; Dr. Roske reports to be an employee of Roche Pharma AG; Dr. Schett reports grants from Roche Pharma AG and Chugai Pharma Europe Ltd., during the conduct of the study; Dr. Schmalzing reports personal fees from Roche Pharma AG and Chugai Pharma Europe, during the conduct of the study; personal fees from Roche Pharma AG and Chugai Pharma Europe, outside the submitted work; Dr. Tausche has nothing to disclose; Dr. Tony reports grants from Roche Pharma AG and Chugai Pharma Europe Ltd., during the conduct of the study; personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd., outside the submitted work; Dr. Wendler reports grants from Roche Pharma AG and Chugai Pharma Europe Ltd., during the conduct of the study; personal fees from Roche Pharma AG and Chugai Pharma Europe Ltd., outside the submitted work.

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ABSTRACT Objectives: To validate standard self-reporting questionnaires for depression screening in patients with rheumatoid arthritis (RA) and compare these measures to each other and to the MontgomeryÅsberg Depression Rating Scale (MADRS), a standardized structured interview. Methods: In 9 clinical centers across Germany, depressive symptomatology was assessed in 262 adult RA patients at baseline (T0) and at 12 ± 2 weeks follow-up (T1) using the WHO Five WellBeing Index (WHO-5), the Patient Health Questionnaire-9 (PHQ-9), and the Beck Depression Inventory (BDI-II). Construct validity of these depression questionnaires (using convergent and discriminant validity) was evaluated using Spearman correlations at both time points. The test-retest reliability of the questionnaires was evaluated in RA patients who had not undergone psychotherapeutic intervention or received antidepressants between T0 and T1. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS, a structured interview, as gold standard. Results: According to the Spearman correlation coefficients all questionnaires met convergent validity criteria (ρ > |0.50|) with the BDI-II performing best while correlations with age and disease activity for all questionnaires met the criteria for discriminant validity (ρ < |0.50|). The only questionnaire to meet the predefined retest reliability criterion (ρ ≥ 0.70) was the BDI-II (rs = 0.77) which also achieved the best results for both sensitivity and specificity >80% when using the MADRS as the gold standard.

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Conclusions: The BDI-II best met the predefined criteria and the PHQ-9 met most validity criteria with lower sensitivity and specificity.

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SIGNIFICANCE AND INNOVATIONS •

The BDI-II and PHQ-9 are valid tools for screening for depression in RA patients.

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Use of standardized self-administered depression questionnaires provides important screening information at a low time cost.

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Regular screening for depression, one of the most frequent comorbidities in RA patients, is important.

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INTRODUCTION Rheumatoid arthritis (RA) is a severe chronic inflammatory disease with significant socioeconomic impact. In recent years, conventional as well as biologic disease modifying anti-rheumatic drugs (DMARDs) used in a treat-to-target approach have significantly improved patient prognosis. Yet, RA is still a chronic disease with no cure. A German longitudinal study reported that 17% of working RA patients needed to take early retirement due to their illness within three years after study entry and approximately another 4% were applying for it [1]. One of the most frequent reasons for obtaining disability benefits in Germany is mental disorders (e.g. 43% in 2013) [2] and in 2014, 19.2% of all retirements as a result of disability were due to affective disorders [3]. According to a recent large international cohort study focusing on the prevalence of various comorbidities in RA patients, a depressive disorder occurred in 15% of these patients and was the most common comorbidity, which highlights the relevance of this challenge in rheumatology [4]. Beside these results, medical literature suggests heterogeneous prevalence rates for depression ranging from 6.4% to 41.5% in RA with most of the studies reporting rates above 10% [5-9]. The large variation in these estimates is due to different means of diagnosis, cultural background, study duration, or varying sample size [7, 10]. However, reported results show a higher prevalence of depression in RA patients compared to healthy individuals but not compared to other rheumatic diseases [9-11]. In rheumatic diseases, the impact of symptoms such as pain, limitations of physical functioning, sleep disturbances, and fatigue is considerable and may not only cause, but coincide with or even mimic a depressed mood [12, 13]. The question of whether or not an individual RA patient develops depressive symptoms may also be related to the patient’s (pain) coping abilities, illness perceptions, and

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social resources to manage daily challenges [14-22]. In order to effectively investigate these complex relationships, there is a critical need for proper instruments to evaluate the underlying symptomatology. Yet, there is lack of information as to whether self-administered depression questionnaires provide results comparable to structured interviews, whether their results are replicable and whether more extensive instruments perform better than brief ones in screening for depression. Although there is a considerable body of literature about tools measuring depressive symptoms in RA, specific information on psychometric properties of common tools is still missing, which is in particular the case in view of a direct comparison of these tools for patients with rheumatic diseases [6, 7, 23-31]. Therefore, the aim of the Validation of Depression Questionnaires for Patients with Rheumatoid Arthritis (VADERA) study presented in this report was to validate a suitable self-reporting questionnaire for the detection of depressive symptomatology in RA patients. For this purpose, the World Health Organization Five Well-Being Index (WHO-5), the Patient Health Questionnaire-9 (PHQ-9), and the Beck Depression Inventory (2nd edition) (BDI-II) were compared to each other and to a structured patient interview using the Montgomery-Åsberg Depression Rating Scale (MADRS) [32-35, 36]. We also screened additional common questionnaires such as the Center for Epidemiologic Studies Depression Scale (CES-D) and the Hospital Anxiety Depression Scale (HADS) but ultimately favoured questionnaires that only measured one construct (i.e. depressiveness), that referred to two weeks as a period for symptom duration and corresponded to the diagnostic criteria for depression. The MADRS was chosen as a comparison tool due to its moderate time-consumption during application, its reasonable time needed for training study personnel and its coverage of most of the depressive symptoms according to the diagnostic criteria for depression.

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PATIENTS AND METHODS Study procedures In the nine study centers, outpatients diagnosed with RA were asked to complete the following set of outcome measures upon completion of the informed consent form (ICF): i) questionnaires addressing symptoms of depression (WHO-5, PHQ-9, BDI-II) plus a structured interview on depressive symptomatology (MADRS), and ii) the Health Assessment Questionnaire – Disability Index (HAQ-DI) [37]. Until the MADRS was completed, interviewers were blinded to the scores of the questionnaires. All measures were recorded at baseline (T0) and at week 12 ± 2 weeks at follow-up (T1). Additional information on demographic (e.g. age, sex, disease duration, concomitant diseases) and disease-related characteristics (e.g. DAS28, a visual analogue scale on pain, rheumatoid factor, anti-cyclic citrullinated peptide positivity, current anti-rheumatic therapy) were also included in the data collection of the study. Institutional review board approval was obtained before enrollment of the first patient in October 2012. The last patient completed the study in June 2013. Analysis population and eligibility criteria Patients diagnosed with RA who were at least 18 years of age, who had a consultation at one of the participating clinics, had not received psychotherapy, antidepressants, or inpatient psychiatric treatment in the 3 months before baseline (T0) and had sufficient non-missing data for the analyses, were eligible for the analysis set under condition of their fully informed written and oral consent. Patients with a concurrent history of depression were excluded in order to avoid biased results of the MADRS. No exclusions in relation to the diagnosis of RA were used in eligibility criteria for the study however patients diagnosed with fibromyalgia were not included. To assure that a sufficient number of patients were available for this validation evaluation; a sample size of 300 patients was planned. This Page 9


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number of patients is similar to previous validation studies in the literature [36]. The nine study centers are all member of the working group for evaluation of systemic effects of RA (SYRA). Assessment of depressive symptoms Mental state was assessed using the WHO-5, PHQ‐9, and BDI-II questionnaires, three standardized self-reporting depression questionnaires with different levels of detail, followed by the MADRS, the structured interview. The WHO-5 questionnaire contains five items related to cheerfulness, calmness, feelings of vigor, feelings of being well rested after sleep, and personal interest. The respondent rates each question on a 6-point scale ranging from 0 ("at no time") to 5 ("all of the time") according to the proportion of time over the preceding 2 weeks that applies to the attribute in question. Resulting raw sum scores are converted into a percentage score ranging from 0 to 100 by multiplying the raw score with 4, where 0 indicates the worst possible emotional well-being and 100 the best. Raw sum scores of 12 (i.e. a percentage score of 48) and below indicate further need for testing for depression [32]. The PHQ-9 assesses the frequency of depressed mood over the past 2 weeks, scoring each item on a 4-point scale ranging from 0 ("not at all") to 3 ("nearly every day"). PHQ-9 sum scores of 5 and more indicate depressive symptomatology ranging from mild to severe [33]. The PHQ-9 may also be used to screen for major depression by using another scoring algorithm incorporating an additional item on functional impairment. The BDI-II consists of 21 items that are typical signs of depression. All items are scored on a 4-point scale reaching from 0 to 3 according to the individual answer that is chosen. The BDI incorporates individual ratings and anchors for each item. A sum score is calculated from these answers. In this study, a score of at least 14 was considered to represent clinically meaningful symptom severity which is equal to mild depressive symptoms [34]. While the PHQ-9 and the BDI-II include an item on suicidal ideation, the WHO-5 does not. The MADRS, an Page 10



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interview addressing 10 characteristics of depressive symptomatology, was used as the gold standard. The symptom-related information provided by each patient is rated on item-specific scales ranging from 0 (best) to 6 (worst) in order to evaluate individual symptom severity. Sum scores exceeding 12 indicate clinical relevance suggesting mild to severe symptomatology according to the underlying result as measured by the interviewer [35]. For reasons of rating consistency and validity in applying the MADRS, all study investigators were required to complete a standardized training course before study start to assure that the presentation of interview questions and the order of questions were consistent across all participating study sites. Statistical analyses According to Campbell and Fiske, construct validity may be evaluated by means of convergent and discriminant validity where scores measuring the same construct (i.e. convergence) are supposed to reveal higher correlation coefficients than those measuring different constructs (discriminant) [38]. Spearman correlation coefficients (rs) between each of the 4 outcome measures for depressive symptoms were calculated at T0 and T1 to evaluate their convergent validity. Discriminant validity was investigated using Spearman correlation of test scores with age and the DAS28 as a compound measure of RA disease activity. The a priori criteria for convergent validity was a correlation coefficient of ρ > │0.50│ which is even more conservative than proposed in recent literature (ρ > 0.45) and considered a large correlation while for discriminant validity, coefficients of ρ < |0.50| were expected [39, 40]. Absolute values are reported due to the WHO-5 scale having an opposite direction which was another reason for two-sided inferential testing. To address variability of values, the upper (for discriminant validity) or lower limit (for convergent validity) of the two-sided 95% confidence interval were considered (upper & lower CI limit). The asymptotic two-sided 95% confidence interval was derived after the Fisher’s z transformation. Page 11


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The standardized response means (SRM) was used to evaluate internal responsiveness. For this evaluation, the depression questionnaires’ ability to detect changes in emotional state between T0 and T1 was to be determined in patients with presumptive diagnosis of a depressive disorder at T0 and willing to undergo further diagnostic work-up and antidepressive therapy. Due to the small number of patients (n = 14) and the short treatment duration of 10-14 weeks between T0 and T1, no reliable conclusions could be drawn and are not discussed in this report. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS interview. For these analyses, a MADRS score >12 was used to define presence of depressive symptoms [36]. Since a questionnaire screening for a disease should have a high sensitivity and specificity, the a priori criteria for testing sensitivity and specificity was the best sensitivity given 80% specificity and the best specificity given 80% sensitivity. Bootstrapping was used for calculating the two-sided 95% confidence intervals (CIs) for the analyses of sensitivity and specificity. In order to evaluate the test accuracy, the area under the curve (AUC) of the Receiver Operating Characteristic (ROC)-curve was used. The a priori accuracy criterion was set at an AUC of 80%. The best cut-off values to identify mild depressive symptomatology for each questionnaire were determined using the threshold estimate for the best sensitivity at the given specificity. The test-retest reliability (the consistency of a test across time) for each of the depression questionnaires was evaluated in patients without depression who had not undergone psychotherapeutic intervention and had not received treatment with anti-depressant drugs between T0 and T1. The a priori test-retest reliability criterion was a correlation of ρ ≥ 0.70, the recommended reliability of a test [39, 40]. Descriptive results are presented as mean (standard deviation) if not stated otherwise. Inferential tests were two-tailed. Statistical analyses were computed using SAS and R software packages [41, 42]. Page 12



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RESULTS Descriptive sample characteristics A total of 290 RA patients from 9 centers across Germany provided written consent to participate in this study. For 277 patients (96%), sufficient data were available for inclusion in the validation analysis set. Fifteen patients with documented depression at baseline were excluded from the analysis resulting in a total sample of 262 patients. Mean (S.D.) patient age was 59.8 (13.2) years and 78% of the population were female (Table 1) which is similar to the (overall) numbers reported by Dougados and colleagues in their previous large sample study on comorbidities in RA [4]. Mean (S.D.) duration of RA disease in the patient sample was 12.5 (9.4) years and the serological evaluation at baseline showed rheumatoid factor positive in 68% of the patients, anti-citrullinated protein antibody (ACPA) positive in 62% and CRP elevated to >5 mg/l in 30% of patients. The mean (S.D.) number of swollen joints was 2.5 (4.2) and the mean number of tender joints was 4.1 (5.8). A mean (S.D.) DAS28 score of 3.4 (1.5) suggested that participants had moderately active disease on average and were somewhat limited in physical activities (mean (S.D.) HAQ-DI of 0.98 (0.73)). The most common comorbidities reported by patients at baseline were musculoskeletal disease including osteoporosis (38%), hypertension (35%) and hypercholesterolemia (14%). At baseline, the mean (S.D.) scores for all assessments of depressive symptomatology were below the predefined cut-off criteria of interest for this study (MADRS: 7.3 (6.4), BDI-II: 9.3 (7.6), PHQ-9: 5.2 (4.0), WHO-5: 61.1 (23.6)) (Table 2). According to the predefined cutpoints, the percentage of patients with relevant depressive symptomatology varied from 18.5% for the MADRS to 49.3% for the PHQ-9. A combination of these measures in view of the observed results, suggested depressive symptomatology in 10.1% (combination of all

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tools) to 26.1% (combination PHQ-9/WHO-5) of the study participants (supplemental Table A). Convergent and discriminant validity At both timepoints, Spearman correlation estimates of all measures investigating symptoms of depression fulfilled the aforementioned validity criterion of ρ > |0.50| (p-values ≤ 0.05) with the majority of coefficients remaining above the threshold confidence limit (CL) (Table 3). The only exceptions were the convergent correlations between WHO-5 and MADRS at both questionings (T0: upper 95% CL(rs) = -0.49, T1: upper 95% CL(rs) = -0.43) and of PHQ-9 and MADRS at T1 (lower 95% CL(rs) = 0.48) which were found to be slightly below ρ = |0.50|. A correlation of the aforementioned measures with age showed substantially lower coefficients ranging from rs = 0.00 (T1: age with PHQ-9) to rs = 0.17 (T0: age with WHO-5) affirming discriminant validity. Correlations between WHO-5, PHQ-9, BDI-II, and MADRS with DAS28 revealed similar results with slightly higher coefficients ranging from rs = 0.22 (T0: DAS28 with BDI-II) to rs = 0.35 (T1: DAS28 with MADRS), even with the upper 95% CL for the latter still remaining below ρ = |0.50| (Table 4). According to these results, convergent and discriminant validity can be assumed, although there were minor limitations in view of convergence particularly for the WHO-5 with the MADRS. Sensitivity and specificity The sensitivity and specificity of the depression questionnaires (BDI-II, PHQ-9, WHO-5) using the MADRS score for depression (MADRS score >12) as the gold standard indicated the best sensitivity and specificity for the BDI-II followed by the PHQ-9 and the WHO-5 (Table 5). The BDI-II had a sensitivity of 87% (95% CI: 75%-96%) at a specificity of 80% and a specificity of 86% (95% CI 72%-94%) at a sensitivity of 80%. The results of the Page 14



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PHQ-9 and the WHO-5 were somewhat weaker and only differed slightly (PHQ-9: sensitivity at 80% specificity: 75% (95% CI: 58%-88%), specificity at 80% sensitivity: 75% (95% CI: 49%-87%); WHO-5: sensitivity at 80% specificity: 68% (95% CI: 51%-82%), specificity at 80% sensitivity: 69% (95% CI 59%-83%)). The AUC of the ROC-curve (a measure for the probability of a correct test result) indicated a high accuracy for the BDI-II with an AUC of 91% (95% CI: 87%-95%) and an acceptable accuracy for the PHQ-9 (83% (95% CI: 76%-90%)) and WHO-5 (84% (95% CI: 77%-90%)). The BDI-II returned sufficiently reliable results of test accuracy in comparison to the MADRS, the 95% CI for the AUC of the ROC were above 80% (Figure 1). The questionnaires’ cut-offs best reflecting mild depressive symptomatology according to MADRS by means of Youden’s index were: 12 for the BDI-II, 6 for the PHQ-9, and raw score of 16 (i.e. a percentage score of 64) for the WHO-5. Test-retest reliability In patients not undergoing psychotherapeutic treatment, the correlational estimates of retest reliability were above ρ = 0.70 for the BDI-II (rs = 0.77) and the MADRS (rs = 0.73). However, the confidence interval limits of both tools were not above the threshold (BDI-II: 95% CI(rs): 0.68-0.84, MADRS: 95% CI(rs): 0.65-0.81). Corresponding correlational estimates of the PHQ-9 (rs = 0.63) and the WHO-5 (rs = 0.67) remained below the cutpoint. These results suggest that the replicability of test scores for symptoms of depression are limited in RA-patients when using a 10 to 14 weeks follow-up period however coefficients of more extensive tools (MADRS and BDI-II) performed better than those of brief inventories (PHQ-9 and WHO-5). DISCUSSION The study results indicated that the BDI-II best met the predefined criteria for convergent and discriminant validity, had the best sensitivity and specificity and showed an accuracy (AUC) Page 15


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of greater than 80% in RA patients. Results for the PHQ-9 and the WHO-5 met most of the validity criteria for convergent and discriminant validity but both the sensitivity and specificity were below the results of the BDI-II, which also was the case in view of results on retest-reliability. The novelty of this study is its comparative design with respect to questionnaires (i.e. BDI-II, PHQ-9, and WHO-5) for screening for depressive symptoms in RA patients while incorporating a structured interview for evaluating sensitivity and specificity of the questionnaires. Results from our study suggest that more detailed questionnaires have better psychometric properties. Our results support using the BDI-II for routine screening when referring to symptom profiles applied in diagnostic criteria such as the ICD or the DSM. The BDI-II returns a far more detailed picture of existing symptoms than the PHQ-9 or the WHO-5 and thus gives a good opportunity to address these findings in an instant follow-up. Adding to this fact, the BDI-II is the only questionnaire in this study which is based on a distinct theory of the etiology of depression, known as Beck's Cognitive Theory of Depression. In cognitive behavioral therapy, this approach is one of the most common models to explain and address depressive thinking by identifying individual cognitive biases (e.g. negative self-attribution, dichotomous thinking) and cognitive mindsets – so-called schemas – and relating them to the view of an individual’s past, present, future, and self [43]. Corresponding to this model, literature shows that depressive symptoms may not merely be attributed to current disease activity but also to the patient’s individual appraisal of the current life-situation, cognitive information processing, availability and perception of social support, or the use of coping strategies [14, 15, 19, 22, 44-45]. This is also complemented by our findings on the relation of DAS28 to the potential screening tools which only showed moderate correlations at best (rs≤0.35). However, relations of disease activity to depressive symptoms as reflected by the questionnaires might become more pronounced when strictly referring to patient-reported outcome measures [46]. Page 16



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However, in routine clinical practice, a trade-off has to be made between the amount of information that potentially can be gathered and the amount of time that patients and health professionals are able to spend on completing, scoring and interpreting assessment tools. Another important aspect is the availability of the tool. While the WHO-5 and the PHQ-9 are available at no additional costs, the BDI-II usually requires licensing fees to be paid. Hence, the question is whether rheumatologists are willing to spend some money on fees to have access to a more detailed screening tool while probably not being reimbursed for going that extra mile. Until corresponding reimbursement procedures are established, the decision on whether or not to screen for depression and which tool to apply is up to each rheumatologist or the healthcare professional. To date, screening for depressive disorders is still far from standard of care in rheumatologic treatment. Thus, closer networking between rheumatologists and mental health professionals is necessary in order to properly follow up on conspicious screening results (e.g individual clinical diagnostic work-up, initiation of psychotherapy, emergency consultations). This includes use of concise structured interviews by trained health professionals such as the MADRS which in subsequent diagnostic steps are complemented by more detailed tools. Even in patients without current depressive symptoms, a regular screening for depressive disorders is worthwhile, given the importance of depression as a risk factor for non-adherence to medical treatment which seems to occur frequently in RA patients [47-49]. The proportion of RA patients positive for depression symptomatology was lowest with the MADRS structured interview. Besides differing views (interviewer versus patient) on the patient’s individual well-being, this finding may also be attributed to the differing content and cut-points of the tools [7]. These standard cut-points come from the test manuals and are referenced in a variety of previous studies, future studies addressing similar issues are well advised to refer to these thresholds. However, as the results of our ROC-analysis showed, a Page 17


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slight modification of the cut-points resulted in improved specificity and sensitivity when comparing the questionnaires to the MADRS in RA patients. This is likely to be of interest for depression screening in clinical routine practice in order to reduce false test results. However, the best way to find the optimal cut-points, would be to evaluate the results of the screening tool in relation to whether or not there was a subsequent clinical diagnosis of depression or another mental disorder incorporating depressive symptoms. As previously shown, a potential overlap of RA and depression-related symptoms (sometimes referred to as criterion contamination) does neither interfere with nor contradict an application of these tools in order to screen for depression in clinical practice [28, 29, 50]. Although making a diagnosis of depression always requires an individual case evaluation by a clinical expert, self-administered depression questionnaires provide important standardized screening information with comparably little cost in time. Limitations to the findings of this study result from the patient sample which was recruited in Germany only, using translated versions of the depression screening tools. Thus, our findings are related to the German versions of the questionnaires, whereas to the best of our knowledge there is only separate psychometric information available for the MADRS [36]. There are a variety of additional tools available that have not been tested in this study that capture depressive symptoms as well. As we only report about the findings of the BDI-II, the PHQ-9 and the WHO-5, it remains questionable whether more detailed tools would generally provide better psychometric outcomes. Finally, it should be noted that deviations from the findings of convergence were only observed for the PHQ-9 and the WHO-5, when incorporating the MADRS which is reflecting the evaluation of patient-reported symptoms of depression from the perspective of a trained healthcare professional. This different perspective on the patient situation which previously has been described for disease characteristics in rheumatologic patients is likely to reflect the main reason of the limitations Page 18



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when investigating relations of structured clinical interviews such as the MADRS to depression questionnaires, including results on sensitivity and specificity [46]. Regular screening for depression, one of the most frequent comorbidities in RA patients, is important. This study indicates the BDI-II and PHQ-9 are valid tools for screening for depression in RA patients. The use of standardized self-administered depression questionnaires provides important screening information at a low time cost.

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TABLES 1

Table 1 Study Population Baseline Characteristics Characteristics

Total (N = 262)

Years of Age [Mean (S.D.)]

59.8 (13.2)

Gender female / male

204 (78%) / 58 (22%)

Duration of RA in years [Mean (S.D.)]

12.5 (9.4)

RF Status positive (>12 U/ml) / negative

157 (68%) / 74 (32%)

ACPA Status Positive (>5RE/ml) / negative

139 (62%) / 85 (38%)

CRP >5 mg/l

69 (30%)

ESR (mm/hr) [Mean (S.D.)]

19.2 (17.5)

Swollen joint count [Mean (S.D.)]

2.5 (4.2)

Tender joint count [Mean (S.D.)]

4.1 (5.8)

DAS28-Score [Mean (S.D.)]

3.4 (1.5)

RA therapy at baseline DMARDs

203 (77%)

Glucocorticoids

162 (62%)

NSAID

132 (50%)

Biologics

114 (44%)

Opiates

18 (8%)

HAQ-DI-Score [Mean (S.D.)]

0.98 (0.73)

MADRS score >12

48 (18.5%)

1

Number (%) of patients with non-missing data is presented. Abbreviations: S.D. = standard

deviation, RA = rheumatoid arthritis, RF = rheumatoid factor, ACPA = anti-citrullinated protein antibody, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate (BSR), DAS = Disease Activity Score, DMARDS = Disease-Modifying Anti-rheumatic Drugs, NSAID = Nonsteroidal Antiinflammatory Drugs, HAQ-DI = Health Assessment Questionnaire-Disability Index, MADRS = Montgomery-Åsberg-Depression-Rating-Scale

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Table 2 Mean depression questionnaire scores at baseline N

Mean (S.D.)

Minimum Maximum

MADRS (range 0 (best)-60 (worse))

259

7.3 (6.4)

0-36.0

BDI-II (range 0 (best)-63 (worse))

261

9.3 (7.6)

0-45.0

PHQ-9 (range 0 (best)-27 (worse))

223

5.2 (4.0)

0-21.0

WHO-5 (range 0 (worse)-100 (best))

224

61.1 (23.6)

0-100.0

Questionnaire (range of scores possible)

Abbreviations: MADRS = Montgomery-Åsberg-Depression-Rating-Scale, BDI-II = Beck Depression Inventory (2nd edition), PHQ = Patient Health Questionnaire, WHO = World Health Organization The WHO-5 and the PHQ-9 questionnaires were not collected at one study center; therefore fewer patients were available for the evaluation of these questionnaires.

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Table 3 Spearman correlation coefficients for convergent validity1 Two-sided 95% Confidence Limits With Correlation Variable Variable N Estimate Lower Upper

1

p-values

Baseline (T0) BDI-II

MADRS

258

0.73

0.67

0.79