Anxiety, Distress, and Depression in Elderly Rheumatoid Arthritis Patients Текст научной статьи по специальности «Клиническая медицина»

mediterranean journal 33

of RHEUMATOLOGY 2022

G2022 The Author(s).

This work is licensed under a Creative Commons Attribution 4.0 International L

ORIGINAL

Anxiety, Distress, and Depression in Elderly Rheumatoid Arthritis Patients

Dimitrios Karokis1 Q, Dimitrios Karamanis2 1' , Sofia Xesfingi2 t£, loannis Antonopoulos3, Eydokia Politi4, Andreas Bounas5, Chrysa Lykoura6, Paraskevi Voulgari7

1Rheumatologist, Private Practice, Patras, Greece, 2Adjunct Lecturer, School of Social Sciences, Hellenic Open University, Patras, Greece, 3Rheumatologist, Private Practice, Aigion, Greece, 4Rheumatologist, Private Practice, Arta, Greece, 5Rheumatologist, Private Practice, Patras, Greece, ®Trainee in Rheumatology, University Hospital Patras, Greece, 7Professor of Rheumatology, Department of Rheumatology, School of Health, Sciences, Faculty of Medicine, University of loannina, Greece

ABSTRACT

Rheumatoid arthritis (RA) and affective disorders (anxiety/depression) constitute important pathologies in the elderly population, and their coexistence creates synergistically increased problems in functional ability and quality of life of the patients. Purpose: Evaluation of anxiety, distress, and depression in elderly (>65 years old) patients with RA. Patients - methods: 114 patients from the cities of Patras, Arta and loannina (all located in Western Greece) were included. Demographics and medical information regarding RA were recorded, including disease duration, medication, previous treatments, disease activity measures, comorbidities etc. Patients answered the State-Trait Anxiety Inventory (STAI), General Health Questionnaire-28 (GHQ28) and Health Assessment Questionnaire -Disability Index (HAQ-DI) questionnaires, for evaluation of anxiety, general health and functional ability, respectively. Statistical analysis was made by using STATA. Results: 88 women (78.07%) and 25 men (21.93%) with median age 70 years and median disease duration 10 years were studied. Female patients, with longer disease duration and higher disease activity, had statistically significant higher levels of anxiety, worse general health and decreased functional ability. A strongly significant association was found between the levels of anxiety and distress, with disease activity and functional inability. Conclusions: Levels of anxiety and distress are strongly associated with disease activity and functional inability in elderly patients with RA. Women with longer disease have higher levels of anxiety and distress. Controlling disease activity is of upmost importance for improvement of anxiety and distress and functional ability. Larger studies are needed for evaluation of anxiety and distress in elderly patients with RA.

Mediterr J Rheumatol 2022;33(4):394-406 https://doi.org/10.31138/mjr.33.4.394

Article Submitted: 31 Mar 2022; Revised Form: 22 Jun 2022; Article Accepted: 4 Jul 2022; Available Online: 31 Dec 2022

Keywords: rheumatoid arthritis, anxiety, depression, STAI, GHQ28, HAQ-DI, elderly

Corresponding Author:

Dimitrios Karokis, MD, MSC Private Practice Rheumatologist 20 Maizonos Str, 26223 Patras, Greece E-mail: karokisdimitris@gmail.com Tel.: +30 2610 225 430, +30 6937 169 016

INTRODUCTION

Demographic aging and extension of life expectancy have increased the number of elderly people (>65 years) worldwide, and their number is expected to reach about 88.5 million in 2050, comparing to 40.2 million in 2010.1 More than 20% of the elderly population suffers from

some kind of psychiatric disorder,2 more often anxiety and depression, whereas the prevalence of depression in the elderly ranges from 14.4% to 48.5%.3 Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory systemic disease, which can lead to significant structural damage and diminished

394 Cite this article as: Karokis D, Karamanis D, Xesfingi S, Antonopoulos I, Politi E, Bounas A, Lykoura C, Voulgari P. Anxiety, Distress, and Depression in Elderly Rheumatoid Arthritis Patients. Mediterr J Rheumatol 2022;33(4):394-406.

quality of life.4 RA has a worldwide prevalence of 0.51%, which is obviously smaller in the southern countries comparing to the northern ones, and in rural areas comparing to urban.5 Epidemiological studies of RA in Greece have shown a prevalence of 0.57-0.67%.6,7 RA is 2-3 times more frequent in women. A strong genetic predisposition ("shared epitope"), as well as female sex, smoking, periodontal disease, obesity and chronic inhalation of small particles (dust, silica, asbestos etc) have been identified as risk factors for RA.4 Adverse prognostic factors for worse outcome of RA have been shown to be female sex, positive rheumatoid factor (RF) or/and anti-citrullinated protein antibodies (ACPA or anti-CCP), HLA DR-4 shared epitope, early erosions, increased indices of inflammation (Erythrocyte Sedimentation Rate, ESR and C-Reactive Protein (CRP), polyarthritic involvement, deranged functional ability, smoking, obesity, low socioeconomic status and comorbidities.8

RA patients can have several comorbidities. The most serious one is cardiovascular disease, which is the main cause for increased morbidity in RA patients and reduced life expectancy by 6-7 years.9 Other important comorbidities include infections, cancers, osteoporosis, mental and psychiatric disorders, whereas several side effects can be caused by the various therapeutic agents used for RA treatment.

A major effect of the existence of various comorbidities in patients with RA is polypharmacy. Both numbers of comorbidities and medications are increased with age and disease duration, with most of the RA patients receiving a considerable number of medications, apart from analgesics or other Over-the-counter (OTCs).10 More than one third of RA patients are over 65 years of age,11 but despite this fact, elderly patients are under-represented in clinical trials, mainly due to exclusion criteria.12 RA in the elderly is characterized by more acute onset, more systematic symptoms, more frequent involvement of big and proximal joints, and worse outcome. There are also a lot of comorbidities, polypharmacy, increased prevalence of depression and cognitive disturbances, increased cardiovascular risk, and increased risk for infections and cancers due to immunosenescense. There is also an increased risk of side effects from the various therapeutic agents, with a need for dose adjustment or drug withdrawal. In general, treating an elderly patient with RA sets a serious challenge and demands increased alertness.11 Several studies and meta-analyses have shown a 17-38% prevalence of depression in RA patients,13 with a relative risk of 1.46 comparing to general population.14 Anxiety is also frequent in patients with RA, with a prevalence of 16%, which is higher in patients with RA who have comorbid major depression than in either the general population of patients with RA or age-matched healthy

controls.15 Anxiety and depression can cause a vicious circle of non-compliance, increased symptoms and exacerbations of the disease, deterioration of functional ability, more depression and anxiety etc.16 Depression is also responsible for an increased suicidal ideation in RA patients.17 It is thus obvious that co-existence of RA and anxiety/depression can cause synergistically augmented problems and further negatively affect quality of life in RA patients. The interaction of these disease entities in the elderly age group has not been adequately studied so far.

Our objective with this analysis was to estimate the levels of anxiety and perceived general health in elderly patients with RA, their relation with various demographic characteristics and medical data, and compare with relevant data from the literature.

MATERIALS AND METHODS

Patients-methods

A sample of 114 patients were included in the study, aged > 65 years, during the period from 1/3/21 to 31 /5/21 . The patients came from the areas of Patras, Aigio, loannina, and Arta (all in Western Greece) and were recruited in private rheumatology practices, the outpatient rheumatology departments of the University Hospital of loannina and the University Hospital of Patras, and via patient associations. The patients were consecutively included, provided that they fulfilled the inclusion criteria (diagnosis of RA, age > 65), and signed informed consent. They were asked to fill in the State-Trait Anxiety Inventory(STAI), General Health Questionnaire-28 (GHQ28) and Health Assessment Questionnaire (HAQ) questionnaires, whereas demographics and medical details (duration of disease, smoking, body mass index, current and past treatments for RA and other comorbidities, ESR, CRP, Clinical Disease Activity Index-CDAI) were completed by the main researcher or the other doctors.

Questionnaires - measurement tools For the estimation of anxiety, the Greek version of STAI was used. STAI is a general tool for measurement of anxiety, consisting of 20 questions about anxiety at present (STAI-S) and another 20 questions about anxiety as a characteristic of one's personality (STAI-T). The answers are graded from 1 to 4, with the highest grade meaning more anxiety, and total and sub-categories scores are created. The STAI was translated and weighted for the Greek population by Fountoulakis et al.18 Mental health was evaluated using the GHQ28 questionnaire, created by Goldberg and translated-weighted for the Greek population by Garyfallos et al.19

The GHQ28 estimates the existence and severity of non-psychotic mental symptoms. It consists of four groups of questions (seven questions in each group,

Table 1. Demographic characteristics.

All patients Gender HAQ-DI CDAI

Man Woman p-value Low High p-value Low High p-value

Variables N=114 N=25 N=89 N=79 N=35 N=70 N=44

Demographics

Gender - n(%) <0.001 0.001 0.090

Male 25(21.93) 25(100.00) 0(0.00) 24(30.38) 1 (2.86) 19(27.14) 6(13.64)

Female 89 (78.07) 0(0.00) 89(100.00) 55(69.62) 34(97.14) 51 (72.86) 38(86.36)

Age in years - median (IQR) 70.0(66.0-74.0) 70.0 (66.0-73.0) 70.0 (65.0-75.0) 0.498 70.0(66.0-74.0) 70.0(65.0-79.0) 0.071 69.0(66.0-74.0) 70.0 (66.0-76.5) 0.370

Marital Status - n(%) 0.024 0.003 0.521

Divorced/Single/Widow 45 (39.47) 5(20.00) 40(44.94) 24 (30.38) 21 (60.00) 26(37.14) 19(43.18)

Married 69 (60.53) 20(80.00) 49(55.06) 55 (69.62) 14(40.00) 44(62.86) 25(56.82)

Roommates - n(%) 0.749 0.899 0.463

0 34 (29.82) 6(24.00) 28(31.46) 23(29.11) 11 (31.43) 18(25.71) 16(36.36)

1 36(31.58) 9(36.00) 27 (30.34) 26(32.91) 10(28.57) 24(34.29) 12 (27.27)

2-4 44(38.60) 10(40.00) 34(38.20) 30 (37.97) 14(40.00) 28(40.00) 16(36.36)

Education (ISCED Levels) - n(%) 0.718 0.919 0.435

0-1 - Primary 46(40.35) 11(44.00) 35(39.33) 31 (39.24) 15(42.86) 26(37.14) 20(45.45)

2-4 - Secondary 43(37.72) 10(40.00) 33(37.08) 30 (37.97) 13(37.14) 26(37.14) 17(38.64)

5-8 - Tertiary 25(21.93) 4(16.00) 21 (23.60) 18 (22.78) 7 (20.00) 18(25.71) 7(15.91)

Income - n(%) 0.117 0.978 0.035

Low (<550€) 33(28.95) 4(16.00) 29(32.58) 23(29.11) 10(28.57) 21 (30.00) 12 (27.27)

Medium (551-1000Q 44(38.60) 9(36.00) 35(39.33) 30 (37.97) 14(40.00) 21 (30.00) 23(52.27)

High (>1001 €) 37 (32.46) 12(48.00) 25(28.09) 26(32.91) 11 (31.43) 28(40.00) 9 (20.45)

Residency - n(%) 0.379 0.064 0.113

Urban 81(71.05) 16(64.00) 65(73.03) 52 (65.82) 29 (82.86) 46(65.71) 35 (79.55)

Rural 33(28.95) 9(36.00) 24(26.97) 27(34.18) 6(17.14) 24(34.29) 9 (20.45)

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p-values refer to T-test/Mann-Whitney test or Chi-square test/Fisher's exact test. HAQ-DI Low category refers to values between 0 and 1, while High category to values between 1.1 and 3. CDAI Low category refers to values between 0 and 10, while High category to values between 10.1 and 76.

scored 0-3) referring to somatic symptoms (A), anxiety and somnolence (B), everyday functional ability (C) and symptoms of depression (D). The highest possible score is 84, whereas a score above 24 is considered as a threshold to suspect non-psychotic mental symptoms and is characterized as "bad health-distress".20 The HAQ-DI was used to assess the patients' functional ability. Since it was originally developed in 1978 at Stanford University, has been widely used in RA (among several other chronic rheumatic and non-rheumatic diseases) to assess disability, whereas a higher HAQ score at the early stages of RA has been recognized as an adverse prognostic risk factor for more severe disease and worse outcome.21 The HAQ-DI questionnaire consists of 20 questions in 8 groups, referring to everyday living activities and scored by 0-3. The total score is divided by 8 and the higher scores correspond to heavier disability.22 Activity of the disease was assessed using the ESR and CRP values, as well as the CDAI score.

Outcomes and statistical analysis Patients were classified per gender, HAQ-DI levels (Low category refers to values between 0 and 1, while High category to values between 1.1 and 3) and CDAI levels (Low category refers to values between 0 and 10, while High category to values between 10.1 and 76). The primary outcomes were the levels of reported STAI (anxiety) and GHQ28 (general health / distress). Secondary ones included the levels of the respective sub-indexes, that is STAI-T, STAI-S, somatic symptoms (GHQ28-A), anxiety and somnolence (GHQ28-B), everyday functional ability (GHQ28-C), and symptoms of depression (GHQ28-D). In all cases and for consistency, high levels of the reported outcomes were considered index values above median (50th percentile) (see Table 3). Continuous variables are presented as median with interquartile range (IQR) and categorical data as absolute with relative frequencies. The normality of the data was evaluated using the Skewness/Kurtosis test. The Student's t-test (for normally distributed variables) or Mann-Whitney test (for non-normally distributed variables) was used to compare the continuous variables, while chi-square test or Fisher's exact test (when the expected values within a cell was below five) for discrete variables. We applied univariate logistic regression analyses and one multivariate model for each dichotomous outcome, that included baseline characteristics that were found significant (p < 0.05) in the univariate. Logistic regressions' results are reported as odds ratios (OR) with the 95% confidence interval (CI). A nominal p-value < 0.05 was considered statistically significant. Internal reliability of the questionnaires was assessed and verified by Cronbach's alpha. The analysis was performed using STATA software (version 14.1).

RESULTS

Patients' demographics and medical/clinical characteristics are shown in Tables 1 and 2. Eighty nine (89) patients (78.07%) were females and twenty-five (25) patients (21.93 %) males. Median age was 70 years (IQR 66 - 74). Median disease duration was 10 years (females 11 years, males 5 years). Median BMI was 27.3 (IQR 25.0 - 30.4) and 49 patients (42.98%) were RF positive with significant differences between genders [4 (24%) men vs 43 (48.31%) women p = 0.030], and 37 patients (32.74%) were CCP positive. Median CRP was 0.4 (IQR 0.2 - 0.8), while median HAQ-DI was 0.0 (IQR 0.0 - 0.8) for men vs. 0.9 (IQR 0.3 - 1.4) for women (p = 0.001). Median CDAI was 8.5 (IQR 6 - 13) and above half of the patients belonged in the Low CDAI category (50.88%). Current and previous treatments for their disease (RA) are reported in Supplementary Table S1. Methotrexate (52.63%), glucocorticoids (43.86%), anti-TNF (22.81%) were the three most common current treatments. The median number of treatments was 2 (IQR 1 - 2), whereas the hydroxychloroquine was significant different between Low and High HAQ-DI Categories (16.46% vs. 34.29%, p = 0.034).

Primary and secondary outcomes are reported in Table 3. The median values for the outcomes were respectively: STAI 87 (IQR 67 - 100), STAI-S 43 (IQR 33 - 51), STAI-T 42 (IQR 34 - 54), GHQ28 22 (IQR 16 - 31), GHQ28-A 6 (IQR 4 - 9), GHQ28-B 6 (IQR 4 - 10), GHQ28-C 8 (IQR 6 - 11), and GHQ28-D 1 (IQR 0 - 3). For each outcome/ variable, two dichotomous versions, specifically high levels (values above median or 50th percentile) and very high levels (values above 75th percentile), are also presented. Results concerning the significant differences between genders, HAQ-DI levels and CDAI levels for all three versions of the outcomes are overall the same. Female patients had on average statistically significantly worse (higher) scores for all outcomes, except the Social Dysfunction (GHQ28-C). With respect to different levels of HAQ-DI, there is evidence for significant different values for all outcomes except STAI-S and Severe Depression (GHQ28-D), while different levels of CDAI are associated with all outcomes except Severe Depression (GHQ28-D). High positive correlations of HAQ-DI and CDAI with the primary outcomes are depicted in Figure 1. The univariate associations with all outcomes were examined for all baseline demographic and clinical characteristics, and treatments (Supplementary Table S2). Female gender and longer duration of the disease were associated with worse reported levels for most of the outcomes. Interestingly, married patients reported significantly better social function (GHQ28-C). The following variables were not shown to be statistically significant in most of the univariate associations: Number of roommates, education level, income, residence, obesity and the comorbidities. ESR is found

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Table 2. Medical and clinical characteristics.

All patients Gender HAQ-DI CDAI

Man Woman p-value Low High p-value Low High p-value

Variables N=114 N=25 N=89 N=79 N=35 N=70 N=44

BMI in kg/m2- median (IQR) 27.3(25.0-30.4) 26.9(25.5-31.1) 28.1 (25.0-30.4) 0.405 26.4(24.7-30.0) 29.3(26.0-31.2) 0.103 27.4 (24.8-30.4) 26.8(25.2-30.6) 0.589

BMI Category - n(%) 0.954 0.162 0.548

<25 kg/m2 27 (23.68) 6 (24.00) 21 (23.60) 22 (27.85) 5(14.29) 19(27.14) 8(18.18)

25-29.9 kg/m2 53(46.49) 11 (44.00) 42(47.19) 37 (46.84) 16(45.71) 31 (44.29) 22 (50.00)

>30 kg/m2 34(29.82) 8 (32.00) 26(29.21) 20 (25.32) 14(40.00) 20(28.57) 14(31.82)

Smoker - n(%) 24(21.05) 4(16.00) 20(22.47) 0.483 18 (22.78) 6(17.14) 0.496 15(21.43) 9 (20.45) 0.901

Previous Smoker - n(%) 20(17.54) 8 (32.00) 12(13.48) 0.031 17(21.52) 3(8.57) 0.094 15(21.43) 5(11.36) 0.169

Years of disease - median (IQR) 10.0(5.0-15.0) 5.0(3.0-10.0) 11.0(5.0-17.0) 0.002 10.0(3.0-15.0) 13.0(8.0-21.0) 0.035 10.0(4.0-15.0) 11.5(6.0-15.0) 0.182

Hypertension - n(%) 64(56.14) 16(64.00) 48(53.93) 0.370 47 (59.49) 17(48.57) 0.278 37 (52.86) 27(61.36) 0.373

Diabetes -n(%) 20(17.54) 6(24.00) 14(15.73) 0.337 12(15.19) 8(22.86) 0.321 13(18.57) 7(15.91) 0.716

Thyroid disease - n(%) 25(21.93) 3(12.00) 22 (24.72) 0.174 18 (22.78) 7 (20.00) 0.740 11(15.71) 14(31.82) 0.043

Cancer - n(%) 4(3.51) 0(0.00) 4(4.49) 0.281 2 (2.53) 2(5.71) 0.394 1(1.43) 3(6.82) 0.128

Lipidaemia - n(%) 45(39.47) 13(52.00) 32 (35.96) 0.147 29(36.71) 16(45.71) 0.364 29(41.43) 16(36.36) 0.590

Osteoporosis - n(%) 27 (23.68) 2 (8.00) 25(28.09) 0.037 18 (22.78) 9(25.71) 0.734 17 (24.29) 10(22.73) 0.849

Inflamm Bowel Disease - n(%) 3(2.63) 0(0.00) 3 (3.37) 0.352 2 (2.53) 1 (2.86) 0.920 0 (0.00) 3(6.82) 0.027

Fibromyalgia - n(%) 18(15.79) 1 (4.00) 17(19.10) 0.067 9(11.39) 9(25.71) 0.053 6 (8.57) 12 (27.27) 0.008

COPD - n(%) 12(10.53) 3(12.00) 9(10.11) 0.786 6(7.59) 6(17.14) 0.125 6 (8.57) 6(13.64) 0.391

No. of Comorbidities - n(%) 0.835 0.219 0.006

0-1 32 (28.07) 8(32.00) 24 (26.97) 26(32.91) 6(17.14) 26(37.14) 6(13.64)

2-3 55(48.25) 12(48.00) 43(48.31) 36(45.57) 19(54.29) 33(47.14) 22 (50.00)

4-7 27 (23.68) 5(20.00) 22 (24.72) 17(21.52) 10(28.57) 11 (15.71) 16(36.36)

TKE - median (IQR) 19.5(10.0-26.0) 16.0(8.0-28.0) 20.0(12.0-26.0) 0.507 18.0(10.0-28.0) 20.0(13.0-26.0) 0.948 18.5(10.0-25.0) 20.5(13.0-31.0) 0.010

CRP - median (IQR) 0.4(0.2-0.8) 0.3(0.2-0.5) 0.4(0.2-0.8) 0.885 0.4 (0.2-0.7) 0.5(0.2-0.9) 0.695 0.4(0.2-0.7) 0.5(0.2-1.0) 0.005

RF - n(%) 49(42.98) 6(24.00) 43(48.31) 0.030 35(44.30) 14(40.00) 0.671 30(42.86) 19(43.18) 0.973

CCP - n(%) 38(33.33) 5(20.00) 33 (37.08) 0.111 27(34.18) 11 (31.43) 0.776 22(31.43) 16(36.36) 0.590

HAQ-DI - median (IQR) 0.8(0.1-1.3) 0.0(0.0-0.8) 0.9(0.3-1.4) 0.001 0.5 (0.0-0.9) 1.5(1.3-2.0) <0.001 0.8(0.0-1.0) 1.0(0.3-1.5) 0.107

HAQ-DI Categories - n(%) 0.003 <0.001 0.105

0-1 79 (69.30) 24(96.00) 55(61.80) 79(100.00) 0 (0.00) 53(75.71) 26(59.09)

1-2 29 (25.44) 0 (0.00) 29(32.58) 0(0.00) 29 (82.86) 13(18.57) 16(36.36)

2-3 6 (5.26) 1 (4.00) 5(5.62) 0(0.00) 6(17.14) 4(5.71) 2 (4.55)

CDAI - median (IQR) 8.5(6.0-13.0) 8.0(3.0-10.0) 10.0(7.0-13.0) 0.063 8.0(4.0-11.0) 11.0(8.0-18.0) <0.001 7.0 (3.5-8.0) 14.5(11.5-20.3) <0.001

CDAI Categories - n(%) 0.195 0.033 <0.001

Remission (0.0-2.8) 12(10.53) 5 (20.00) 7(7.87) 11(13.92) 1 (2.86) 12(17.14) 0 (0.00)

Low (2.9-10.0) 58 (50.88) 14(56.00) 44(49.44) 42(53.16) 16(45.71) 58(82.86) 0 (0.00)

Moderate (10.1-22.0) 35 (30.70) 5 (20.00) 30(33.71) 23(29.11) 12(34.29) 0(0.00) 35 (79.55)

High (22.1 -76.0) 9 (7.89) 1 (4.00) 8(8.99) 3(3.80) 6(17.14) 0(0.00) 9(20.45)

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p-values refer to T-test/Mann-Whitney test or Chi-square test/Fisher's exact test. HAQ-DI Low category refers to values between 0 and 1, while High category to values between 1.1 and 3. CDAI Low category refers to values between 0 and 10, while High category to values between 10.1 and 76. IQR: interquartile range; BMI: body mass index; kg: kilogram; m: meter; n: number; COPD: chronic obstructive pulmonary disease; ESR: Erythrocyte Sedimentation Rate; CRP: C-reactive protein; RF: Rheumatoid Factor; CCP: Cyclic Citrullinated Peptide; HAQ-DI: Health Assessment Questionnaire Disability Index; CDAI: Clinical Disease Activity Index.

Figure 1. Scatter plots for HAQ-DI, CDAI, STAI and GHQ28.

to be positively associated with all anxiety indexes (STAI, STAI-S, STAI-T), while higher number of treatments is found to have significant associations with high levels of anxiety (STAI), distress (GHQ28), somatic symptoms (GHQ28-A), and social disfunction (GHQ28-C). Higher functional disability (HAQ-DI) and disease activity (CDAI) were found to be strongly associated with worse reported outcomes and multivariate analysis (Table 4) verified this association in most of the cases.

DISCUSSION

The patients in our study had some interesting characteristics. Female/male ratio was 3.5/1, similar to the usual and expected ratio. RF positivity was about 43% and ACPA positivity was about 33%, quite lower comparing to the literature.8 RA in the elderly population has been shown to have somewhat lower seropositivity,11 but not at such a degree. There is no obvious reason for this finding in the patients in our study, but it could be due to chance and/or the small number of participants. The patients had generally a long median disease duration (10 years) and quite low disease activity (evaluated by CDAI), which can be considered as a realistic situation given the long disease duration and explained as a result of a proper therapeutic strategy. The patients in our study were taking a median of 2 medications for their disease, and most of them had 2-3 comorbidities (48.25%) with a median of 3 additional medications, consistent with data from the literature.10 Female patients in our study had significantly higher anxiety and distress, and worse functional ability. Obviously,

older age and longer disease duration contributed to this difference. Additionally - and expectedly, adverse risk factors were age, higher disease activity, need for intense treatment (biologics, corticosteroids), and number of treatments.

These findings are quite consistent with data from the literature, where disease activity is a main factor of anxiety and depression, and the close relationship of anxiety/depression and reduced functional ability in a vicious circle of mutual deterioration, is also evident in the findings of our study.14,16,23,24 Older RA patients are known to experience more significant impairment of health-related quality of life compared to younger patients, and psychological distress is a considerable factor contributing to this.25 Additional finding of the present study is the association of anxiety and distress with gender and disease duration. The increased prevalence of anxiety, distress, and depression in RA patients is largely reasonable and expected, as the RA patient has to manage the psychological load of a chronic disease, the derangement or loss of their personal and/or social roles, problems at work, compliance to treatment, medication side effects etc. Anxiety and depression have a negative effect on functional ability, adding on the inability caused by structural damage and chronic pain and fatigue.14,26 Proinflammatory cytokines (ie, Tumour necrosis factor [TNFa], Interleukin [IL]-1, IL-6), which circulate in abundance in patients with RA, can affect certain brain areas which relate to depression, neuroendocrine function and metabolism of neurotransmitters.14 Cases

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Table 3. STAI and GHQ28 Outcomes.

All patients Gender HAQ-DI CDAI

Man Woman p-value Low High p-value Low High p-value

Variables N=114 N=25 N=89 N=79 N=35 N=70 N=44

STAI

median (IQR) 87.0(67.0-100.0) 79.0(58.0-89.0) 89.0(71.0-104.0) 0.012 84.0(66.0-98.0) 93.0(73.0-110.0) 0.065 80.0(63.0-95.0) 94.0(78.5-111.0) 0.005

High levels (>87) - n(%) 54(47.37) 8 (32.00) 46(51.69) 0.082 34 (43.04) 20(57.14) 0.164 26(37.14) 28(63.64) 0.006

Very High levels (>100) -n(%) 28(24.56) 2 (8.00) 26(29.21) 0.029 15(18.99) 13(37.14) 0.038 14(20.00) 14(31.82) 0.154

O Irtl 0 median (IQR) 43.0(33.0-51.0) 38.0(31.0-47.0) 45.0 (35.0-55.0) 0.020 43.0(33.0-51.0) 47.0(36.0-57.0) 0.208 41.0(32.0-50.0) 48.5(36.5-57.5) 0.025

High levels (>43) - n(%) 56(49.12) 10(40.00) 46(51.69) 0.302 38(48.10) 18(51.43) 0.743 28(40.00) 28(63.64) 0.014

Very High levels (>51) - n(%) CTAI.T 28(24.56) 2 (8.00) 26(29.21) 0.029 16(20.25) 12(34.29) 0.108 13(18.57) 15(34.09) 0.019

O Irtl 1 median (IQR) 42.0 (34.0-50.0) 37.0(31.0-42.0) 43.0(36.0-51.0) 0.018 40.0(32.0-48.0) 47.0(36.0-55.0) 0.028 39.0(31.0-47.0) 47.0(39.0-53.5) 0.003

High levels (>42) - n(%) 53(46.49) 6 (24.00) 47(52.81) 0.011 31 (39.24) 22 (62.86) 0.020 26(37.14) 27(61.36) 0.012

Very High levels (>50) - n(%) 27 (23.68) 4(16.00) 23(25.84) 0.306 15(18.99) 12(34.29) 0.076 11(15.71) 16(36.36) 0.012

GHQ28

median (IQR) 22.0(16.0-31.0) 18.0(11.0-22.0) 23.0(17.0-32.0) 0.007 19.0(15.0-25.0) 31.0(22.0-41.0) <0.001 19.0(15.0-25.0) 27.0(19.0-33.5) 0.007

High levels (>22) - n(%) 54(47.37) 6 (24.00) 48(53.93) 0.008 29(36.71) 25(71.43) 0.001 25(35.71) 29(65.91) 0.002

Very High levels (31) -n(%) 25(21.93) 2 (8.00) 23(25.84) 0.057 11 (13.92) 14(40.00) 0.002 13(18.57) 12 (27.27) 0.274

GHQ28-A / Somatic Symptoms

median (IQR) 6.0(4.0-9.0) 5.0(3.0-6.0) 6.0(5.0-10.0) 0.013 5.0(3.0-7.0) 9.0(7.0-12.0) <0.001 5.0(3.0-7.0) 7.0(5.0-11.0) 0.005

High levels (>6) - n(%) 50(43.86) 6 (24.00) 44(49.44) 0.024 22 (27.85) 28(80.00) <0.001 22(31.43) 28(63.64) 0.001

Very High levels (>9) - n(%) 26(22.81) 2 (8.00) 24(26.97) 0.046 10(12.66) 16(45.71) <0.001 12(17.14) 14(31.82) 0.069

GHQ28-B / Anxiety/Insomnia

median (IQR) 6.0(4.0-10.0) 4.0(3.0-7.0) 7.0(4.0-10.0) 0.038 6.0(3.0-8.0) 8.0(6.0-13.0) 0.001 6.0(3.0-8.0) 7.0(4.5-10.5) 0.033

High levels (>6) - n(%) 53(46.49) 7 (28.00) 46(51.69) 0.036 31 (39.24) 22 (62.86) 0.020 26(37.14) 27(61.36) 0.012

Very High levels (>10)- n(%) 22 (19.30) 2 (8.00) 20(22.47) 0.105 10(12.66) 12(34.29) 0.007 11(15.71) 11(25.00) 0.221

GHQ28-C / Social Dysfunction

median (IQR) 8.0(6.0-11.0) 7.0(5.0-9.0) 8.0(7.0-11.0) 0.140 7.0(6.0-10.0) 10.0(8.0-14.0) <0.001 7.0(6.0-9.0) 9.5(7.0-13.0) 0.003

High levels (>8) - n(%) 50(43.86) 8 (32.00) 42(47.19) 0.176 27(34.18) 23(65.71) 0.002 23(32.86) 27(61.36) 0.003

Very High levels (>11)- n(%) 23(20.18) 5 (20.00) 18(20.22) 0.980 11 (13.92) 12(34.29) 0.012 9(12.86) 14(31.82) 0.014

GHQ28-D / Severe Depression

median (IQR) 1.0(0.0-3.0) 1.0(0.0-1.0) 1.0(0.0-3.0) 0.088 1.0(0.0-2.0) 1.0(0.0-5.0) 0.087 1.0(0.0-2.0) 1.0(0.0-3.0) 0.818

High levels (>1)-n(%) 42 (36.84) 5 (20.00) 37(41.57) 0.048 27(34.18) 15(42.86) 0.376 23(32.86) 19(43.18) 0.266

Very High levels (>3) - n(%) 21 (18.42) 3(12.00) 18(20.22) 0.349 12(15.19) 9(25.71) 0.181 13(18.57) 8(18.18) 0.958

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p-values refer to T-test/Mann-Whitney test or Chi-square test/Fisher's exact test. High levels for each outcome were considered values above 50% percentile (median value). Very high levels were considered values above 75% percentile. HAQ-DI Low category refers to values between 0 and 1, while High category to values between 1.1 and 3. CDAI Low category refers to values between 0 and 10, while High category to values between 10.1 and 76. IQR: interquartile range; n: number.

Table 4. Multivariate logistic regression analyses.

High STAI High STAI-S High STAI-T High GHQ28 High GHQ28-A Somatic Symptoms High GHQ28-B Anxiety/ insomnia High GHQ28-C Social Dysfunction High GHQ28-D Severe depression

Models: (1) (2) (3) (4) (5) (6) (7) (8)

OR, 95% CI, p-value OR, 95% CI, p-value OR, 95% CI, p-value OR, 95% CI, p-value OR, 95% CI, p-value OR, 95% CI, p-value OR, 95% CI, p-value OR, 95% CI, p-value

Submodel (a)

HAQ-DI 1.88 (0.96 -3.67) p=0.064 1.68 (0.90 -3.14) p=0.104 2.92 (1.35 -6.36) p=0.007 3.13 (1.43 -6.85) p=0.004 9.70 (3.08 -30.62) p<0.001 2.00 (1.07 -3.76) p=0.031 2.72 (1.21 -6.13) p=0.015 1.80 (0.91 -3.54) p=0.090

CDAI 1.02 (0.96 -1.08) p=0.542 1.03 (0.98 -1.09) p=0.227 1.00 (0.93 -1.08) p=0.924 1.05 (0.99 -1.11) p=0.120 1.09 (1.02 -1.17) p=0.012 1.04 (0.98 -1.09) p=0.201 1.05 (1.00 -1.11) p=0.042 0.98 (0.92 -1.04) p=0.485

Submodel (b)

HAQ-DI scale 1.12 (0.46 -2.74) p=0.796 0.90 (0.35 -2.31) p=0.826 1.58 (0.59 -4.21) p=0.364 2.32 (0.84 -6.42) p=0.104 9.58 (3.31 -27.72) p<0.001 1.97 (0.80 -4.82) p=0.138 2.19 (0.75 -6.40) p=0.152 1.15 (0.47 -2.83) p=0.753

CDAI scale 2.13 (0.87 -5.24) p=0.098 2.65 (1.05 -6.68) p=0.039 1.79 (0.72 -4.40) p=0.208 3.03 (1.29 -7.14) p=0.011 3.77 (1.44 -9.87) p=0.007 2.30 (1.02 -5.18) p=0.044 3.02 (1.12 -8.17) p=0.029 1.27 (0.56 -2.88) p=0.562

Model (1) adjusted for previous smoking, years of disease, ESR, anti-TNF and number of treatments. Model (2) adjusted for age, number of roommates, years of disease, TKE, anti-TNF and anti-IL6. Model (3) adjusted for gender, previous smoking, COPD and TKE. Model (4) adjusted for gender, years of disease and number of treatments. Model (5) adjusted for gender, residency, osteoporosis, fibromyalgia and number of treatments. Model (6) adjusted for gender. Model (7) adjusted for age, marital status, income, anti-TNF and number of treatments. Model (8) adjusted for years of disease and anti-TNF. In Submodel (a) HAQ and CDAI are introduced to the models (1) to (8) as continuous variables. In Submodel (b) HAQ and CDAI are introduced to the models (1) to (8) as a two-scales categorical variable. HAQ-DI: Health Assessment Questionnaire Disability Index; CDAI: Clinical Disease Activity Index.

of acute RA evolution after a major stress, have indicated the possibility of common immunological mechanisms between the two entities, and a reverse pathophysiological relation, which is still being investigated.24 Limitation of this study is the relatively small number of patients, (due to the strict time-frame, as this study was conducted for a thesis in a Master's programme in Management of Aging and Chronic Diseases, Hellenic Open University), which in turn might be responsible for particular characteristics of the patient population, ie, RF-ACPA positivity, etc.

CONCLUSION

The strong relationship between anxiety, distress and depression with disease activity and functional (in) ability, was confirmed in this study. Females of older age and with longer disease duration had significantly higher levels of anxiety and distress. Control of disease activity is of upmost importance for reducing anxiety/ distress symptoms and improving functional ability. This particular age group of RA patients (elderly >65 years) is very interesting and presents specific particularities. Larger and more robust studies to research on anxiety, depression, and mental health generally in this patient population would be extremely useful.

AUTHOR CONTRIBUTION

Dimitrios Karokis was the lead investigator and writer. Dimitrios Karamanis was the lead supervisor, co-writer and statistician. Sofia Xesfingi was the second supervisor. The rest of the writers contributed to the stratification of patients. All writers reviewed and approved manuscript.

ACKNOWLEDGEMENTS

We would like to thank patients' associations (Association of Rheumatic Patients of Patras, and Hellenic Association against Rheumatism) for their contribution to the stratification of patients.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

FUNDING

No funding was available for this study. REFERENCES

1. Harada CN, Natelson Love MC, Triebel KL. (2013). Normal Cognitive Aging. Clin Geriatr Med 2013 Nov;29(4):737-52.

2. World Health Organization (2017). Mental health of older adults. http://www.who.int/en/news-room/fact-sheets/detail/ mental-health-ofolder-adults

3. El-Gilany AH, Elkhawaga GO, Sarraf BB. Depression and its

mediterranean journal 33

of RHEUMATOLOGY 2022

associated factors among elderly: A community-based study in Egypt. Arch Gerontol Geriatr 2018 Jul-Aug;77:103-7.

4. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid Arthritis. Nat Rev Dis Primers. 2018 Feb 8;4:18001.

5. Smolen, JS, Aletaha D, Mclnnes IB. Rheumatoid Arthritis. Lancet 2016;388:2023-38.

6. Anagnostopoulos I, Zinzaras E, Alexiou I, Papathanasiou A, Davas E, Koutroumpas A, Barouta G, Sakkas L. The prevalence of rheumatic diseases in central Greece: a population survey. BMC Musculoskeletal Disorders 2010;11:98.

7. Andrianakos A, Trontzas P, Christoyannis F, Kaskani E, Nikolia Z, Tavaniotou E, Georgountzos A, Krachtis P; ESORDIG Study Group. Prevalence and management of rheumatoid arthritis in the general population of Greece-the ESORDIG study. Rheumatology (Oxford) 2006;45(12):1549-54.

8. Firestein & Kelley's Textbook of Rheumatology (2021), 11th edition, Elsevier.

9. Lassere MN, Rappo J, Portek IJ, Sturgess A, Edmonds JP. How many life years are lost in patients with rheumatoid arthritis? Secular cause-specific and all-cause mortality in rheumatoid arthritis, and their predictors in a long-term Australian cohort study. Intern Med J 2013;43:66-72.

10. Jack JD, McCutchan R, Maier S, Schirmer M. Polypharmacy in Middle-European Rheumatoid Arthritis-Patients: A Retrospective Longitudinal Cohort Analysis With Systematic Literature Review. Front Med 2020;7:573542.

11. Serhal L, Lwin MN, Holroyd C, Edwards CJ. Rheumatoid arthritis in the elderly: Characteristics and treatment considerations. Autoimmun Rev 2020 Jun;19(6):102528.

1 2. Strait A, Castillo F, Choden S, Li J, Whitaker E, Falasinnu T, et al. Demographic Characteristics of Participants in Rheumatoid Arthritis Randomized Clinical Trials A Systematic Review. JAMA Network Open 2019;2(11):e1914745.

13. Espinoza G, Maldonado G, Narvaez J, Guerrero R, Citera G, Rios C. Beyond Rheumatoid Arthritis Evaluation: What are we missing? Open Access Rheumatol 2021 Mar 25;13:45-55.

14. Valleran IA, Patten SB, Barnabe S. Depression and the risk of rheumatoid arthritis. Curr Opin Rheumatol 2019;31:279-84.

15. Sturgeon JA, Finnan PH, Zautra AJ. Affective disturbance in rheumatoid arthritis: psychological and disease-related pathways. Nat Rev Rheumatol 2016;12(9):532-42.

16. DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med 2000;160:2101-7.

17. Treharne GJ, Lyons AC, Kitas GD. Suicidal ideation in patients with rheumatoid arthritis. Research may help identify patients at high risk. BMJ 2000;321:1290.

18. Fountoulakis KN, Papadopoulou M, Kleanthous S, Papadopoulou A, Bizeli V, Nimatoudis I, et al. Reliability and psychometric properties of the Greek translation of the State-Trait Anxiety Inventory form Y: preliminary data. Ann Gen Psychiatry 2006;5:2.

1 9. Garyfallos G, Karastergiou A, Adamopoulou A, Moutzoukis C, Alagiozidou E, Mala D, et al. Greek version of the General Heath Questionnaire: accuracy of translation and validity. Acta Psychiatr Scand 1991;84(4):371-8.

20. Sterling M. General health questionnaire-28 (GHQ-28). J Physiotherapy 2011;57(4):259.

21. Quintana-Duque MA, Rondon-Herrera F, Mantilla RD, Calvo-Paramo E, Yunis JJ, Varela-Nariño A, et al. Predictors of remission, erosive disease and radiographic progression in a Colombian cohort of early onset rheumatoid arthritis: a 3-year follow-up study. Clin Rheumatol 2016;35(6):1463-73.

22. Bruce B, Fries FJ. The Stanford Health Assessment Questionnaire: Dimensions and Practical Applications, Review. Health Qual Life Outcomes 2003 Jun 9;1:20.

23. Kekow J, Moots R, Khandker R, Melin J, Freundlich B, Singh A. Improvements in patient-reported outcomes, symptoms of

depression and anxiety, and their association with clinical remission among patients with moderate-to-severe active early rheumatoid arthritis. Rheumatology 2011;50:401-9.

24. Nerurkar L, Siebert S, Mclnnes IB, Cavanagh J. Rheumatoid arthritis and depression: an inflammatory perspective. Lancet Psychiatry 2019 Feb;6(2):164-73.

25. Goulia P, Voulgari PV, Tsifetaki N, Drosos AA, Hyphantis T. Comparison of health-related quality of life and associated psychological factors between younger and older patients with established rheumatic disorders. Aging Ment Health 2020;14(7):819-27.

26. Lwin MN, Serhal L, Holroyd C, Edwards CJ. Rheumatoid Arthritis: The Impact of Mental Health on Disease: A Narrative Review. Rheumatol Ther 2020;7:457-71.

ISCED: International Standard Classification of Education; IQR: interquartile range; n: number.

Supplementary Table S1. Treatments and previous treatments.

All patients Gender HAQ-DI CDAI

Man Woman p-value Low High p-value Low High p-value

Variables N=114 N=25 N=89 N=79 N=35 N=70 N=44

Treatments ■ n(%)

Hydroxychloroquine 25(21.93) 3(12.00) 22 (24.72) 0.174 13(16.46) 12(34.29) 0.034 19(27.14) 6(13.64) 0.090

Methotrexate 60(52.63) 18(72.00) 42(47.19) 0.028 44(55.70) 16(45.71) 0.325 40(57.14) 20(45.45) 0.224

Leflunomide 5(4.39) 1 (4.00) 4(4.49) 0.915 3(3.80) 2(5.71) 0.645 3(4.29) 2 (4.55) 0.947

anti-TNF 26(22.81) 4(16.00) 22 (24.72) 0.359 17(21.52) 9(25.71) 0.622 12(17.14) 14(31.82) 0.069

anti-IL6 11(9.65) 1 (4.00) 10(11.24) 0.279 8(10.13) 3(8.57) 0.795 7(10.00) 4(9.09) 0.873

anti-CTLA4 1 (0.88) 0(0.00) 1(1.12) 0.594 1(1.27) 0(0.00) 0.504 0 (0.00) 1 (2.27) 0.205

Jak-inhibitors 5(4.39) 3(12.00) 2 (2.25) 0.069 4(5.06) 1 (2.86) 0.596 2 (2.86) 3(6.82) 0.315

anti-CD20 5(4.42) 0(0.00) 5(5.68) 0.223 2 (2.53) 3(8.82) 0.136 1 (1.45) 4(9.09) 0.054

glucocorticoids 50 (43.86) 11(44.00) 39(43.82) 0.987 33(41.77) 17(48.57) 0.500 29(41.43) 21 (47.73) 0.509

No. of Treatments - median (IQR) 2.0(1.0-2.0) 2.0(1.0-2.0) 2.0(1.0-2.0) 0.912 2.0(1.0-2.0) 2.0(1.0-3.0) 0.124 2.0(1.0-2.0) 2.0(1.0-2.0) 0.583

Previous Treatments ■ n(%)

Hydroxychloroquine 16(14.04) 0(0.00) 16(17.98) 0.022 11 (13.92) 5(14.29) 0.959 7(10.00) 9 (20.45) 0.118

Methotrexate 46 (40.35) 6 (24.00) 40(44.94) 0.059 29(36.71) 17(48.57) 0.234 24 (34.29) 22 (50.00) 0.096

Leflunomide 14(12.28) 1 (4.00) 13(14.61) 0.153 10(12.66) 4(11.43) 0.854 6 (8.57) 8(18.18) 0.128

anti-TNF 22 (19.30) 3(12.00) 19(21.35) 0.295 10(12.66) 12(34.29) 0.007 11 (15.71) 11 (25.00) 0.221

anti-IL6 5 (4.39) 0 (0.00) 5(5.62) 0.226 3 (3.80) 2(5.71) 0.645 0 (0.00) 5(11.36) 0.007

anti-CTLA4 5 (4.39) 0 (0.00) 5(5.62) 0.226 3 (3.80) 2(5.71) 0.645 2 (2.86) 3 (6.82) 0.315

Jak-inhibitors 1 (0.88) 0 (0.00) 1(1.12) 0.594 0 (0.00) 1 (2.86) 0.131 0(0.00) 1 (2.27) 0.205

anti-CD20 0 (0.00) 0 (0.00) 0(0.00) - 0 (0.00) 0 (0.00) - 0(0.00) 0 (0.00) -

glucocorticoids 58 (50.88) 11 (44.00) 47(52.81) 0.436 43 (54.43) 15(42.86) 0.254 35(50.00) 23 (52.27) 0.813

No. of Previous treatments - median (IQR) 1.0(0.0-2.0) 1.0(0.0-1.0) 2.0(0.0-2.0) 0.007 1.0(0.0-2.0) 2.0(0.0-2.0) 0.253 1.0(0.0-2.0) 2.0(0.0-3.0) 0.010

No. of Medicines - median (IQR) 3.0(2.0-4.0) 2.0(2.0-5.0) 3.0(2.0-4.0) 0.711 2.0(2.0-5.0) 3.0(2.0-4.0) 0.174 2.0(2.0-4.0) 4.0(2.5-6.0) <0.001

p-vaiues refer to T-test/Mann-Whitney test or Chi-square test/Fisher's exact test. HAQ-Di Low category refers to values between 0 and 1, while High category to values between 1.1 and 3. CDAI Low category refers to values between 0 and 10, while High category to values between 10.1 and 76. n: number.

High High High High

STAI (1) STAI-S (2) STAI-T (3) GHQ28 (4)

OR, 95% CI, OR, 95% CI, OR, 95% CI, OR, 95% CI,

Variables p-value p-value p-value p-value

Female 2.27 (0.89 - 5.83) 1.60(0.65-3.97) 3.54(1.29 - 9.75) 3.71 (1.35-10.20)

p=0.087 p=0.306 p=0.014 p=0.011

Age in years 0.96(0.90 - 1.02) 0.94(0.88-1.00) 0.97(0.91 - 1.03) 1.03(0.97 - 1.09)

p=0.181 p=0.045 p=0.327 p=0.383

M cirri orl 1.41 (0.66-3.01) 1.58(0.74-3.39) 0.74(0.35- 1.57) 0.58(0.27 - 1.24)

iviai i icU p=0.377 p=0.237 p=0.427 p=0.161

Roommates 1.13 (0.72 - 1.77) 1.62(1.02 - 2.57) 1.07(0.68- 1.69) 1.01(0.65- 1.59)

p=0.609 p=0.042 p=0.761 p=0.953

Education 0.83(0.51 - 1.35) 0.96(0.59- 1.55) 0.77(0.48- 1.26) 0.74(0.45- 1.20)

(ISCED Levels) p=0.457 p=0.868 p=0.304 p=0.222

Income 0.71 (0.44-1.15) 0.89(0.56- 1.43) 0.63(0.39- 1.02) 0.75(0.47 - 1.21)

p=0.161 p=0.640 p=0.063 p=0.242

Residency in 1.07(0.47 -2.40) 0.81(0.36- 1.84) 0.79(0.35- 1.80) 0.63(0.28- 1.45)

Rural region p=0.879 p=0.619 p=0.580 p=0.280

BMI in kg/m2 1.03(0.95 - 1.12) 1.04(0.96- 1.14) 1.01(0.93-1.10) 1.01(0.93-1.10)

p=0.501 p=0.312 p=0.784 p=0.802

BMI Category 1.28 (0.77 - 2.13) 1.27 (0.76 - 2.11) 1.20(0.72 -2.00) 1.20(0.72 - 1.99)

p=0.346 p=0.362 p=0.484 p=0.495

Smoker 1.41 (0.57 -3.50) 1.29(0.52 -3.20) 0.97 (0.39 - 2.40) 0.60(0.24- 1.52)

p=0.456 p=0.580 p=0.942 p=0.281

Previous Smoker 0.31 (0.10-0.91) 0.38(0.13- 1.07) 0.23 (0.07 - 0.74) 0.41 (0.14-1.17)

p=0.034 p=0.067 p=0.014 p=0.094

Years of disease 1.03(0.99 - 1.07) 1.03(0.99- 1.07) 1.03(0.99- 1.07) 1.05(1.01 - 1.09)

p=0.111 p=0.109 p=0.134 p=0.014

Years of disease 2.15(1.01-4.59) 2.55(1.19-5.46) 1.72(0.81 -3.63) 2.50(1.17 - 5.36)

above median p=0.047 p=0.017 p=0.159 p=0.019

Hypertension 0.54(0.25 - 1.14) 0.71(0.33 - 1.49) 0.78(0.37 - 1.64) 1.27(0.60-2.68)

p=0.106 p=0.360 p=0.509 p=0.526

Diabetes 0.89 (0.34 - 2.36) 0.82(0.31 -2.17) 1.94(0.72 -5.21) 1.45(0.55-3.84)

p=0.816 p=0.686 p=0.189 p=0.455

Thyroid disease 0.84 (0.34 - 2.06) 1.42(0.58 -3.49) 0.58(0.23- 1.44) 0.84(0.34-2.06)

p=0.704 p=0.439 p=0.239 p=0.704

High GHQ28-A Somatic Symptoms

(5)

OR, 95% CI, p-value

3.10(1.13-8.52) p=0.029

0.98(0.92 - 1.05) p=0.628 0.71 (0.33 - 1.53)

p=0.385 1.28(0.81 -2.03)

p=0.298 0.75(0.46 - 1.22)

p=0.243 1.01 (0.63 - 1.62)

p=0.953 0.24 (0.09 - 0.61)

p=0.003 1.03(0.94 - 1.12)

p=0.534 1.14(0.68-1.91) p=0.622 0.45(0.17 - 1.20)

p=0.109 0.49(0.17 - 1.38)

p=0.176 1.04 (1.00 - 1.08)

p=0.052 1.81 (0.85 -3.84)

p=0.125 1.14(0.54 -2.42)

p=0.725 1.06(0.40 -2.80)

p=0.910 1.01 (0.41 -2.47) p=0.987

High GHQ28-B Anxiety/ insomnia

(6)

OR, 95% CI, p-value

High GHQ28-C Social Dysfunction

(7)

OR, 95% CI, p-value

2.75(1.04-7.27 p=0.041

0.99(0.93- 1.05

p=0.735 0.63(0.30- 1.36

p=0.240 1.02(0.65- 1.60

p=0.937 0.68(0.42 - 1.11

p=0.127 0.85(0.53- 1.36

p=0.492 0.46(0.20- 1.

p=0.076 0.95(0.88- 1.04

p=0.287 0.70(0.42 - 1.18 p=0.181 0.63(0.25- 1.59

p=0.325 0.43(0.15-1.22 p=0.111 1.02(0.98- 1.06

p=0.257 1.72(0.81-3.63

p=0.159 0.90(0.43- 1.89

p=0.776 0.73(0.27 - 1.95

p=0.524 0.71 (0.29-1.76 p=0.464

1.90(0.74-4.87) p=0.182 1.08(1.02-1.15)

p=0.014 0.24(0.11 -0.54) p=0.001 0.93(0.59- 1.46)

p=0.752 0.62(0.37 - 1.03)

p=0.065 0.59 (0.37 - 0.97)

p=0.037 0.65(0.28- 1.49)

p=0.307 0.97(0.90- 1.06)

p=0.544 1.06(0.64- 1.77) p=0.810 0.45(0.17 - 1.20)

p=0.109 0.36(0.12 - 1.08)

p=0.070 1.03(1.00- 1.07)

p=0.089 1.56(0.74-3.31)

p=0.246 1.14(0.54-2.42)

p=0.725 1.35(0.51 -3.57)

p=0.545 0.66(0.26- 1.65) p=0.374

High GHQ28-D Severe depression

(8)

OR, 95% CI, p-value

2.85(0.97 -8.31)

p=0.056 1.01 (0.95 - 1.08)

p=0.703 0.50(0.23 - 1.09) p=0.082 0.91 (0.57 - 1.46)

p=0.695 0.66(0.39 - 1.12) p=0.122 0.67(0.40 - 1.10) p=0.116 0.81 (0.34 - 1.90) p=0.622 1.06(0.96 - 1.17)

p=0.223 1.72(0.98 -3.03) p=0.061 1.29(0.51 -3.26)

p=0.584 0.37(0.11-1.19)

p=0.096 1.04 (1.00 - 1.08)

p=0.051 2.76 (1.26 - 6.08) p=0.011 1.24(0.57 -2.70)

p=0.580 0.69(0.24 - 1.97)

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0.95(0.38 -2.41) p=0.922

Variables

Cancer

Lipidaemia

Osteoporosis

Inflamm Bowel Disease

Fibromyalgia

COPD

No. of Comorbidities

No. of Comorbidities above median

ESR CRP RF CCP

HAQ-DI

HAQ-DI scale (2 Categories)

CDAI

CDAI scale (2 Categories)

High STAI (1) OR, 95% CI, p-value High STAI-S (2) OR, 95% CI, p-value High STAI-T (3) OR, 95% CI, p-value

3.47(0.35 -34.76) 1.04(0.14-7.69) 3.60(0.36-36.06)

p=0.290 p=0.972 p=0.276

0.82(0.39 - 1.76) 0.73(0.34- 1.56) 1.01 (0.47-2.16)

p=0.615 p=0.422 p=0.976

0.70(0.29 - 1.69) 0.64(0.27 - 1.55) 0.90(0.38-2.15)

p=0.433 p=0.323 p=0.808

2.27 (0.20 - 26.03) 2.11 (0.18 - 24.22)

p=0.510 p=0.548

1.94(0.69 -5.45) 2.36(0.82 -6.85) 1.54(0.56-4.26)

p=0.210 p=0.113 p=0.405

1.64(0.49 -5.53) 1.51(0.45-5.11) 3.95(1.00-15.56)

p=0.427 p=0.504 p=0.049

0.98(0.75 - 1.27) 1.00(0.77 - 1.29) 1.10(0.86- 1.43)

p=0.858 p=0.986 p=0.446

0.90(0.43 - 1.90) 1.06(0.50-2.24) 1.28(0.60-2.70)

p=0.780 p=0.874 p=0.524

1.04(1.01 - 1.07) 1.03 (1.00- 1.06) 1.03(1.01 - 1.06)

p=0.015 p=0.024 p=0.019

1.15(0.60 -2.20) 1.08(0.58-2.02) 1.27(0.60-2.67)

p=0.680 p=0.797 p=0.530

1.29(0.61 -2.73) 1.14(0.54-2.41) 0.58(0.27 - 1.23)

p=0.500 p=0.726 p=0.155

1.37(0.63 -3.01) 1.45(0.66-3.18) 0.65(0.29- 1.44)

p=0.429 p=0.357 p=0.292

2.33(1.28-4.24) 1.78(1.02 - 3.09) 3.44(1.78-6.66)

p=0.006 p=0.042 p<0.001

1.76(0.79 -3.96) 1.14(0.51-2.54) 2.62(1.15 - 5.98)

p=0.168 p=0.744 p=0.022

1.06 (1.00- 1.13) 1.06 (1.00- 1.12) 1.06 (1.00 - 1.11)

p=0.037 p=0.050 p=0.049

2.96(1.35-6.49) 2.63(1.20 - 5.74) 2.69 (1.23 - 5.86)

p=0.007 p=0.016 p=0.013

Continued from previous page

High High GHQ28-A High GHQ28-B High GHQ28-C High GHQ28-D

GHQ28 Somatic Symptoms Anxiety/ insomnia Social Dysfunction Severe depression

(4) (5) (6) (7) (8)

OR, 95% CI, OR, 95% CI, OR, 95% CI, OR, 95% CI, OR, 95% CI,

p-value p-value p-value p-value p-value

4.02(0.40 -40.29) 4.02 (0.40 - 40.29)

p=0.237 p=0.237

1.11(0.52 -2.35) 1.21 (0.56 -2.58) 0.87(0.41 - 1.86) 2.20 (1.02 - 4.75) 0.91 (0.42 - 2.00)

p=0.794 p=0.627 p=0.725 p=0.045 p=0.819

0.70(0.29- 1.69) 0.36(0.14-0.94) 0.60(0.25- 1.47) 2.27 (0.94 - 5.49) 1.01 (0.41 -2.48)

p=0.433 p=0.036 p=0.264 p=0.070 p=0.981

2.27(0.20-26.03) 0.63 (0.06 - 7.26) 0.57(0.05-6.51) 0.63(0.06-7.26) 3.55(0.31 -40.82)

p=0.510 p=0.713 p=0.649 p=0.713 p=0.309

1.13(0.41-3.12) 3.05(1.05-8.87) 2.02 (0.72 - 5.68) 1.75(0.63-4.85) 0.83 (0.29 - 2.43)

p=0.808 p=0.040 p=0.183 p=0.282 p=0.738

3.80(0.97 - 14.95) 1.92(0.57 -6.50) 1.70(0.50-5.76) 1.32(0.40-4.39) 1.83(0.55 -6.13)

p=0.056 p=0.294 p=0.391 p=0.653 p=0.325

1.12(0.87 - 1.44) 1.13(0.87 - 1.45) 1.02(0.79- 1.31) 1.21(0.93- 1.57) 1.13(0.86 - 1.48)

p=0.393 p=0.361 p=0.905 p=0.155 p=0.373

1.20(0.57 -2.54) 1.15(0.54 -2.44) 0.96(0.45-2.02) 1.54(0.72 -3.27) 1.67(0.77 -3.61)

p=0.633 p=0.718 p=0.905 p=0.263 p=0.196

1.03(1.00- 1.06) 1.01 (0.98 - 1.03) 1.01(0.98- 1.03) 1.01(0.98- 1.04) 1.00(0.97 - 1.02)

p=0.056 p=0.609 p=0.696 p=0.453 p=0.772

1.22(0.60-2.47) 0.94(0.55 - 1.61) 1.04(0.58- 1.85) 0.93(0.55- 1.59) 0.90(0.55 - 1.46)

p=0.577 p=0.830 p=0.899 p=0.798 p=0.661

0.63(0.30- 1.33) 0.52(0.24 - 1.11) 0.50(0.23- 1.07) 0.93(0.44- 1.97) 0.38 (0.17 - 0.86)

p=0.227 p=0.090 p=0.073 p=0.852 p=0.020

0.62(0.28- 1.37) 0.46(0.20 - 1.05) 0.90(0.41 - 1.97) 0.90(0.41 - 1.98) 0.71 (0.31-1.62)

p=0.236 p=0.065 p=0.792 p=0.790 p=0.413

4.57 (2.08 ■ 10.01) 8.15(3.05-21.80) 2.45(1.33-4.49) 3.65(1.75-7.65) 1.97(1.13-3.41)

p<0.001 p<0.001 p=0.004 p=0.001 p=0.016

4.31 (1.81 ■ 10.27) 10.36(3.94-27.27) 2.62 (1.15-5.98) 3.69 (1.59 - 8.57) 1.44(0.64 -3.28)

p=0.001 p<0.001 p=0.022 p=0.002 p=0.379

1.08(1.02-1.15) 1.12(1.04-1.21) 1.05(1.00- 1.11) 1.07 (1.02-1.14) 1.00(0.96 - 1.05)

p=0.010 p=0.004 p=0.056 p=0.012 p=0.972

3.48(1.57 - 7.71) 3.82(1.72 - 8.48) 2.69 (1.23 - 5.86) 3.25(1.47-7.14) 1.55(0.71 -3.39)

p=0.002 p=0.001 p=0.013 p=0.003 p=0.269

-P^

o

CT)

Supplementary Table S2. Univariate logistic regression analyses.

Continued from previous page

High High High High High GHQ28-A High GHQ28-B High GHQ28-C High GHQ28-D

STAI (1) STAI-S (2) STAI-T (3) GHQ28 (4) Somatic Symptoms (5) Anxiety/ insomnia (6) Social Dysfunction (7) Severe depression (8)

OR, 95% CI, OR, 95% CI, OR, 95% CI, OR, 95% CI, OR, 95% CI, OR, 95% CI, OR, 95% CI, OR, 95% CI,

Variables p-value p-value p-value p-value p-value p-value p-value p-value

Treatments

Hydroxycloroquine 1.27(0.52 -3.10) 1.16(0.48 -2.83) 1.08(0.44-2.64) 1.03(0.42 -2.52) 1.01 (0.41 -2.47) 1.08(0.44-2.64) 0.82 (0.33 - 2.02) 0.76(0.30 - 1.96)

p=0.602 p=0.746 p=0.865 p=0.943 p=0.987 p=0.865 p=0.661 p=0.572

Methotrexate 1.44(0.69 -3.03) 1.24(0.59 -2.60) 1.35(0.64-2.83) 0.94(0.45- 1.97) 1.10(0.52 -2.32) 0.76(0.36- 1.61) 1.97(0.92 -4.20) 0.98(0.46 -2.12)

p=0.335 p=0.569 p=0.431 p=0.875 p=0.797 p=0.478 p=0.079 p=0.967

Leflunomide 0.73(0.12 -4.58) 1.58(0.25 -9.94) 0.76(0.12 -4.76) 1.71 (0.27 - 10.70) 0.85(0.13 -5.32) 0.27 (0.03 - 2.56) 0.31 (0.03 - 2.86) 0.41 (0.04 -3.88)

p=0.738 p=0.623 p=0.768 p=0.569 p=0.860 p=0.256 p=0.299 p=0.440

anti-TNF 2.60(1.04-6.51) p=0.041 4.81 (1.75-13.23) p=0.002 1.47(0.61 -3.54) p=0.396 2.11(0.86-5.18) p=0.105 2.06 (0.85 - 5.04) p=0.111 1.47(0.61 -3.54) p=0.396 3.15(1.25-7.90) p=0.015 2.50 (1.02 -6.12) p=0.045

anti-IL6 0.22(0.04 - 1.07) p=0.060 0.20 (0.04-0.99) p=0.048 0.40(0.10- 1.59) p=0.193 0.22(0.04- 1.07) p=0.060 0.25(0.05 - 1.25) p=0.091 0.40(0.10- 1.59) p=0.193 0.45(0.11 - 1.79) p=0.255 0.15(0.02 - 1.24) p=0.078

Jak-inhibitors 0.73(0.12 -4.58) p=0.738 0.25(0.03 -2.29) p=0.218 0.76(0.12 -4.76) p=0.768 0.73(0.12 -4.58) p=0.738 0.85(0.13 -5.32) p=0.860 1.77 (0.28 - 11.11) p=0.542 1.98(0.32 - 12.42) p=0.467 0.41 (0.04 -3.88) p=0.440

anti-CD20 4.82(0.52 -44.96) p=0.168 1.62(0.26 - 10.14) p=0.609 5.00(0.54-46.68) p=0.158 4.82 (0.52 - 44.96) p=0.168 5.60(0.60 -52.31) p=0.131 - 5.39(0.58 -50.35) p=0.139 2.76(0.44- 17.41) p=0.279

glucocorticoids 1.39(0.66 -2.94) 0.92(0.44 - 1.94) 1.29(0.61-2.71) 1.61(0.76-3.40) 1.35(0.64 -2.85) 1.29(0.61-2.71) 2.09(0.98-4.47) 1.09(0.51 -2.36)

p=0.384 p=0.833 p=0.509 p=0.213 p=0.434 p=0.509 p=0.056 p=0.822

No. of Treatments 1.70(1.01 -2.83) 1.36(0.83 -2.23) 1.45(0.89-2.38) 1.48(0.89-2.48) 1.36(0.82 -2.26) 1.13(0.69- 1.85) 2.71 (1.63-4.51) 1.08(0.66 - 1.77)

p=0.044 p=0.221 p=0.139 p=0.132 p=0.233 p=0.637 pcO.OOl p=0.764

No. of Treatments 2.80 (0.80 - 9.74) 2.59(0.74 -8.99) 2.91(0.84-10.15) 7.42(1.55-35.46) 5.08(1.31 -19.73) 1.99(0.61 -6.54) 8.74 (1.83 - 41.85) 1.08(0.33 -3.57)

above median p=0.106 p=0.135 p=0.093 p=0.012 p=0.019 p=0.256 p=0.007 p=0.898

High levels for each outcome were considered values above 50% percentile (median value). All Previous Treatments had insignificant univariate associations with the outcomes.

BMI: body mass index; kg: kilogram; m: meter; COPD: chronic obstructive pulmonary disease; ESR: Erythrocyte Sedimentation Rate; CRP: C-reactive protein; RF: Rheumatoid Factor; CCP: Cyclic Citrullinated Peptide; HAQ-DI: Health Assessment Questionnaire Disability Index; CDAI: Clinical Disease Activity

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