Is the Prevalence of Arterial Hypertension in Rheumatoid Arthritis and Osteoarthritis

Online Resource Is the prevalence of arterial hypertension in rheumatoid arthritis and osteoarthritis associated with disease? Rheumatology International

Jadranka Morović-Vergles, Lea Šalamon, Daniela Marasović-Krstulović, Tatjana Davorin Šakić, Olga Badovinac, Tonko Vlak, Srđan Novak , Nives Štiglić-Rogoznica, Marino Hanih, Dražen Bedeković, Simeon Grazio, Mira Kadojić, Jasminka Milas-Ahić, Višnja Prus, Doris Stamenković, Daniela Šošo, Branimir Anić, Đurđica Babić-Naglić, Stjepan Gamulin.

Corresponding author: Prof. Jadranka Morović-Vergles, M.D., Ph.D. Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, Dubrava University Hospital, Av. G. Šuška 6, 10 040 Zagreb, Croatia E-mail: [email protected] 2

Table 1-S. Hypertensive and normotensive patients in RAa and OAb RA (N=627) P value (HTRA OA (N=352) vs. HTOA) HTc (N=373) NTd (N=254) P-value( HT vs. HT (N=258) NT (N=94) P-value (HT vs. NT) NT) Sex female, n[%(95%CIe)] 314 208 0.450 0.435 223 72 0.027 [84.2 (80.2, 87.6) [81.0 (75.7, 85.3)] [86.4 (81.7, 90.0)] [76.6 (67.1, 84.0)] ] Age, yrs 63.0 (56.0-70.0) 54.0 (45.0-62.0) <0.001 <0.001 69.0 (61.0-74.0) 59.0 (50.0-69.0) <0.001 Aged 65 yrs, 157 51 <0.001 <0.001 167 32 <0.001 n[%(95%CI)] [42.1 (37.2, 47.2) [20.1 (15.6, 25.5)] [64.7 (58.7, 70.3)] [34.0 (25.2, 44.0)] ] Disease duration (yrs) 8.0 (3.0 -16.0) 5.0 (2.0 -12.0) 0.002 0.008 6.00 (2.0-12.0) 3.0 (1.0-7.0) <0.001 HT awareness (yrs) 7.0 (3.0-13.0) 0 NDg 0.002 9.0 (5.0-16.0) 0 ND BMIf 27.17 25.30 <0.001 <0.001 30.41 27.50 <0.001 (24.66 - 30.26) (22.58 -28.03) (26.73 -33.00) (24.96 - 31.03) BMI 25 n[%(95%CI)] 266 129 <0.001 <0.001 218 70 0.020 [71.3 (66.5, 75.7) [50.7 (44.6, 56.8)] [85.2 (80.4, 89.0)] [74.5 (64.8, 82.2)] ] W/Hh ratio 0.90 0.86 <0.001 0.464 0.90 0.89 0.177 (0.85 - 0.95) (0.80 - 0.92) (0.85 - 0.96) (0.82 - 0.96) VASPi 50.00 50.00 (25.25 0.007 0.340 55.00 40.00 <0.001 (39.00 - 70.00) - 70.00) (40.00 - 70.00) (28.00 - 50.00) VASGHj 50.00 42.00 0.064 0.618 50.00 43.50 0.147 (30.00 - 70.00) (20.00 - 60.00) (30.00 - 64.50) (30.00 - 60.00) HAQk 1.50 1.19 0.002 ND ND ND (0.70 - 2.13) (0.60 - 1.88) DAS28-CRPl 4.41 (1.52) 4.21 (1.58) 0.129 ND ND Dyslipidemia, 173 76 <0.001 0.030 147 37 0.010 n[%(95%CI)] [46.4 (41.4, 51.5) [29.9 (24.6, 35.8)] [57.0 (50.9, 62.9)] [39.4 (30.1, 49.5)] ] DMm n[%(95%CI)] 47 13 0.002 0.010 52 7 0.005 [12.6 (9.6, 16.4)] [5.1 (3.0, 8.5)] [20.2 (15.8, 25.5)] [7.4 (3.6, 14.5)]

Laboratory data ESRn 28 (15 – 45) 22 (12 – 40) 0.007 <0.001 15 (9- 24) 12 (8 – 20) 0.114 CRPo (mg/L) 9.40 6.70 0.007 <0.001 2.95 2.00 0.016 (4.00-21.00) (2.38-16.94) (1.30-3.83) (1.40 – 3.10) Cholp (mmol/L) 5.61 5.30 <0.001 0.565 5.80 5.70 0.263 3 (4.90 – 6.50) (4.73 – 5.90) (4.84 – 6.60) (4.80 – 6.38) TGq (mmol/L) 1.45 1.22 <0.001 <0.001 1.700 1.60 0.008 (1.10 – 1.90) (0.93 – 1.60) (1.30 – 2.31) (1.09 – 1.90) HDLr (mmol/L) 1.40 1.43 0.403 0.920 1.40 1.50 0.073 (1.19 – 1.80) (1.20 – 1.79) (1.19 – 1.70) (1.20 – 1.80) LDLs (mmol/L) 3.40 3.12 <0.001 0.038 3.23 3.01 0.100 (2.90 – 4.05) (2.70 – 3.70) (2.50 – 3.969 (2.30 – 3.73) Glct (mmol/L) 5.00 4.90 0.007 <0.001 5.50 5.40 0.350 (4.50 – 5.60) (4.40 – 5.30) (4.90 – 6.00) (5.00 – 5.89) Creatinine (mmol/L) 78.00 74.00 <0.001 0.768 79.00 78.00 0.629 (69.00 – 88.75) (65.00 – 82.25) (68.00 – 89.00) (70.00 – 84.25) RFu (IU/mL) 46.3 28.8 0,268 ND ND ND ND (10.0-155.0) (8.0-139.5)

Smoking habit Nonsmokers 221 130 0.046 <0.001 189 56 0.014 n[%(95%CI)] [59.2 (54.9, 64.9)] [51.2 (45.1, 57.3) [73.3 (67.6, 78.3)] [59.69 (49.6, 69.0) ] ] Exsmokers, n[%(95%CI)] 89 50 0.217 0.010 40 15 0.917 [23.9 (19.9, 28.5)] [19.7 (15.3, 25.0) [15.5 (11.6, 20.4)] [16.0 (9.9, 24.7)] ] - duration yrs. 20.00 20.00 0.122 0.449 20.00 15.00 0.170 (13.50-30.00) (10.00-25.00) (10.00-30.00) (7.00-20.00) Current smokers 63 74 <0.001 0.048 29 23 0.002 n[%(95%CI)] [16.9 (13.4-21.0)] [29.1 (23.9-35.0)] [11.2 (7.9-15.6)] [24.5 (16.9-34.0)]

- duration yrs. 30.00 27.00 0.039 0.423 30.00 28.00 0.462 (20.00-40.00) (20.00-34.00) (22.00-33.50) (20.00-37.00) - cigarettes/day 15 (10-20) 10 (10-20) <0.001 0.041 10 (4-20) 20 (10-20) 0.001

Medication Antirheumatics NSADsv users 180 133 0.328 0.002 163 69 0.073 n[%(95%CI)] [48.3 (43.3, 53.4)] [52.6 (46.5, 58.7) [63.2 (57.2, 98.9)] [73.4 (63.7, 81.3)] ] MTXw users, 180 132 0.362 ND 0 0 ND n[%(95%CI)] [48.3 (43.3, 53.4)] [52.0 (45.9, 58.1) ] Leflunomide users 59 26 0.048 ND 0 0 ND ,n[%(95%CI)] [15.8 (12.5, 19.8)] [10.3 (7.1, 14.6)] 4

Chloroquine users, 26 33 0.559 ND 0 0 ND n[%(95%CI)] [10.2 (7.5, 13.7)] [8.8 (5.9, 12.9)]

Sulphosalazine users, 96 61 0.659 Nd 0 0 ND n[%(95%CI)] [25.7 (21.5, 30.4)] [24.1 (19.3, 29.7) ] Glucocorticoide - users, n[%(95%CI)] 314 213 0.913 ND 0 0 ND [84.2 (80.2, 87.6)] [83.9 (78.9, 87.9) ] - duration (month) 4.0 (1.0-8.0) 2.0 (1.0-6.0) 0.008 ND 0 0 ND - dose (mg/day) 20.0 (10.0-20.0) 20.0 (10.0-20.0) 0.632 ND 0 0 ND Anti-TNFy, n[%(95%CI)] 16 24 0.009 ND 0 0 0 [4.3 (2.7, 6.9)] [9.5 (6.5, 13.7)] Analg users, 134 71 0.037 0.945 92 29 0.401 n[%(95%CI)] [35.9 (31.2, 40.9)] [28.0 (22.8, 33.8) [35.7 (30.1, 41.7)] [30.9 (22.5, 40.3)] ] Opioids users, 0 1 [0.4] ND ND 91 30 0.557 n[%(95%CI)] [35.3 (29.7, 41.3)] [31.9 (23.3, 41.9)] Antihypertensives ACE-Ix, n[%(95%CI)] 150 0 ND 0.002 137 0 ND [40.2 (35.3, 45.8)] [53.1 (49.0, 59.1)] BBz , n[%(95%CI)] 113 0 ND 0.930 79 0 ND [30.3 (25.9, 35.1)] [30.6 (25.3, 36.5)] DIURaa , n[%(95%CI)] 121 0 ND 0.004 113 0 ND [32.4 (27.9, 37.3)] [43.8 (37.9, 49.9)] ATRAab , n[%(95%CI)] 13 0 ND 0.173 15 0 ND [3.5 (2.1, 5.9)] [5.8 (3.5, 9.4)] CCBac, n[%(95%CI)] 94 0 ND 0.001 96 0 ND [25.2 (21.1, 29.2)] [37.2 (31.5, 43.2)] Anti-HTad , drugs. no 2 (1-2) 0 ND 0.008 2 (1-3) 0 ND Anti-HT users, 280 0 ND 0.002 222 0 ND n[%(95%CI)] [75.1 (70.5, 79.2)] [86.0 (81.2, 89.7)]

Statins, n[%(95%CI)] 68 17 <0.001 0.003 75 10 0.001 [18.2 (14.6, 22.0)] [6.7 (4.2, 10.5)] [29.1 (23.9, 34.9)] [10.6 (5.9, 18.4)] Results are expressed as percentages and 95%CI, median values (interquartile range) or mean values (standard deviation) as appropriate. aRA, rheumatoid arthritis; bOA, osteoarthritis; cHT, hypertenson; dNT, normotension; eCI, confidence interval, fBMI, body mass index; g ND, non-done, hW/H, waist/hip, iVASP, pain visual analog scale; jVASGH, General health visual analog scale; kHAQ, Health assessment questionnaire; lDAS28-CRP, Disease activity score, 28 joints and C- 5 reactive protein; mDM, diabetes mellitus; nESR, erythrocyte sedimentation rate; oCRP, C-reactive protein; pChol, plasma cholesterol, qTG, plasma trigycerides, rHDL, high- density lipoprotein, sLDL, low-density lipoprotein; tGlc, plasma glucose; uRF, rheumatoid factor; vNSAIDs, non-steroidal anti-inflammatory drugs; wMTX, methotrexate, yTNF, tumor necrosis factor; xACE-I, angiotensin-converting enzyme inhibitors; zBB, β-blockers; aaDIUR, diuretics; abATRA, angiotensin-II receptor antagonists; acCCB, calcium channel blockers; adAnti-HT, antihypertensives. 6

Comments to table 1-S Comparison of HT and NT (normotensive) RA and OA patients In both RA and OA patients, the HT subgroup was characterized by older patients and a higher proportion of the elderly, a longer duration of the disease (RA or OA), higher BMI and a greater proportion of overweight/obese patients, higher VASP, a higher proportion of dyslipidemic and DM patients and higher plasma LDL and triglyceride concentrations, compared with the NT patients. VASGH and HDL values were similar in HT and NT in both RA and OA patients. The following variables had dissimilar differences between HT and NT patients in RA and OA: the proportion of female HT and NT patients was similar in the RA group, but higher in the HT patients of the OA group; WHR was higher in HT RA patients than in NT RA patients, but similar in HT and NT OA patients; ESR, CRP, Chol, LDL, and Glc concentrations were higher in HT than in NT patients in the RA group, but were similar in the HT and NT patients in the OA group. (Statistically significant difference for CRP in OA was so small that had no clinical significance). Regarding variables measured only in the RA group, DAS28-CRP values and RF concentration were similar in the HT and NT patients, whereas HAQ was higher in the HT than in the NT patients. Comparing HT and NT patients regarding smoking the HT group had a higher proportion of nonsmokers, a similar proportion of ex-smokers, and a lower proportion of current smokers than did the NT group for both RA and OA. The smoking duration of ex-smokers was similar in among the HT and NT patients with RA and with OA. For current smokers, the duration of smoking was similar and the number of cigarettes per day was higher in HT RA patients than in NT RA patients and lower in HT OA patients than in NT OA patients. Regarding medications there were no statistically significant differences in the proportions of users of non-steroidal anti-inflammatory drugs (NSAIDs) between HT and NT patients in either the RA or OA group. The same was found for RA-specific medication, including various disease modifying anti-rheumatic drugs (DMARDs), glucocorticoids (GCs) and anti-tumor necrosis factor (anti-TNF) drugs. An exception to this finding was leflunomide, with a higher proportion of users in HT group and the use was associated with a higher prevalence of HT. than in nonusers (69.4 in users % vs. 58.1%, , P=0.048). Regarding GCs, only the duration of therapy was associated with HT; duration was longer in HT than in NT patients. The proportions of antihypertensive users, in terms of their general use and in terms of specific drugs, were higher in OA HT patients than in the RA HT patients, except in the case β- 7 blockers and angiotensin-II receptor antagonists, which were used by similar proportions of patients in both groups. Statins were used by a higher proportion of HT than NT patients in both the RA and OA groups, and the proportion of HT users was higher in OA than in RA patients. Comparison of hypertensive RA and OA patients The HT OA subgroup was characterized by higher age, a greater proportion of elderly patients, longer awareness of HT, higher BMI, a greater proportion of overweight/obese patients, a higher proportion of dyslipidemic and DM patients, and higher TG and Glc concentrations compared to HT RA patients. In contrast, the disease duration (RA or OA) was longer and ESR, CRP and LDL concentrations were higher in HT RA than in HT OA patients. The proportion of females, WHR, VASP, VASGH and Chol, HDL and creatinine concentrations were similar in HT RA and OA patients. 8

Table 2-S. Logistic regression analysis with HTa as dependent variable. Variable OR (95%CI) P-value RAb group (n=627) Age 1.063 (1.038-1.090) <0.001 RA_duration 1.018 (0.985-1.053) 0.289 BMIc 1.108 (1.047-1.173) <0.001 W/Rd ratio 0.620 (0.042-9.193) 0.728 VASPe 1.006 (0.995-1.017) 0.304 HAQf 0.972 (0.718-1.315) 0.853 Dyslipidemia 1.316 (0.805-2.1529 0.273 DMg 1.348 (0.445-4.090) 0.597 ESRh 1.008 (0.995-1.022) 0.217 Choli 1.002 (0.921-1.089) 0.971 LDLj 1.047 (0.806-1.360) 0.732 TGk 1.206 (0.920-1.581) 0.174 Creatinine 1.014 (1.000-1.028) 0.042 Glcl 1.113 (0.874-1.418) 0.386 Cigarette per day 0.977 (0.943-1.013 0.212 Glucocorticoid . duration of therapy 1.036 (0.976-1.099) 0.246 OAm group (n=352) Age 1.052 (1.020-1.085) 0.001 OA duration 1.036 (0.994-1.079) 0.095 BMIc 1.126 (1.051-1.207) 0.001 VASPd 1.023 (1.009-1.037) 0.001 Dyslipidemia 1.818 (1.011-3.270) 0.046 DMe 1.606 (0.637-4.046) 0.315 TGf 1.223 (0.875-1.710) 0.239 Cigarettes per day 0.950 (0.890-1.014) 0.126 Variables significantly different between HT and NT subgroups (table 1-S) were introduced in the model. HTa, hypertension; RAb, rheumatoid arthritis; BMIc , body mass index; W/Rd ,waist/hip; VASPe,pain visual analog scale; HAQf, Health assessment questionnaire;DMg ,diabetes mellitus; ESRh erythrocyte sedimentation rate; Choli,plasma cholesterol;LDLj low-density lipoprotein, TGk plasma triglicerides; Glcl , plasma glucose, mOA, osteoarthritis,.