Arthritis Care & Research Vol. 72, No. 6, June 2020, pp 822–828 DOI 10.1002/acr.23910 © 2020 The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. BRIEF REPORT Impact of Comorbidity on Physical Function in Patients With Ankylosing Spondylitis and Psoriatic Arthritis Attending Rheumatology Clinics: Results From a Cross-­Sectional Study Cristina Fernández-Carballido,1 María A. Martín-Martínez,2 Carmen García-Gómez,3 Santos Castañeda,4 Carlos González-Juanatey,5 Fernando Sánchez-Alonso,2 Rosario García de Vicuña,6 Celia Erausquin-Arruabarrena,7 Javier López-Longo,8 María D. Sánchez,9 Alfonso Corrales,10 Estefanía Quesada-Masachs,11 Eugenio Chamizo,12 Carmen Barbadillo,13 Javier Bachiller-Corral,14 Tatiana Cobo-Ibañez,15 Ana Turrión,16 Emilio Giner,17 Javier Llorca,18 and Miguel A. González-Gay,19 on behalf of the Cardiovascular in Rheumatology Project Collaborative Group Objective. To evaluate the impact of comorbidities on physical function in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Methods. This was a cross-­sectional analysis of the baseline visit from the Cardiovascular in Rheumatology study. Multivariate models with physical function as the dependent variable (Bath Ankylosing Spondylitis Functional Index and Health Assessment Questionnaire for AS and PsA, respectively) were performed. Independent variables were a proxy for the Charlson Comorbidity Index (CCIp; range 0–27), sociodemographic data, disease activity (erythrocyte sedimentation rate [ESR] and Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] in AS; Disease Activity Score in 28 joints [DAS28] using the ESR in PsA), disease duration, radiographic damage, and treatments. Results were reported as beta coefficients, 95% confidence intervals (95% CIs), and P values. Results. We included 738 patients with AS and 721 with PsA; 21% of patients had >1 comorbidity. Comorbidity burden (CCIp) was independently associated with worse adjusted physical function in patients with PsA (β = 0.11). Also, female sex (β = 0.14), disease duration (β = 0.01), disease activity (DAS28-­ESR; β = 0.19), and the use of nonsteroidal antiinflammatory drugs (β = 0.09), glucocorticoids (β = 0.11), and biologics (β = 0.15) were associated with worse function in patients with PsA. A higher education level was associated with less disability (β = –0.14). In patients with AS, age (β = 0.03), disease activity (BASDAI; β = 0.81), radiographic damage (β = 0.61), and the use of biologics (β = 0.51) were independently associated with worse function on multivariate analyses, but CCIp was not. Conclusion. The presence of comorbidities in patients with PsA is independently associated with worse physical function. The detection and control of the comorbidities may yield an integral management of the disease. INTRODUCTION of therapy for patients with AS and PsA. Patients with AS have increased comorbidity when compared to the general popula- Physical function is a crucial consideration in patients tion, particularly with regard to some specific disorders, such as with spondyloarthritis (SpA) and, along with health-­ related cardiovascular disease (CVD) and osteoporosis (1). Patients with quality of life, is considered a major outcome in patients with PsA also have increased comorbidities, such as CVD, diabe- ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Fur- tes mellitus, metabolic syndrome, and depression, and more than thermore, functional improvement is one of the ultimate goals 50% have >1 comorbidity (2). Supported by AbbVie, Spain. Dr. González-Gay’s work was supported by Spain; 3Carmen García-Gómez, MD, PhD: Consorci Sanitari de Terrassa, Fondo de Investigaciones Sanitarias, Spain (grants PI06/0024, PI09/00748, Barcelona, Spain; 4Santos Castañeda, MD, PhD: Hospital Universitario de La PI12/00060, PI15/00525, PI18/00043, RD12/0009/0013 [RIER], and Princesa, IIS-IP, and cátedra UAM-Roche, Universidad Autónoma de Madrid, RD16/0012 [RIER]) and by the Instituto de Salud Carlos III, Spain. Madrid, Spain; 5Carlos González-Juanatey, MD, PhD: Hospital Lucus Augusti, 1 Cristina Fernández-Carballido, MD, PhD: Hospital Universitario San Lugo, Spain; 6Rosario García de Vicuña, MD, PhD: Hospital Universitario de Juan de Alicante, Alicante, Spain; 2María A. Martín-Martínez, MD, Fernando La Princesa, IIS-IP, Madrid, Spain; 7Celia Erausquin-Arruabarrena, MD, PhD: Sánchez-Alonso, MD, MSc: Sociedad Española de Reumatología, Madrid, Hospital Universitario Dr Negrín, Las Palmas, Spain; 8Javier López-Longo, 822 COMORBIDITY IMPACT ON PHYSICAL FUNCTION IN SpA | 823 Patients. For this study, 738 patients with AS (modified New SIGNIFICANCE & INNOVATIONS York criteria) and 721 with PsA (Moll and Wright criteria) were ana- • A large number of comorbidities has been identi- lyzed. The study was performed following the principles outlined fied in a nation-wide cohort of patients with spon- in the Helsinki Declaration, and written informed consent was dyloarthritis (SpA). obtained from all subjects before their inclusion in the CARMA pro- • Comorbidity burden was independently associat- ed with physical function in patients with psoriatic ject. The study protocol was approved by the Ethics Committee ­arthritis (PsA). for Clinical Research of Lugo, Galicia, Spain (protocol #2009/077). • Associations between female sex and worse phys- ical function and between higher education level Variables and operative definitions. Dependent and better function were identified in patients with variable. The main outcome was physical function, measured PsA. through the Spanish validated versions of the Bath Ankylosing • Associations between physical function and some well-known related factors, such as age, disease Spondylitis Functional Index (BASFI) in patients with AS, and the ­activity, and radiographic damage, were confirmed Health Assessment Questionnaire (HAQ) in patients with PsA. in Spanish patients with SpA. Independent variables. The independent variables includ- ed: 1) demographic data: age, sex, and education level; 2) disease activity: assessed in patients with AS by persistently Although both conditions have an impact on physical func- raised erythrocyte sedimentation rate (ESR) or C-­reactive pro- tion, which is directly related to disease activity and structural tein and by the Bath Ankylosing Spondylitis Disease Activity damage (3,4), other factors may also deteriorate physical func- Index (BASDAI), Spanish validated version; in patients with tion in patients with chronic inflammatory rheumatic diseases. For PsA, the Disease Activity Score in 28 joints (DAS28) using example, comorbidity has been found to be relevant in patients the ESR was used; 3) disease duration; 4) radiographic dam- with rheumatoid arthritis (RA), where functional status becomes age, defined in this study as “spinal radiographic changes” worse with increasing levels of comorbidity, independently of for AS and “presence of erosions” for patients with PsA, ob- disease activity (5). However, fewer studies have focused on the served in standard radiographs; 5) treatments for the rheu- impact of comorbidity on physical function in patients with AS and matic disease and comorbidities; 6) comorbidities recorded PsA, even though the physical function impairment and the quality as dichotomous variables and also quantitatively by using of life limitations of such patients are similar to those with RA (6). a proxy of the Charlson Comorbidity Index (CCI), which is Taking together all these considerations, the main purpose of the a well-­known validated index to measure comorbidity dis- current study was to analyze the impact of comorbidities on phys- ease status (8). The CCI is a weighted score of 19 different ical function in Spanish patients with AS and PsA. comorbidities, selected according to their potential influ- ence on mortality. The sum of the weights of each condition can range from 0 to 33, and the CCI score is an indicator PATIENTS AND METHODS of disease burden. The proxy we used (CCIp) consisted of Study design. This was a cross-­ sectional study draw- a ­minor modification of the original CCI, made by pooling all of ing on baseline data from the Cardiovascular in Rheumatology the tumors (solid, leukemia, and lymphoma) into a single item, (CARMA) project, an ongoing multicenter 10-­ year prospective named Cancer. The remaining comorbidities were collected national study of a cohort of patients with chronic inflammatory and rated as in the original CCI. Consequently, the sum of the rheumatic diseases. It included patients with RA, AS, and PsA, ­possible scores in our proxy ranged between 0 and 27. along with age-­and sex-­matched subjects without chronic inflam- matory rheumatic diseases from 67 randomly selected Spanish Statistical analysis. Descriptive analyses were performed outpatient rheumatology clinics (recruited from July 2010 to for the demographic and clinical variables. Afterward, bivariate ­January 2012). The patients’ recruitment criteria have previously analyses were conducted to investigate the associations between been published (7). the independent variables and physical function. Numerical MD, PhD: Hospital Universitario Gregorio Marañón, Madrid, Spain; 9María 18 Javier Llorca, MD, PhD: University of Cantabria, IDIVAL, Santander, Spain; D. Sánchez, MD: Hospital Universitario Clínico, Salamanca, Spain; 10Alfonso 19 Miguel A. González-Gay, MD, PhD: Hospital Universitario Marqués de Corrales, MD, PhD: Hospital Universitario Marqués de Valdecilla, Santander, Valdecilla, IDIVAL, Santander, Spain, and University of the Witwatersrand, Spain; 11Estefanía Quesada-Masachs, MD, PhD: Hospital Universitario Vall de Johannesburg, South Africa. Hebrón, Barcelona, Spain; 12Eugenio Chamizo, MD: Hospital Universitario No potential conflicts of interest relevant to this article were reported. de Mérida, Mérida, Spain; 13Carmen Barbadillo, MD: Hospital Universitario Address correspondence to Miguel A. González-Gay, MD, PhD, Servicio de Puerta de Hierro-Majadahonda, Madrid, Spain; 14Javier Bachiller-Corral, Reumatología, Hospital Universitario Marqués de Valdecilla, IDIVAL, Avenida MD: Hospital Universitario Ramón y Cajal, Madrid, Spain; 15Tatiana Cobo- Cardenal Herrera Oria s/n 39011, Santander, Spain. E-mail: miguelaggay@ Ibañez, MD, PhD: Hospital Universitario Infanta Sofía, Madrid, Spain; 16Ana hotmail.com. Turrión, MD, PhD: Hospital Universitario Príncipe de Asturias, Alcalá de Submitted for publication September 27, 2018; accepted in revised form Henares, Spain; 17Emilio Giner, MD: Hospital Obispo Polanco, Teruel, Spain; April 23, 2019. 824 | FERNÁNDEZ-­CARBALLIDO ET AL v­ariables were assessed using Student’s t-­ test or the Mann-­ Table 1. Comorbidities of the patients with ankylosing spondylitis Whitney U test. Qualitative variables were assessed by chi-­square, and psoriatic arthritis* Yates’ correction, or Fisher’s exact tests in 2 × 2 tables. To study AS PsA the association between single comorbidities or CCIp scores and Variable (n = 738) (n = 721) P 2 physical function, 2 different multivariate linear models were per- BMI, mean ± SD kg/m 27.4 ± 4.4 28.2 ± 4.7 <0.001† Hypertension 190 (25.7) 213 (29.5) 0.105 formed, with physical function as the dependent variable (BASFI Hypercholesterolemia 199 (27) 257 (35.6) <0.001† and HAQ, respectively), adjusted for potentially confounding Obesity (BMI ≥30) 186 (25.2) 209 (29.1) 0.097 ­factors. Current smokers 254 (34.4) 157 (21.8) <0.001† The selection of the independent variables in the multivari- Past smokers 240 (32.5) 227 (31.5) – Never smokers 244 (33.1) 337 (46.7) – ate models was based on those found to be statistically significant Myocardial infarction 21 (2.9) 11 (1.5) 0.085 in the bivariate analyses and also on clinical judgement. Estimates Congestive heart failure 4 (0.5) 7 (1.0) 0.344 for these associations are shown as beta coefficients, 95% con- Peripheral vascular 8 (1.1) 7 (1.0) 0.830 disease fidence intervals (95% CIs), and P values. All analyses were per- Dementia 1 (0.1) 0 (0.0) 0.323 formed using SPSS software, version 22.0. Statistical significance Chronic obstructive 20 (2.71) 9 (1.3) 0.045† was assumed at a P value less than 0.05. pulmonary disease Ulcer disease 32 (4.3) 26 (3.6) 0.476 Diabetes mellitus 52 (7.1) 61 (8.5) 0.312 RESULTS Cerebrovascular disease 3 (0.4) 0 (0.0) 0.087 Mild liver disease 20 (2.7) 33 (4.6) 0.057 Clinical and demographic features of the patients Hemiplegia 0 (0.0) 0 (0.0) – Moderate or severe 18 (2.4) 14 (1.9) 0.517 and comorbidities. We analyzed 1,459 patients (738 AS and renal disease 721 PsA) whose demographic and clinical features are summa- Diabetes mellitus with 3 (0.4) 5 (0.7) 0.458 rized in Supplementary Table 1, available on the Arthritis Care & end-organ damage Cancer‡ 17 (2.3) 16 (2.2) 0.914 Research web site at http://onlin​elibr​ary.wiley.com/doi/10.1002/ Moderate or severe liver 4 (0.5) 2 (0.3) 0.430 acr.23910/​abstract. Briefly, patients with AS had an earlier dis- disease ease onset and were younger at the time of study inclusion than Metastatic cancer 1 (0.1) 0 (0.0) 0.323 CCIp, median (IQR) 1 (1–1) 1 (1–1) 0.912 those with PsA. In addition, the AS cohort had a higher percent- CCIp = 1 585 (79.3) 567 (78.6) – age of men than that of patients with PsA. A similar percentage CCIp >1 153 (20.7) 154 (21.4) 0.769 of patients in both groups were receiving biologic therapies, * Values are the number (%) unless indicated otherwise. AS = but more patients with AS received nonsteroidal antiinflamma- ankylosing spondylitis; PsA = psoriatic arthritis; BMI = body mass index; CCIp = Charlson Comorbidity Index proxy; IQR = interquartile tory drugs (NSAIDs), whereas a higher number of patients with range (25–75). PsA used conventional synthetic disease-­modifying antirheumatic † Statistically significant. ‡ Solid tumors, leukemia, and lymphoma pooled. drugs (DMARDs), combined therapies (synthetic plus biologic DMARDs), and glucocorticoids. The comorbidities and CCIp percentages of the 2 groups are versus 3.0 [IQR 1.2–5.1] for those with CCIp = 1; P = 0.353). shown in Table 1. Regarding traditional CVD risk factors, patients However, we observed that patients with PsA and more comor- with PsA had a higher body mass index (BMI) and hypercholes- bidities had worse physical function (HAQ 0.75 [IQR 0.25–1.25] terolemia prevalence. In contrast, we found more current smokers for CCIp >1) than patients with just 1 comorbidity (HAQ 0.25 [IQR among patients with AS. Apart from a higher prevalence of chronic 0.0–0.75]; P < 0.001). obstructive pulmonary disease (COPD) among patients with AS and a nonsignificant increase of mild liver disease in patients Independent variables associated with physical with PsA, no other differences in the prevalence of the different function. AS cohort. On bivariate analyses (Table 2), physical comorbidities between the 2 groups were identified. Regarding function was associated with age, female sex, disease dura- the comorbidity burden, 21% of patients had >1 comorbidity tion, disease activity (BASDAI and ESR), and spinal radiograph- (CCIp >1) in both groups; more specifically, patients with AS had ic damage. In addition, treatment with NSAIDs and glucocor- a mean ± SD CCIp of 1.32 ± 0.73, whereas those with PsA had ticoids was associated with physical function. In contrast, a a CCIp of 1.30 ± 0.66. higher education level was associated with less disability. We also identified an association between physical function and Physical function and comorbidity. When we analyzed some individual comorbidities (obesity, hypertension, hiatal physical function distribution (using BASFI in the AS group and hernia, thyroid disease, or an increase in triglycerides) or the HAQ for patients with PsA) across different levels of comorbidity, use of statins, on bivariate analyses. However, we did not iden- we did not detect differences in patients with AS (median BASFI tify an association between physical function and comorbidity 3.3 [interquartile range (IQR) 1.6–5.6] for patients with CCIp >1 burden (CCIp). COMORBIDITY IMPACT ON PHYSICAL FUNCTION IN SpA | 825 Table 2. Comorbidity and physical function: variables associated with BASFI in patients with AS and with HAQ in patients with PsA, unadjusted estimates* AS PsA Variables β 95% CI P β 95% CI P Age at inclusion 0.04 (0.03, 0.06) <0.001† 0.01 (0.00, 0.01) <0.001† Sex (ref. male) 0.74 (0.34, 1.14) <0.001† 0.36 (0.27, 0.44) <0.001† Disease duration 0.02 (0.01, 0.04) <0.001† 0.01 (0.01, 0.02) <0.001† Education level (ref. primary) Basic 1.07 (0.08, 2.05) 0.03† 0.23 (0.04, 0.24) 0.02† Secondary –0.16 (–0.59, –0.26) 0.45 –0.17 (–0.28, –0.06) <0.01† University –1.01 (–1.46, –0.56) <0.001† –0.24 (–0.35, –0.13) <0.001† CCIp 0.17 (–0.08, 0.41) 0.19 0.21 (0.14, 0.27) <0.001† Obesity 0.77 (0.36, 1.19) <0.001† 0.19 (0.09, 0.29) <0.001† Statins 0.66 (0.17, 1.15) 0.01† 0.08 (–0.02, 0.19) 0.13 Hypertension 0.74 (0.33, 1.15) <0.001† 0.20 (0.11, 0.30) <0.001† Triglycerides‡ 0.40 (0.15, 0.65) <0.001† 0.11 (0.05, 0.17) <0.001† GI bleeding 0.51 (–0.69, 1.71) 0.403 0.49 (–0.20, 1.19) 0.16 Hiatal hernia 1.39 (0.71, 2.07) <0.001† 0.17 (–0.02, 0.36) 0.07 Thyroid disease 1.60 (0.44, 2.76) 0.01† 0.18 (–0.01, 0.37) 0.06 NSAID 0.78 (0.41, 1.14) <0.001† 0.12 (0.03, 0.21) 0.01† Biologic DMARD 0.21 (–0.14, 0.58) 0.240 0.12 (0.03, 0.21) 0.01† GC 0.99 (0.33, 1.65) <0.001† 0.25 (0.13, 0.36) <0.001† DAS28-­ESR – NA – 0.24 (0.21, 0.27) <0.001† BASDAI 0.82 (0.77, 0.88) <0.001† – NA – ESR 0.03 (0.01, 0.04) <0.001† 0.01 (0.00, 0.01) <0.001† Radiographic damage§ 0.82 (0.31, 1.34) <0.001† 0.03 (–0.07, 0.14) 0.499 * The dependent variable for patients with ankylosing spondylitis (AS) was the Bath Ankylosing Spondylitis Functional Index (BASFI; range 0–10) and for patients with psoriatic arthritis (PsA) was the Health Assessment Questionnaire (HAQ; range 0–3). 95% CI = 95% confidence interval; CCIp = Charlson Comorbidity Index proxy; GI = gastrointestinal; NSAID = nonsteroidal antiinflammatory drug; DMARD = disease-­modifying antirheumatic drug; GC = glucocorticoids; DAS28-­ESR = Disease Activity Score in 28 joints using the erythrocyte sedimentation rate; NA = not applicable; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index. † Statistically significant. ‡ Triglycerides analyzed per 100 mg/dl increase. § Defined as “spinal radiographic damage” in patients with AS and “presence of erosions” in patients with PsA. In the multivariate model (Table 3), no association between DISCUSSION physical function and comorbidity burden (CCIp) was found. The present multicenter national survey indicates that the Furthermore, age, disease activity (measured by BASDAI and presence of comorbidities may decrease the reported physi- ESR), and spinal radiographic damage were associated with cal function of the patients with SpA. Comorbidity burden was higher disability. Also, treatment with biologic DMARDs was associated with physical function. At this point, no significant independently associated with physical function in patients with associations with sex or education level were identified in PsA. Moreover, the study confirmed that comorbidity is common patients with AS. among patients with SpA. However, some differences between PsA cohort. In patients with PsA, an independent associ- AS and PsA were observed. In this regard, some CVD risk fac- ation between comorbidity burden and physical function was tors, such as high BMI and hypercholesterolemia, were more observed (Table 2). In this regard, the increase in CCIp was sig- prevalent in patients with PsA. In addition, obesity was associated nificantly associated with higher disability (β = 0.11 [IQR 0.05– with worse function on bivariate analysis in such patients. Obesity 0.17]) on the adjusted multivariate model (Table 3). In addition, negatively influences not only CVD risk but also other disease out- we identified an association between physical function and age, comes. In this regard, being obese and overweight reduces the female sex, disease duration, disease activity (DAS28-­ESR), and chances to achieve minimal disease activity in patients with PsA use of NSAIDs, biologic DMARDs, and glucocorticoids, on bi- receiving traditional or biologic DMARD therapy (9). variate analyses. Apart from age, all of the above-­mentioned as- Smoking is known to be a harmful factor in patients with AS, sociations were confirmed in the multivariate model. Also, some leading to worse outcomes, including radiographic damage (10). comorbidities, such as obesity, hypertension, or the increase in In connection with that, in our survey we found that smoking habit triglycerides, were associated with physical function on bivariate and COPD were more common in patients with AS. Therefore, analysis. Interestingly, a higher education level was associated patients with AS should be encouraged to refrain from smoking with less disability in these patients. as soon as a diagnosis of the disease is made. 826 | FERNÁNDEZ-­CARBALLIDO ET AL Table 3. Comorbidity and physical function: variables associated with BASFI in patients with AS and with HAQ in patients with PsA, adjusted multivariate model* AS PsA Variables β 95% CI P β 95% CI P Age at inclusion 0.03 (0.02, 0.05) <0.001† 0.00 (–0.00, 0.00) 0.906 Sex (ref. male) –0.11 (–0.38, 0.16) 0.430 0.14 (0.06, 0.22) <0.001† Disease duration 0.01 (–0.00, 0.02) 0.095 0.01 (0.00, 0.01) 0.015† Education level (ref. primary) Basic 0.21 (–0.45, 0.86) 0.532 0.14 (–0.03, 0.31) 0.096 Secondary 0.01 (–0.26, –0.29) 0.925 –0.08 (–0.17, –0.01) 0.093 University –0.22 (–0.52, 0.08) 0.154 –0.14 (–0.24, –0.04) 0.004† CCIp 0.03 (–0.13, 0.20) 0.701 0.11 (0.05, 0.17) <0.001† NSAID 0.11 (–0.14, 0.37) 0.390 0.09 (0.02, 0.17) 0.017† Biologic DMARD 0.51 (0.27, 0.76) <0.001† 0.15 (0.07, 0.23) <0.001† GC 0.03 (–0.40, 0.46) 0.899 0.11 (0.01, 0.21) 0.026† DAS28-­ESR – NA – 0.19 (0.16, 0.22) <0.001† BASDAI 0.81 (0.75, 0.86) <0.001† – NA – ESR 0.01 (0.00, 0.02) 0.013† – NI – Radiographic damage‡ 0.61 (0.28, 0.95) <0.001† – NI – * The dependent variable for patients with ankylosing spondylitis (AS) was the Bath Ankylosing Spondylitis Functional Index (BASFI; range 0–10) and for patients with psoriatic arthritis (PsA) was the Health Assessment Questionnaire (HAQ; range 0–3). 95% CI = 95% confidence interval; CCIp = Charlson Comorbidity Index proxy; NSAID = nonsteroidal antiinflammatory drug; DMARD = disease-­modifying antirheumatic drug; GC = glucocorticoids; DAS28-­ESR = Disease Activity Score in 28 joints using the erythrocyte sedimentation rate; NA = not applicable; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; NI = not included in the multivariate model. † Statistically significant. ‡ Defined as “spinal radiographic damage” in patients with AS and “presence of erosions” in patients with PsA. Interestingly, we identified a relationship between comorbidity explain such a discrepancy. Moreover, since comorbidity has burden and physical function in patients with PsA. The most com- been reported to be a major contributor to functional limitation monly reported factors affecting physical function in patients with in late AS (13), this association may be more evident in patients PsA are disease activity and radiographic damage (4). However, with longstanding AS, due to the increase of comorbidities with we believe that comorbidity may also exert some negative influ- aging. ence on the physical function of patients with PsA, and our results Our study also revealed an association between female support this view. In this case, the measurement of physical func- sex and worse function in patients with PsA. This finding is in tion would reflect not only the disease process but also other fac- agreement with previous reports that showed an association of tors related to the patients’ general health. In this way, a recent female sex with worse function and quality of life (14). In patients study from the Assessment of Spondyloarthritis international Soci- with AS, we identified an association between female sex and ety Comorbidities in Spondyloarthritis cohort identified a relation- worse function, but the association was not confirmed on the ship between comorbidity and functional status in patients with adjusted multivariate model. The impact of sex on function is axial and peripheral SpA (11). The understanding of the different still unclear in patients with AS, with some cross-­sectional stud- causes that impact the functional disability becomes more relevant ies reporting worse function among women with AS, whereas now that remission-­inducing therapies are available. However, the a prospective study did not identify sex differences in dis- disability related to causes different from the disease itself may ease activity or physical function over time in AS (15). In our not be improved if they are not properly detected. Therefore, rec- study, although the bivariate analysis showed worse function in ognizing the comorbid conditions that overshadow the outcome women with AS, worse function was not confirmed by the mul- of patients with SpA is important. In fact, recommendations for tivariate model. their identification and management have been recently published The association between higher education level and lower (12). However, to ascertain the impact of the comorbidity control reported disability identified in our patients with PsA has already on long-­term outcomes such as function, longitudinal studies are been reported in patients with SpA (11). The fact that the educa- needed. tion level can influence the way in which the patients handle, or A recent study showed an association between comorbid- report, their disease process cannot be dismissed. ity burden and physical function in patients with SpA (11), but Finally, other well-­ recognized factors with an impact on we could not confirm this association in our patients with AS. physical function, such as age, disease activity, and radiographic ­Methodologic differences, such as different populations and the damage in patients with AS (3), as well as disease duration and use of different indexes to measure comorbidity burden, may disease activity in patients with PsA (4), were also associated with COMORBIDITY IMPACT ON PHYSICAL FUNCTION IN SpA | 827 worse function in our study. Likewise, the association between the Analysis and interpretation of data. Fernández-­ Carballido, Martín-­ use of biologics in AS, and the use of NSAIDs, glucocorticoids, Martínez, García-­Gómez, Castañeda, Sánchez-­Alonso, Llorca, González-­ Gay. and biologics in PsA, with worse physical function, would proba- bly indicate more severe disease. ROLE OF THE STUDY SPONSOR Among the strengths of our study, we highlight the large nationwide sample of patients from daily clinical practice that, AbbVie, Spain had no role in the study design or in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the unlike patients included in clinical trials, had different levels of decision to submit the manuscript for publication. Publication of this article comorbidity and disability. Thus, the results are representative of was not contingent upon approval by AbbVie, Spain. Spanish patients with SpA (AS and PsA) attending rheumatology outpatient clinics. REFERENCES Nevertheless, this study has several limitations. First, it had 1. Bremander A, Petersson IF, Bergman S, Englund M. Population-­ a cross-­ sectional nature, which precludes causal inferences. based estimates of common comorbidities and cardiovascular Second, we used a proxy of the CCI. However, we judged this disease in ankylosing spondylitis. Arthritis Care Res (Hoboken) 2011;63:550–6. proxy as a useful estimate of the comorbidity burden in our cohort, 2. Ogdie A, Schwartzman S, Husni ME. Recognizing and managing because the information collected was not complete to apply the comorbidities in psoriatic arthritis. Curr Opin Rheumatol 2015;27: original CCI. Since there is no standard comorbidity index cur- 118–26. rently used in rheumatology research, variations of the CCI are 3. Machado P, Landewé R, Braun J, Hermann KG, Baraliakos X, Baker used because they have been extensively validated throughout D, et al. A stratified model for health outcomes in ankylosing spon- dylitis. Ann Rheum Dis 2011;70:1758–64. different medical and research contexts. However, the CCI was 4. Husted JA, Tom BD, Farewell VT, Schentag CT, Gladman DD. A lon- primarily developed to predict mortality and not functional dis­ gitudinal study of the effect of disease activity and clinical damage on ability. Furthermore, our proxy was not able to overcome the fact physical function over the course of psoriatic arthritis: does the effect that the CCI does not include osteoporosis or depression, highly change over time? Arthritis Rheum 2007;56:840–9. 5. Radner H, Smolen JS, Aletaha D. Impact of comorbidity on phys- prevalent comorbidities in patients with AS and PsA that may also ical function in patients with rheumatoid arthritis. Ann Rheum Dis be relevant to physical disability. Third, although definitions for 2010;69:536–41. radiographic damage in both diseases were used in the CARMA 6. Zink A, Thiele K, Huscher D, Listing J, Sieper J, Krause A, et al. study protocol, quantification of radiographic damage by using Healthcare and burden of disease in psoriatic arthritis: a comparison with rheumatoid arthritis and ankylosing spondylitis. J Rheumatol validated scores was not performed. This fact may explain the 2006;33:86–90. lack of association between function and radiographic damage 7. Castañeda S, Martín-Martínez MA, González-Juanatey C, Llorca J, in patients with PsA. Nevertheless, since several studies have García-Yebenes MJ, Pérez-Vicente S, et al. Cardiovascular morbidity shown a close relationship between radiographic progression and and associated risk factors in Spanish patients with chronic inflam- matory rheumatic diseases attending rheumatology clinics: baseline disease duration, the multivariate models performed in our study data of the CARMA Project. Semin Arthritis Rheum 2015;44:618–26. were also adjusted for the effects of disease duration. 8. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of In conclusion, as shown in our large series of patients with classifying prognostic comorbidity in longitudinal studies: develop- SpA who were followed up at outpatient rheumatology units, ment and validation. J Chronic Dis 1987;40:373–83. the presence of comorbidities may decrease the reported phys- 9. Lupoli R, Pizzicato P, Scalera A, Ambrosino P, Amato M, Peluso R, et al. Impact of body weight on the achievement of minimal disease ical function of patients with SpA. In this setting, a high preva- activity in patients with rheumatic diseases: a systematic review and lence of comorbidities has been shown. More importantly, as the meta-­analysis. Arthritis Res Ther 2016;18:297. comorbidity burden increases, the reported physical function of 10. Villaverde-García V, Cobo-Ibáñez T, Candelas-Rodríguez G, Seoane- the patients with PsA decreases. The detection and control of the Mato D, Campo-Fontecha PD, Guerra M, et al. The e ­ ffect of ­smoking on clinical and structural damage in patients with a ­ xial spondy- comorbidities may yield an integral management of the disease. loarthritis: a systematic literature review. Semin Arthritis Rheum 2017;46:569–83. AUTHOR CONTRIBUTIONS 11. Nikiphorou E, Ramiro S, van der Heijde D, Norton S, Moltó A, Dougados M, et al. Association of comorbidities in spondyloarthritis All authors were involved in drafting the article or revising it critically with poor function, work disability, and quality of life: results from for important intellectual content, and all authors approved the final version the Assessment of SpondyloArthritis International Society Comor- to be submitted for publication. Dr. González-­Gay had full access to all of bidities in Spondyloarthritis Study. Arthritis Care Res (Hoboken) the data in the study and takes responsibility for the integrity of the data 2018;70:1257–62. and the accuracy of the data analysis. Study conception and design. Fernández-­ Carballido, Castañeda, 12. Baillet A, Gossec L, Carmona L, de Wit M, van Eijk-Hustings Y, González-­Gay. Bertheussen H, et al. Points to consider for reporting, screening for Acquisition of data. Fernández-­ Carballido, Martín-­ Martínez, García-­ and preventing selected comorbidities in chronic inflammatory rheu- Gómez, Castañeda, González-­ Juanatey, Sánchez-­ Alonso, García de matic diseases in daily practice: a EULAR initiative. Ann Rheum Dis Vicuña, Erausquin-­ Arruabarrena, López-­ Longo, Sánchez, Corrales, 2016;75:965–73. Quesada-­Masachs, Chamizo, Barbadillo, Bachiller-­Corral, Cobo-­Ibañez, 13. Ward MM, Learch TJ, Gensler LS, Davis JC Jr, Reveille JD, Turrión, Giner, Llorca, González-­Gay. Weisman MH. Regional radiographic damage and functional limita- 828 | FERNÁNDEZ-­CARBALLIDO ET AL tions in patients with ankylosing spondylitis: differences in early and (Hospital General Universitario de Elda, Alicante); José M. Senabre, José late disease. Arthritis Care Res (Hoboken) 2013;65:257–65. C. Rosas (Hospital de la Marina Baixa, Alicante); Isabel Rotés, Estefanía 14. Eder L, Thavaneswaran A, Chandran V, Gladman DD. Gender dif- Moreno, Alba Erra, Dolors Grado (Hospital de San Rafael, Barcelona); ference in disease expression, radiographic damage and disability Javier Calvo, Amalia Rueda (Hospital General Universitario, Valencia); among patients with psoriatic arthritis. Ann Rheum Dis 2013;72: Ingrid Möller, Isabel Rodríguez (Instituto Poal, Barcelona); Enrique Raya, 578–82. Pilar Morales, Ana Nieto, Inmaculada Jiménez, Cesar Magro (Hospital Clínico Universitario San Cecilio, Granada); Ana Ruibal Escribano (Hos- 15. Webers C, Essers I, Ramiro S, Stolwijk C, Landewé R, van der pital Santiago Apostol, Vitoria-­Gasteiz); Sergio Ros Expósito (Hospital de Heijde D, et al. Gender-­attributable differences in outcome of ankylosing Viladecans, Barcelona); Ginés Sánchez Nievas, Enrique Júdez Navarro, spondylitis: long-­term results from the Outcome in Ankylosing Spondy- Manuela Sianes Fernández, María Angeles García Morales, Isabel litis International Study. Rheumatology (Oxford) 2016;55:419–28. Labiano Bastero, Gloria García Consuegra, Natalia Palmou (Hospital General de Albacete); Silvia Martínez Pardo, Manel Pujol, Elena Riera Alonso, Georgina Salvador (Hospital Mutua Terrassa, Terrassa); Beatriz González APPENDIX A: CARDIOVASCULAR IN RHEUMATOLOGY Alvarez, Alberto Cantabrana (Hospital Nuestra Sra. de Candelaria, Santa PROJECT COLLABORATIVE GROUP Cruz de Tenerife); Sagrario Bustabad, Esmeralda Delgado (Hospital Uni- versitario de Canarias, La Laguna, Tenerife); Alejandro Muñoz, Sergio Members of the Cardiovascular in Rheumatology (CARMA) Project Col- Rodriguez Montero, Luis María Jimenez (Hospital Universitario de Valme, laborative Group are as follows: Eugenia Gonzalez de Rabago, Elena Sevilla); Javier Rivera Redondo, Teresa Gonzalez Hernandez (Instituto Alonso Blanco Morales, J. Carlos Fernández Lopez, Natividad Oreiro Provincial de Rehabilitación, Madrid); Francisco J. González Polo (Hospi- Villar, Antonio Atanes Sandoval, Francisco J. Blanco García (Complejo tal de Cantoblanco, Madrid); Raul Menor Almagro (Hospital de Jerez de la Hospitalario A Coruña, Xubias de Arriba, A Coruña); Cayetano Alegre Frontera, Jerez de la Frontera, Cádiz); José M. Moreno, Carla Lannuzzelli De Miquel, María J. González Fernández, Ramón Huguet Codina, Barroso (Hospital Obispo Polanco, Teruel); Laura Cebrián Méndez, Beatriz Yoldi, Mercedes Ramentol (Instituto Dexeus, Barcelona); Gabriela María Teresa Navío (Hospital Infanta Leonor, Madrid); Encarnación Ávila, Sara Marsal Barril (Hospital Universitari Vall d’Hebron, Barcelo- Pagán, Pablo Mesa del Castillo (Hospital Los Arcos, Murcia); Esperanza na); Martina Steiner, Santiago Muñoz (Hospital Infanta Sofía, Madrid); Naredo, Ana Cruz (Hospital Severo Ochoa, Madrid); Isabel Mateo, Julio Fernando Gamero, José García Torón (Hospital S. Pedro de Alcántara, Sánchez, María Galindo, Javier García González (Hospital Universitar- Cáceres); Pilar Espino, Inmaculada Ros, Mónica Ibáñez, Claudia Murillo io 12 de Octubre, Madrid); Eduardo Collantes, Desiree Ruiz, Pilar Font (Hospital Son Llatzer, Palma de Mallorca); Jesús Tornero Molina (Hos- (Hospital Universitario Reina Sofía, Córdoba); Gema Bonilla (Hospital pital Universitario de Guadalajara); Raimon Sanmartí, Horacio Berman, Universitario La Paz, Madrid); Antonio López Meseguer (Hospital Sonia Cabrera, Virginia Ruiz (Hospital Clinic i Provincial, Barcelona); Gutierrez Ortega, Valdepeñas, Ciudad Real); Manuel J. Moreno, María José Oscar Fontseré Patón, Benjamín Fernández Gutierrez, Lydia Abasolo Moreno Martínez, María Dolores Beteta Fernández, Luis F. Linares (Hos- (Hospital Clínico Universitario San Carlos, Madrid); Jose Manuel Pina pital Virgen de la Arrixaca, Murcia); Mercedes Morcillo, María L. González (Hospital de Barbastro, Huesca); Joan M. Nolla (Hospital Universitario Gómez (Hospital del Escorial, Madrid); Natalia A. Rivera, Olaia Fernán- de Bellvitge, Barcelona); Miriam García Arias, Mirem Uriarte-­Ecenarro, dez Berrizbeitia, María Luz García Vivar (Hospital de Basurto, Bilbao); Jesús A. García Vadillo (Hospital Universitario De La Princesa, Madrid); Manel Riera, Yolanda María León (Hospital Dos de Maig, Barcelona); Antonio Fernández Nebro, Sara Manrique Arija, María Angeles Belmonte Joan Maymó, Miriam Amirall, Silvia Iniesta Escolano, Silvia Sánchez Serrano, López, Inmaculada Ureña, María V. Irigoyen, Virginia Coret Cagigal María Pilar Lis Bona (Hospital del Mar, Barcelona); Jordi Fiter, Julia (Hospital Regional Universitario Carlos Haya, Málaga); Daniel Piel- Fernández Melón, Luis Espadaler (Hospital Universitario Son Espases, fort Garrido, Angel María García Aparicio, Rebeca Belmonte Gómez, Palma de Mallorca); Olga Maiz, Joaquín Belzunegui, Inmaculada Banegil Pastora Granados Bautista, Azucena Hernandez Sanz (Hospital Virgen (Hospital de Donostia, Donostia); César Díaz (Hospital de la Santa Creu i de la Salud, Toledo); ­Francisco J. Manero, Fernando Jimenez Zorzo, Sant Pau, Barcelona); Ramón Valls (Hospital de Palamós, Gerona); Iván Eugenio Giménez Ubeda, Jesús Marzo Gracía, Chesús Beltrán Audera, Castellví, María Bonet, Estefania Moreno Ruzafa (Hospital Comarcal de Marta Medrano, Ángela Pecondón (Hospital Universitario Miguel Servet, L’Alt Penedés, Vilafranca del Penedés, Barcelona); Jaime Calvo Alen Zaragoza); ­ Soledad Ojeda, Juan Carlos Quevedo, Félix Francisco, (Hospital Sierrallana, Torrelavega); Trinidad Pérez Sandoval (Complejo Carlos Rodríguez Lozano (Hospital Dr. Negrín, Las Palmas de Gran Canaria); Asistencial de León); Eva Revuelta Evrard (Hospital General de Ciudad Delia Gerona, Carlos González Fernández, Luis Carreño, Indalecio Real); Javier R. Godo, Cruz Fernández Espartero (Hospital General de Monteagudo (Hospital Gregorio Marañon, Madrid); Javier del Pino (Hos- Móstoles, Madrid); Francisco J. Navarro Blasco, José Antonio González pital Universitario de Salamanca); María Enriqueta Peiró (Hospital Univer- (Hospital General Universitario de Elche, Alicante); José A. Miranda-­Filloy sitario Marqués de Valdecilla, Santander); Cristina Fernández-­Carballido (Hospital Xeral Calde, Lugo).