International Journal of Rheumatic Diseases 2015; 18: 873–879
ORIGINAL ARTICLE
Comorbidities in patients with psoriatic arthritis: a comparison with rheumatoid arthritis and psoriasis Kemal NAS,1 Murat KARKUCAK,2 Bekir DURMUS,3 Saliha KARATAY,4 Erhan CAPKIN,2 Arzu KAYA,5 Derya UCMAK,6 Zeynel Abidin AKAR,7 Remzi CEVIK,7 Erkan KILIC,8 Gamze KILIC8 and Salih OZGOCMEN8 1
Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Sakarya University, Sakarya, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Karadeniz Technical University, Trabzon, 3Erenkoy Physical Medicine and Rehabilitation Hospital, Faculty of Health Sciences, Association of Public Hospitals Northern Anatolian Region of Istanbul, Istanbul, 4Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Gazi University, Ankara, 5 Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Firat University, Elazig, 6Department of Dermatology, 7 Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Dicle University, Diyarbakir, and 8Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Erciyes University, Kayseri, Turkey 2
Abstract Aim: Psoriatic arthritis (PsA) is a chronic, inflammatory disease. The purpose of this study was to examine the association between PsA and comorbid conditions. This is the first study to investigate comorbid diseases in PsA in Turkey. Methods: This study was performed under the auspices of the Anatolian Group for the Assessment in Rheumatic Diseases (ANGARD) and involved participation by six university research hospitals. Patients diagnosed with and treated for PsA on the basis of clinical, radiological and laboratory findings and expert opinion were monitored using standardized examination methods and jointly prepared forms. Clinical status, accompanying systemic diseases and surgical history were recorded. Results: One hundred and seventy-three patients with PsA (75 male, 98 female, mean age 41.8) and 138 patients with rheumatoid arthritis (RA) (17 male, 121 female, mean age 48.6) and 67 with psoriasis (PsO) (43 male, 24 female, mean age 36.1) were included in the study. No accompanying disease was determined in 72.8% of PsA, 50.0% of RA and 80.6% of PsO groups. In regression analysis, patients with PsA had higher risk for cataract/glaucoma surgery (odds ratio [OR] = 11.99; 95% CI 1.36–105.4, P = 0.025) compared to patients with RA, and higher risk for hypertension (HT) (OR = 4.26; 95% CI 1.27–14.23, P = 0.018) compared to the patients with PsO. Conclusion: Patients with PsA have relatively lower frequency of comorbidities like diabetes mellitus, HT and cataract/glaucoma surgery compared to the patients with RA. The increased risk for having cataract/glaucoma surgery in RA compared to PsA may be particularly attributed to the more prevalent glucocorticoid use in RA. Key words: comorbid diseases, psoriasis, psoriatic arthritis, rheumatoid arthritis. Correspondence: Kemal Nas, MD, PhD. Professor, Division of Rheumatology, Department of Physical Medicine and Rehabilitation, School of Medicine, Sakarya University, Korucuk, Sakarya, 54290 Turkey. Fax: +90-264-2759192. Email: [email protected]
INTRODUCTION In addition to inflammatory arthritis, chronic inflammatory diseases often lead to multiple organ and system involvement.1 Comorbidities accompanying the
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
K. Nas et al.
systemic involvement adversely affect the course of the disease, increase mortality rates and raise the economic costs of the disease.2 Survival studies in rheumatic diseases cite accompanying comorbidities, uncontrolled inflammation, disease severity, disease-modifying antirheumatic drugs (DMARDs) used and the side-effects of drugs such as glucocorticoids and anti-tumor necrosis factor (anti-TNF) blockers among the factors affecting mortality.3,4 The interaction between inflammatory diseases with mortality and related factors has been investigated mostly in RA. The high mortality rates in RA are attributed to comorbidities, particularly cardiovascular diseases, increased incidence of infections, the development of various malignancies, smoking and the drugs used in the treatment.5,6 An increased prevalence of cardiovascular diseases such as myocardial infarction and stroke has been determined in RA.7 Cardiovascular diseases have been the most investigated elements in terms of risk factors associated with comorbid diseases in RA. Cardiovascular risk factors such as hypertension, hypercholesterolemia, hyperglycemia and smoking are more common in patients with RA compared to the normal population. Depression, gastrointestinal ulcers, hepatitis B and C infections and asthma and chronic obstructive pulmonary disease are all seen more frequently in patients with RA compared to the normal population.8 Studies assessing comorbidities in various inflammatory diseases are usually compared against RA. Psoriatic arthritis (PsA) is a chronic inflammatory disease capable of involving the peripheral and axial joints in addition to the skin and various organs. The patterns of PsA involvement are symmetric or asymmetric arthritis, distal interphalangeal predominant arthritis, spondylitis and arthritis mutilans.9 Psoriasis (PsO) usually antedates arthritis in 80% of patients with PsA.10 A recent systematic review underscores that the results of comorbidity studies in PsA is inconsistent related to the heterogeneity of the control groups.11 A few studies have examined comorbid conditions in PsA; overall, those that have compared comorbidities to general population/healthy controls have shown an increased cardiovascular risk in PsA,12–15 whereas various results were reported in studies using RA as the controls.15–17 In addition to chronic systemic inflammation increasing cardiovascular risk in PsA, previous PsO is usually present. Therefore, some of the studies have compared PsA with PsO as the control group. However, coexisting cutaneous and joint involvement in PsA may cause an overwhelming inflammatory status and alter the risk of comorbidity. In that case the use of an appropriate
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control group versus PsA is particularly important. Only a few studies compared comorbidity in patients with PsA versus patients with both RA and PsO.15–18 In the present study, patients with PsA were compared with RA and PsO, in order to establish two separate groups of one with inflammatory arthritis and one with cutaneous involvement. Considering the genetic background of the disease and differences across populations, assessing the comorbidities in different races, like a Turkish population, also gains importance. Therefore the aim of this study was to investigate comorbid conditions in patients with PsA and to compare these with control groups consisting of patients with RA and PsO.
METHODS This study was conducted under the auspices of the Anatolian Group for the Assessment in Rheumatic Diseases (ANGARD). This group is a scientific collaboration of Turkish physiatrists and rheumatologists. Its primary aim is to organize and conduct clinical trials and to disseminate knowledge in the field of musculoskeletal medicine. The group has issued publications in the field of rheumatic diseases.19–26 ANGARD centers participating in this study were university hospitals serving as tertiary centers in their regions. ANGARD first proposed and designed the aims and methodology in this study. Patients were recruited consecutively (between January 2010 and February 2014) from the joint database of the rheumatology clinics of six university hospitals located in the eastern part of Turkey (Firat University, Elazig; Ataturk University, Erzurum; Dicle University, Diyarbakir; Karadeniz Technical University, Trabzon, Erciyes University, Kayseri; and Inonu University, Malatya). Patients were evaluated using standardized examination protocols and case report forms adopted during meetings with researchers from these centers. This database contains records on patients meeting the 2010 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) criteria for the classification of RA27 and Classification Criteria for Psoriatic Arthritis (CASPAR) criteria for PsA.28 The diagnosis of psoriasis is usually made upon clinical examination of the skin; however, the histopathologic examination was made when the clinical diagnosis was obscure. Consecutive patients with PsA were included in these centers. Also age- and gendermatched control patients with RA as well as patients with PsO who were attending to the rheumatology outpatient clinics or referred from the dermatology clinics
International Journal of Rheumatic Diseases 2015; 18: 873–879
Comorbidities in psoriatic arthritis
Table 1 Demographic and clinical features of the patient groups PsA (n = 173)
Age (years) Years since first symptom Years since diagnosis Height (cm) Weight (kg) BMI (kg/m2) ESR (mm/h) CRP (mg/dL) Current smokers (%) CS use (%) Female gender (%)
RA (n = 138)
PsO (n = 67)
PsA vs. RA
PsA vs. PsO
Mean
SD
Mean
SD
Mean
SD
P
P
41.89 8.96 7.70 164.76 73.31 27.10 23.62 6.49 35.3 20.2 56.6
12.36 8.01 7.68 8.90 14.20 5.53 19.83 9.61 NA NA NA
48.68 10.12 8.61 162.38 71.30 27.14 33.69 5.89 10.1 39.9 87.7
12.05 6.95 6.53 7.26 12.74 5.07 23.55 8.84 NA NA NA
36.1 11.47 10.18 167.59 70.58 25.18 13.50 1.76 31.3 41.8 35.8
13.97 8.66 8.31 8.05 12.74 4.63 12.73 2.61 NA NA NA
0.0001 0.175 0.265 0.01 0.198 0.937 0.0001 0.580 0.0001 0.0001 0.0001
0.004 0.042 0.029 0.024 0.172 0.007 0.0001 0.0001 0.566 0.001 0.004
Numbers in bold are significant. BMI, body mass index; CS, corticosteroid; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis.
for the study were included. All the patients in this study were assessed by specialists for the time between onset of symptoms and diagnosis, current cutaneous manifestations, onset of cutaneous manifestations and arthritis, swollen and tender joint counts, arthritis, inflammatory spinal pain and stiffness (lumbar, thoracic and cervical), enthesopathy, extra-articular features, comorbid systemic or other rheumatic diseases and medications being used. Data recorded on these forms included demographics (gender, age, height, weight, body mass index [BMI]), laboratory findings (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP] acute phase reactants) and Disease Activity Score of 28 joints (DAS28). Comorbid diseases and history of surgical interventions in the study and control groups were assessed from the medical history records or direct consultation by relevant specialists in terms of diabetes mellitus (DM), arterial hypertension (HT), coronary atherosclerotic heart disease (CAHD), cardiac failure/valve disease, hypo/ hyperthyroidism, chronic liver disease and cataract/ glaucoma surgery. All with DM or all with HT was defined as the total number of patients who had DM or HT alone or combined with other comorbidities.
Statistical analysis Statistical analysis was performed on a personal computer using Statistical Package for Social Sciences (SPSS 20.0; IBM, Armonk, NY, USA) software. Data were expressed as mean standard deviation or percentages. The Kolmogorov–Smirnov test was used to analyze the normality of distribution of variables. Categorical
International Journal of Rheumatic Diseases 2015; 18: 873–879
parameters were analyzed using the chi-square and Fisher’s exact tests. Differences between parameters were examined using the independent samples t-test. For comparisons between PsA and other groups (vs. RA and vs. PsO), we calculated the odds ratio (OR) and 95% confidence intervals (95% CI) for comorbid diseases adjusted by the confounding variables in RA: current age, symptom duration, gender, BMI, glucocorticoid use and current smoking; and in PsO: current age, gender, symptom duration, BMI and steroid use in a binary logistic regression model. A P-value < 0.05 was considered statistically significant.
RESULTS Demographic and clinical features of the patient groups are summarized in Table 1. One hundred and seventythree patients with PsA (75 male and 98 female, mean age 41.8) and 138 patients with RA (17 male, 121 female, mean age 48.6) and 67 patients with PsO (43 male, 24 female, mean age 36.1) were enrolled. The majority of patients with PsA (79.8%) also had current PsO, and musculoskeletal manifestations preceded the cutaneous findings in 16.6% of patients. Mean elapsed time between first symptom and diagnosis (diagnostic delay) was 2.6 years in the PsA group. Table 2 shows the crude distribution of comorbid diseases in patients with RA, PsO and PsA. The majority of patients with PsA (73.8%) had no comorbid diseases or history of surgery. The crude percentages of all with DM (alone or combined with other comorbidities), all with HT (alone or combined with other
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Table 2 Distribution of comorbid diseases in patients with psoriatic arthritis, rheumatoid arthritis and psoriasis (crude percentages)
None DM HT DM + HT CAHD Cardiac failure/valve disease DM + CAHD DM + HT + CAHD Hypo/hyperthyroidism Chronic liver disease Others All with DM (alone or combined with other comorbidities) All with HT (alone or combined with other comorbidities) Cataract/glaucoma surgery
PsA n = 173
RA n = 138
PsO n = 67
PsA vs. RA P
PsA vs. PsO P
126 (72.8) 11 (6.4) 11 (6.4) 5 (2.9) 1 (0.6) 4 (2.3) 0 (0) 2 (1.2) 1 (0.6) 0 (0) 12 (7.0) 18 (10.4)
69 (50.0) 15 (10.9) 18 (13.0) 14 (10.1) 1 (0.7) 1 (0.7) 2 (1.4) 0 (0) 6 (4.3) 0 (0) 12 (8.7) 31 (22.5)
54 (80.6) 5 (7.5) 4 (6.0) 4 (6.0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (3.0) 1 (1.5) 2 (3.0) 5 (7.5)
< 0.0001 NS NS 0.015 NS NS NS NS 0.047 NS NS 0.004
NS NS NS NS NS NS NS NS NS NS NS NS
18 (10.4)
32 (23.2)
8 (11.9)
0.002
NS
1 (0.6)
15 (10.9)
0 (0)
0.0001
NS
Values present n (%). Numbers in bold are significant. CAHD, coronary atherosclerotic heart disease; DM, diabetes mellitus; HT, arterial hypertension; NS, not significant; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis.
comorbidities) and cataract/glaucoma surgery were significantly higher in the RA group compared to the patients with PsA.
Comparison of patients with PsA versus RA Logistic regression analysis adjusted for the variables with potential influence on comorbidities and exhibiting differences between groups, such as age, gender, time since onset of symptoms, current smoking status, BMI and steroid use, revealed that patients with RA had a higher risk for cataract/glaucoma surgery (OR = 11.99; 95% CI 1.36–105.4, P = 0.025) but not for DM (alone or combined with other comorbidities) (OR = 1.67; 95% CI 0.78–3.57, P = 0.186) and HT (alone or combined with other comorbidities) (OR = 1.59; 95% CI 0.74–3.43, P = 0.235).
Comparison of patients with PsO and PsA Patients with PsO were younger (36.1 13.97 vs. 41.9 12.36 years, P = 0.004), had a longer duration since onset of symptoms (11.5 8.66 vs. 8.9 8.01 years, P = 0.042), lower BMI (25.2 4.63 vs. 27.1 5.53, P = 0.007) and a higher rate of glucocorticoid use (41.8% vs. 20.2%, P = 0.001) than patients with PsA. Logistic regression analysis adjusted for the variables with potential influence on comorbidities, such as age, gender, time since onset of symptoms and
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BMI and steroid use, revealed that patients with PsA had a higher risk only for HT (alone or combined with other comorbidities) (OR = 4.26; 95% CI 1.27–14.23, P = 0.018).
DISCUSSION Mortality and morbidity, particularly cardiovascular conditions, increase in inflammatory rheumatic diseases.16 In addition to an increase in subclinical atherosclerosis and arterial stiffness in PsA, an increase in comorbid conditions, particularly cardiovascular conditions like traditional risk factors for dyslipidemia, HT, obesity and DM was also shown.11 Comorbid diseases accompanying spondyloarthropathies were investigated in various studies. Subclinical atherosclerosis and related cardiovascular comorbid conditions were shown to increase in ankylosing spondylitis (AS), which is the predominant disease in SpA.12,29 An increased risk of myocardial infarction (MI) was reported in patients with AS which was attributed to the systemic inflammation and changes in the lipid profile.30 A recent review emphasizes that inflammation is a new risk factor for cardiovascular morbidity.31 In addition, severity of inflammation is reported to exhibit a positive correlation with the risk increase. However, only a few studies have investigated comor-
International Journal of Rheumatic Diseases 2015; 18: 873–879
Comorbidities in psoriatic arthritis
bid diseases and related risk factors in PsA as yet. In addition to synovial and entheseal involvement, presence of PsO should also be considered as a risk factor for comorbidities. The prevalence of PsA in patients with PsO ranges between 6% and 42%.12 Several studies showed that cardiovascular morbidity and mortality increased in PsO. One long-term cohort study reported that the risk of mortality rises 1.5-fold more in patients with severe cutaneous involvement.18 These results underscored the potential correlation between cardiovascular risk and cutaneous inflammation. Joint involvement in patients with PsO may further increase the cardiovascular risk by leading to systemic inflammation. Studies therefore compared patients with PsA versus PsO in terms of comorbidity and cardiovascular risks. Ahlehoff et al.13 showed that the risk of cardiovascular mortality, MI and stroke was 1.2-fold higher in 34 300 patients with PsO compared to the general population, and the risk was much higher in those with severe cutaneous involvement and arthritis. Husted et al.32 compared patients with PsA and PsO and documented greater HT in patients with PsA, similar to our results. Inconsistent results were also reported in studies comparing comorbid conditions in patients with RA and PsA. Jamnitski et al.17 compared 489 patients with PsA and 353 patients with RA and determined no significant difference in cardiovascular risk. However, this was a postal survey and low response rate might have an influence on the results and also lack of a control group was also mentioned as the limitations of the study. Han et al.15 compared patients with RA, PsA and AS in terms of cardiovascular risk and determined a similar increased risk of hypertension, 1.3-fold, in all three diseases. Our study revealed a relatively increased percentage for HT in favor of RA which may be related to the high prevalence of corticosteroid usage in RA compared to patients with PsA. Han et al. also reported a greater prevalence of ischemic heart disease and atherosclerosis in all three diseases, but particularly the RA group, compared to the control group. The prevalence of ischemic heart disease was similar in both groups in our study. Additionally, Han et al.15 reported a similar risk of DM in all three disease groups (1.4, 1.5 and 1.2, respectively). Comparison of the demographic characteristics of the RA and PsA groups revealed significant differences in terms of age, one of the main factors associated with morbidity. Moreover, obesity is known to be a factor closely associated with cardiovascular diseases. Tam
International Journal of Rheumatic Diseases 2015; 18: 873–879
et al.33 determined significantly higher levels of obesity in patients with PsA compared to the control group. Similarly, BMI was significantly higher in the PsA group than in the PsO group and was adjusted in the logistic regression model as a potential confounder in our study. Corticosteroid use was significantly higher in patients with RA compared to the patients with PsA (P = 0.0001). Corticosteroids which are intensively used in RA may play an important role in comorbidity. Comorbid conditions that can be affected by corticosteroid use in our study, such as DM, hypertension and cataract surgery, were more common in the RA group. The European League Against Rheumatism (EULAR) has published recommendations concerning the management of cardiovascular risks in inflammatory diseases such as RA, PsA and AS.34 The levels of evidence for the recommendations regarding PsA are lower than those for RA. The insufficient number of studies on PsA and problems of heterogeneity and methodology among these studies may be the major cause. Our study has some limitations, such as the relatively low number of patients involved and the lack of a control group derived from the general population. However, it still provides important information regarding comorbid conditions that may be present in patients with PsA in the Turkish population.35 In conclusion, patients with PsA have lower percentages of comorbidities like DM, HT and cataract/glaucoma surgery compared to those with RA. The increase in comorbidity in the RA group may be particularly attributed to the glucocorticoids and non-steroid inflammatory drugs widely used in RA. Well-designed controlled studies are needed in order to elicit more robust results.
CONFLICT OF INTEREST None.
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clinical approach, management, and outcome. Crit Care Clin 18, 729–48. Goldblatt F, O’Neill SG (2013) Clinical aspects of autoimmune rheumatic diseases. Lancet 382, 797–808. Avi~ na-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D (2008) Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 59, 1690–7. Listing J, Gerhold K, Zink A (2013) The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatology (Oxford) 52, 53–61. Puttevils D, De Vusser P, Geusens P, Dens J (2014) Increased cardiovascular risk in patients with rheumatoid arthritis: an overview. Acta Cardiol 69, 111–8. Dougados M, Soubrier M, Antunez A et al. (2014) Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis 73, 62–8. Veale D, Rogers S, Fitzgerald O (1994) Classification of clinical subsets in psoriatic arthritis. Br J Rheumatol 33, 133–8. Huynh D, Kavanaugh A (2013) Psoriatic arthritis: current therapy and future directions. Expert Opin Pharmacother 14, 1755–64. Jamnitski A, Symmons D, Peters MJ, Sattar N, McInnes I, Nurmohamed MT (2013) Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review. Ann Rheum Dis 72, 211–6. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P (2005) Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 64(Suppl. 2), ii14–7. Ahlehoff O, Gislason GH, Charlot M et al. (2011) Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J Intern Med 270, 147–57. Gladman DD, Ang M, Su L, Tom BD, Schentag CT, Farewell VT (2009) Cardiovascular morbidity in psoriatic arthritis. Ann Rheum Dis 68, 1131–5. Han C, Robinson DW Jr, Hackett MV, Paramore LC, Fraeman KH, Bala MV (2006) Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol 33, 2167–72. Gabriel SE, Michaud K (2009) Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res Ther 11, 229. Jamnitski A, Visman IM, Peters MJ, Boers M, Dijkmans BA, Nurmohamed MT (2011) Prevalence of cardiovascular diseases in psoriatic arthritis resembles that of rheumatoid arthritis. Ann Rheum Dis 70, 875–6. Gelfand JM, Troxel AB, Lewis JD et al. (2007) The risk of mortality in patients with psoriasis: results from a population-based study. Arch Dermatol 143, 1493–9.
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19 Nas K, Karkucak M, Durmusß B et al. (2013) The performance of psoriatic arthritis classification criteria in Turkish patients with psoriatic arthritis. Int J Rheum Dis. doi: 10.1111/1756–185X.12158. [Epub ahead of print]. 20 Ozgocmen S, Akgul O, Altay Z et al. (2012) Expert opinion and key recommendations for the physical therapy and rehabilitation of patients with ankylosing spondylitis. Int J Rheum Dis 15, 229–38. 21 Ozgocmen S, Ardicoglu O, Kamanli A et al. (2009) Pattern of disease onset, diagnostic delay, and clinical features in juvenile onset and adult onset ankylosing spondylitis. J Rheumatol 36, 2830–3. 22 Nas K, Yildirim K, Cevik R et al. (2010) Discrimination ability of ASDAS estimating disease activity status in patients with ankylosing spondylitis. Int J Rheum Dis 13, 240–5. 23 Nas K, Sarac AJ, Gur A et al. (2011) Psychological status is associated with health related quality of life in patients with rheumatoid arthritis. J Back Musculoskelet Rehabil 24, 95–100. 24 Baysal O, Durmusß B, Ersoy Y et al. (2011) Relationship between psychological status and disease activity and quality of life in ankylosing spondylitis. Rheumatol Int 31, 795–800. 25 Durmus B, Altay Z, Baysal O et al. (2011) Can the patientreported outcome instruments determine disease activity in rheumatoid arthritis? Bratisl Lek Listy 112, 55–61. 26 Karatay S, Yildirim K, Ugur M et al. (2013) Prevalence of atopic disorders in rheumatic diseases. Mod Rheumatol 23, 351–6. 27 Aletaha D, Neogi T, Silman AJ et al. (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69, 1580–8. 28 Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H (2006) Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 54, 2665–73. 29 Capkin E, Kiris A, Karkucak M et al. (2011) Investigation of effects of different treatment modalities on structural and functional vessel wall properties in patients with ankylosing spondylitis. Joint Bone Spine 78, 378–82. 30 Mathieu S, Gossec L, Dougados M, Soubrier M (2011) Cardiovascular profile in ankylosing spondylitis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 63, 557–63. 31 John H, Kitas G (2012) Inflammatory arthritis as a novel risk factor for cardiovascular disease. Eur J Intern Med 23, 575–9. 32 Husted JA, Thavaneswaran A, Chandran V et al. (2011) Cardiovascular and othercomorbidities in patients with psoriatic arthritis: a comparison with patients with psoriasis. Arthritis Care Res (Hoboken) 63, 1729–35.
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33 Tam LS, Tomlinson B, Chu TT et al. (2008) Cardiovascular risk profile of patients withpsoriatic arthritis compared to controls – the role of inflammation. Rheumatology (Oxford) 47, 718–23. 34 Peters MJ, Symmons DP, McCarey D et al. (2010) EULAR evidence-based recommendations for cardiovascular risk
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management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 69, 325–31. 35 Yurdakul FG, Eser F, Bodur H, Gul U, Gonul M, Oguz ID (2014) Disease activity and related variables in patients with psoriatic arthritis. Arch Rheumatol 29, 8–13.
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ORIGINAL ARTICLE
Comorbidities in patients with psoriatic arthritis: a comparison with rheumatoid arthritis and psoriasis Kemal NAS,1 Murat KARKUCAK,2 Bekir DURMUS,3 Saliha KARATAY,4 Erhan CAPKIN,2 Arzu KAYA,5 Derya UCMAK,6 Zeynel Abidin AKAR,7 Remzi CEVIK,7 Erkan KILIC,8 Gamze KILIC8 and Salih OZGOCMEN8 1
Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Sakarya University, Sakarya, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Karadeniz Technical University, Trabzon, 3Erenkoy Physical Medicine and Rehabilitation Hospital, Faculty of Health Sciences, Association of Public Hospitals Northern Anatolian Region of Istanbul, Istanbul, 4Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Gazi University, Ankara, 5 Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Firat University, Elazig, 6Department of Dermatology, 7 Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Dicle University, Diyarbakir, and 8Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Erciyes University, Kayseri, Turkey 2
Abstract Aim: Psoriatic arthritis (PsA) is a chronic, inflammatory disease. The purpose of this study was to examine the association between PsA and comorbid conditions. This is the first study to investigate comorbid diseases in PsA in Turkey. Methods: This study was performed under the auspices of the Anatolian Group for the Assessment in Rheumatic Diseases (ANGARD) and involved participation by six university research hospitals. Patients diagnosed with and treated for PsA on the basis of clinical, radiological and laboratory findings and expert opinion were monitored using standardized examination methods and jointly prepared forms. Clinical status, accompanying systemic diseases and surgical history were recorded. Results: One hundred and seventy-three patients with PsA (75 male, 98 female, mean age 41.8) and 138 patients with rheumatoid arthritis (RA) (17 male, 121 female, mean age 48.6) and 67 with psoriasis (PsO) (43 male, 24 female, mean age 36.1) were included in the study. No accompanying disease was determined in 72.8% of PsA, 50.0% of RA and 80.6% of PsO groups. In regression analysis, patients with PsA had higher risk for cataract/glaucoma surgery (odds ratio [OR] = 11.99; 95% CI 1.36–105.4, P = 0.025) compared to patients with RA, and higher risk for hypertension (HT) (OR = 4.26; 95% CI 1.27–14.23, P = 0.018) compared to the patients with PsO. Conclusion: Patients with PsA have relatively lower frequency of comorbidities like diabetes mellitus, HT and cataract/glaucoma surgery compared to the patients with RA. The increased risk for having cataract/glaucoma surgery in RA compared to PsA may be particularly attributed to the more prevalent glucocorticoid use in RA. Key words: comorbid diseases, psoriasis, psoriatic arthritis, rheumatoid arthritis. Correspondence: Kemal Nas, MD, PhD. Professor, Division of Rheumatology, Department of Physical Medicine and Rehabilitation, School of Medicine, Sakarya University, Korucuk, Sakarya, 54290 Turkey. Fax: +90-264-2759192. Email: [email protected]
INTRODUCTION In addition to inflammatory arthritis, chronic inflammatory diseases often lead to multiple organ and system involvement.1 Comorbidities accompanying the
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
K. Nas et al.
systemic involvement adversely affect the course of the disease, increase mortality rates and raise the economic costs of the disease.2 Survival studies in rheumatic diseases cite accompanying comorbidities, uncontrolled inflammation, disease severity, disease-modifying antirheumatic drugs (DMARDs) used and the side-effects of drugs such as glucocorticoids and anti-tumor necrosis factor (anti-TNF) blockers among the factors affecting mortality.3,4 The interaction between inflammatory diseases with mortality and related factors has been investigated mostly in RA. The high mortality rates in RA are attributed to comorbidities, particularly cardiovascular diseases, increased incidence of infections, the development of various malignancies, smoking and the drugs used in the treatment.5,6 An increased prevalence of cardiovascular diseases such as myocardial infarction and stroke has been determined in RA.7 Cardiovascular diseases have been the most investigated elements in terms of risk factors associated with comorbid diseases in RA. Cardiovascular risk factors such as hypertension, hypercholesterolemia, hyperglycemia and smoking are more common in patients with RA compared to the normal population. Depression, gastrointestinal ulcers, hepatitis B and C infections and asthma and chronic obstructive pulmonary disease are all seen more frequently in patients with RA compared to the normal population.8 Studies assessing comorbidities in various inflammatory diseases are usually compared against RA. Psoriatic arthritis (PsA) is a chronic inflammatory disease capable of involving the peripheral and axial joints in addition to the skin and various organs. The patterns of PsA involvement are symmetric or asymmetric arthritis, distal interphalangeal predominant arthritis, spondylitis and arthritis mutilans.9 Psoriasis (PsO) usually antedates arthritis in 80% of patients with PsA.10 A recent systematic review underscores that the results of comorbidity studies in PsA is inconsistent related to the heterogeneity of the control groups.11 A few studies have examined comorbid conditions in PsA; overall, those that have compared comorbidities to general population/healthy controls have shown an increased cardiovascular risk in PsA,12–15 whereas various results were reported in studies using RA as the controls.15–17 In addition to chronic systemic inflammation increasing cardiovascular risk in PsA, previous PsO is usually present. Therefore, some of the studies have compared PsA with PsO as the control group. However, coexisting cutaneous and joint involvement in PsA may cause an overwhelming inflammatory status and alter the risk of comorbidity. In that case the use of an appropriate
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control group versus PsA is particularly important. Only a few studies compared comorbidity in patients with PsA versus patients with both RA and PsO.15–18 In the present study, patients with PsA were compared with RA and PsO, in order to establish two separate groups of one with inflammatory arthritis and one with cutaneous involvement. Considering the genetic background of the disease and differences across populations, assessing the comorbidities in different races, like a Turkish population, also gains importance. Therefore the aim of this study was to investigate comorbid conditions in patients with PsA and to compare these with control groups consisting of patients with RA and PsO.
METHODS This study was conducted under the auspices of the Anatolian Group for the Assessment in Rheumatic Diseases (ANGARD). This group is a scientific collaboration of Turkish physiatrists and rheumatologists. Its primary aim is to organize and conduct clinical trials and to disseminate knowledge in the field of musculoskeletal medicine. The group has issued publications in the field of rheumatic diseases.19–26 ANGARD centers participating in this study were university hospitals serving as tertiary centers in their regions. ANGARD first proposed and designed the aims and methodology in this study. Patients were recruited consecutively (between January 2010 and February 2014) from the joint database of the rheumatology clinics of six university hospitals located in the eastern part of Turkey (Firat University, Elazig; Ataturk University, Erzurum; Dicle University, Diyarbakir; Karadeniz Technical University, Trabzon, Erciyes University, Kayseri; and Inonu University, Malatya). Patients were evaluated using standardized examination protocols and case report forms adopted during meetings with researchers from these centers. This database contains records on patients meeting the 2010 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) criteria for the classification of RA27 and Classification Criteria for Psoriatic Arthritis (CASPAR) criteria for PsA.28 The diagnosis of psoriasis is usually made upon clinical examination of the skin; however, the histopathologic examination was made when the clinical diagnosis was obscure. Consecutive patients with PsA were included in these centers. Also age- and gendermatched control patients with RA as well as patients with PsO who were attending to the rheumatology outpatient clinics or referred from the dermatology clinics
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Table 1 Demographic and clinical features of the patient groups PsA (n = 173)
Age (years) Years since first symptom Years since diagnosis Height (cm) Weight (kg) BMI (kg/m2) ESR (mm/h) CRP (mg/dL) Current smokers (%) CS use (%) Female gender (%)
RA (n = 138)
PsO (n = 67)
PsA vs. RA
PsA vs. PsO
Mean
SD
Mean
SD
Mean
SD
P
P
41.89 8.96 7.70 164.76 73.31 27.10 23.62 6.49 35.3 20.2 56.6
12.36 8.01 7.68 8.90 14.20 5.53 19.83 9.61 NA NA NA
48.68 10.12 8.61 162.38 71.30 27.14 33.69 5.89 10.1 39.9 87.7
12.05 6.95 6.53 7.26 12.74 5.07 23.55 8.84 NA NA NA
36.1 11.47 10.18 167.59 70.58 25.18 13.50 1.76 31.3 41.8 35.8
13.97 8.66 8.31 8.05 12.74 4.63 12.73 2.61 NA NA NA
0.0001 0.175 0.265 0.01 0.198 0.937 0.0001 0.580 0.0001 0.0001 0.0001
0.004 0.042 0.029 0.024 0.172 0.007 0.0001 0.0001 0.566 0.001 0.004
Numbers in bold are significant. BMI, body mass index; CS, corticosteroid; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis.
for the study were included. All the patients in this study were assessed by specialists for the time between onset of symptoms and diagnosis, current cutaneous manifestations, onset of cutaneous manifestations and arthritis, swollen and tender joint counts, arthritis, inflammatory spinal pain and stiffness (lumbar, thoracic and cervical), enthesopathy, extra-articular features, comorbid systemic or other rheumatic diseases and medications being used. Data recorded on these forms included demographics (gender, age, height, weight, body mass index [BMI]), laboratory findings (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP] acute phase reactants) and Disease Activity Score of 28 joints (DAS28). Comorbid diseases and history of surgical interventions in the study and control groups were assessed from the medical history records or direct consultation by relevant specialists in terms of diabetes mellitus (DM), arterial hypertension (HT), coronary atherosclerotic heart disease (CAHD), cardiac failure/valve disease, hypo/ hyperthyroidism, chronic liver disease and cataract/ glaucoma surgery. All with DM or all with HT was defined as the total number of patients who had DM or HT alone or combined with other comorbidities.
Statistical analysis Statistical analysis was performed on a personal computer using Statistical Package for Social Sciences (SPSS 20.0; IBM, Armonk, NY, USA) software. Data were expressed as mean standard deviation or percentages. The Kolmogorov–Smirnov test was used to analyze the normality of distribution of variables. Categorical
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parameters were analyzed using the chi-square and Fisher’s exact tests. Differences between parameters were examined using the independent samples t-test. For comparisons between PsA and other groups (vs. RA and vs. PsO), we calculated the odds ratio (OR) and 95% confidence intervals (95% CI) for comorbid diseases adjusted by the confounding variables in RA: current age, symptom duration, gender, BMI, glucocorticoid use and current smoking; and in PsO: current age, gender, symptom duration, BMI and steroid use in a binary logistic regression model. A P-value < 0.05 was considered statistically significant.
RESULTS Demographic and clinical features of the patient groups are summarized in Table 1. One hundred and seventythree patients with PsA (75 male and 98 female, mean age 41.8) and 138 patients with RA (17 male, 121 female, mean age 48.6) and 67 patients with PsO (43 male, 24 female, mean age 36.1) were enrolled. The majority of patients with PsA (79.8%) also had current PsO, and musculoskeletal manifestations preceded the cutaneous findings in 16.6% of patients. Mean elapsed time between first symptom and diagnosis (diagnostic delay) was 2.6 years in the PsA group. Table 2 shows the crude distribution of comorbid diseases in patients with RA, PsO and PsA. The majority of patients with PsA (73.8%) had no comorbid diseases or history of surgery. The crude percentages of all with DM (alone or combined with other comorbidities), all with HT (alone or combined with other
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Table 2 Distribution of comorbid diseases in patients with psoriatic arthritis, rheumatoid arthritis and psoriasis (crude percentages)
None DM HT DM + HT CAHD Cardiac failure/valve disease DM + CAHD DM + HT + CAHD Hypo/hyperthyroidism Chronic liver disease Others All with DM (alone or combined with other comorbidities) All with HT (alone or combined with other comorbidities) Cataract/glaucoma surgery
PsA n = 173
RA n = 138
PsO n = 67
PsA vs. RA P
PsA vs. PsO P
126 (72.8) 11 (6.4) 11 (6.4) 5 (2.9) 1 (0.6) 4 (2.3) 0 (0) 2 (1.2) 1 (0.6) 0 (0) 12 (7.0) 18 (10.4)
69 (50.0) 15 (10.9) 18 (13.0) 14 (10.1) 1 (0.7) 1 (0.7) 2 (1.4) 0 (0) 6 (4.3) 0 (0) 12 (8.7) 31 (22.5)
54 (80.6) 5 (7.5) 4 (6.0) 4 (6.0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (3.0) 1 (1.5) 2 (3.0) 5 (7.5)
< 0.0001 NS NS 0.015 NS NS NS NS 0.047 NS NS 0.004
NS NS NS NS NS NS NS NS NS NS NS NS
18 (10.4)
32 (23.2)
8 (11.9)
0.002
NS
1 (0.6)
15 (10.9)
0 (0)
0.0001
NS
Values present n (%). Numbers in bold are significant. CAHD, coronary atherosclerotic heart disease; DM, diabetes mellitus; HT, arterial hypertension; NS, not significant; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis.
comorbidities) and cataract/glaucoma surgery were significantly higher in the RA group compared to the patients with PsA.
Comparison of patients with PsA versus RA Logistic regression analysis adjusted for the variables with potential influence on comorbidities and exhibiting differences between groups, such as age, gender, time since onset of symptoms, current smoking status, BMI and steroid use, revealed that patients with RA had a higher risk for cataract/glaucoma surgery (OR = 11.99; 95% CI 1.36–105.4, P = 0.025) but not for DM (alone or combined with other comorbidities) (OR = 1.67; 95% CI 0.78–3.57, P = 0.186) and HT (alone or combined with other comorbidities) (OR = 1.59; 95% CI 0.74–3.43, P = 0.235).
Comparison of patients with PsO and PsA Patients with PsO were younger (36.1 13.97 vs. 41.9 12.36 years, P = 0.004), had a longer duration since onset of symptoms (11.5 8.66 vs. 8.9 8.01 years, P = 0.042), lower BMI (25.2 4.63 vs. 27.1 5.53, P = 0.007) and a higher rate of glucocorticoid use (41.8% vs. 20.2%, P = 0.001) than patients with PsA. Logistic regression analysis adjusted for the variables with potential influence on comorbidities, such as age, gender, time since onset of symptoms and
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BMI and steroid use, revealed that patients with PsA had a higher risk only for HT (alone or combined with other comorbidities) (OR = 4.26; 95% CI 1.27–14.23, P = 0.018).
DISCUSSION Mortality and morbidity, particularly cardiovascular conditions, increase in inflammatory rheumatic diseases.16 In addition to an increase in subclinical atherosclerosis and arterial stiffness in PsA, an increase in comorbid conditions, particularly cardiovascular conditions like traditional risk factors for dyslipidemia, HT, obesity and DM was also shown.11 Comorbid diseases accompanying spondyloarthropathies were investigated in various studies. Subclinical atherosclerosis and related cardiovascular comorbid conditions were shown to increase in ankylosing spondylitis (AS), which is the predominant disease in SpA.12,29 An increased risk of myocardial infarction (MI) was reported in patients with AS which was attributed to the systemic inflammation and changes in the lipid profile.30 A recent review emphasizes that inflammation is a new risk factor for cardiovascular morbidity.31 In addition, severity of inflammation is reported to exhibit a positive correlation with the risk increase. However, only a few studies have investigated comor-
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bid diseases and related risk factors in PsA as yet. In addition to synovial and entheseal involvement, presence of PsO should also be considered as a risk factor for comorbidities. The prevalence of PsA in patients with PsO ranges between 6% and 42%.12 Several studies showed that cardiovascular morbidity and mortality increased in PsO. One long-term cohort study reported that the risk of mortality rises 1.5-fold more in patients with severe cutaneous involvement.18 These results underscored the potential correlation between cardiovascular risk and cutaneous inflammation. Joint involvement in patients with PsO may further increase the cardiovascular risk by leading to systemic inflammation. Studies therefore compared patients with PsA versus PsO in terms of comorbidity and cardiovascular risks. Ahlehoff et al.13 showed that the risk of cardiovascular mortality, MI and stroke was 1.2-fold higher in 34 300 patients with PsO compared to the general population, and the risk was much higher in those with severe cutaneous involvement and arthritis. Husted et al.32 compared patients with PsA and PsO and documented greater HT in patients with PsA, similar to our results. Inconsistent results were also reported in studies comparing comorbid conditions in patients with RA and PsA. Jamnitski et al.17 compared 489 patients with PsA and 353 patients with RA and determined no significant difference in cardiovascular risk. However, this was a postal survey and low response rate might have an influence on the results and also lack of a control group was also mentioned as the limitations of the study. Han et al.15 compared patients with RA, PsA and AS in terms of cardiovascular risk and determined a similar increased risk of hypertension, 1.3-fold, in all three diseases. Our study revealed a relatively increased percentage for HT in favor of RA which may be related to the high prevalence of corticosteroid usage in RA compared to patients with PsA. Han et al. also reported a greater prevalence of ischemic heart disease and atherosclerosis in all three diseases, but particularly the RA group, compared to the control group. The prevalence of ischemic heart disease was similar in both groups in our study. Additionally, Han et al.15 reported a similar risk of DM in all three disease groups (1.4, 1.5 and 1.2, respectively). Comparison of the demographic characteristics of the RA and PsA groups revealed significant differences in terms of age, one of the main factors associated with morbidity. Moreover, obesity is known to be a factor closely associated with cardiovascular diseases. Tam
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et al.33 determined significantly higher levels of obesity in patients with PsA compared to the control group. Similarly, BMI was significantly higher in the PsA group than in the PsO group and was adjusted in the logistic regression model as a potential confounder in our study. Corticosteroid use was significantly higher in patients with RA compared to the patients with PsA (P = 0.0001). Corticosteroids which are intensively used in RA may play an important role in comorbidity. Comorbid conditions that can be affected by corticosteroid use in our study, such as DM, hypertension and cataract surgery, were more common in the RA group. The European League Against Rheumatism (EULAR) has published recommendations concerning the management of cardiovascular risks in inflammatory diseases such as RA, PsA and AS.34 The levels of evidence for the recommendations regarding PsA are lower than those for RA. The insufficient number of studies on PsA and problems of heterogeneity and methodology among these studies may be the major cause. Our study has some limitations, such as the relatively low number of patients involved and the lack of a control group derived from the general population. However, it still provides important information regarding comorbid conditions that may be present in patients with PsA in the Turkish population.35 In conclusion, patients with PsA have lower percentages of comorbidities like DM, HT and cataract/glaucoma surgery compared to those with RA. The increase in comorbidity in the RA group may be particularly attributed to the glucocorticoids and non-steroid inflammatory drugs widely used in RA. Well-designed controlled studies are needed in order to elicit more robust results.
CONFLICT OF INTEREST None.
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