Background: Approximately 1.5 million adults in Germany suffer from an inflammatory rheumatological condition. The most common among these are rheumatoid arthritis and spondyloarthritis—above all axial spondyloarthritis, including ankylosing spondylitis (Bekhterev’s disease) and psoriatic arthritis. These systemic inflammatory diseases often affect the heart as well.
Methods: This review is based on pertinent articles retrieved by a selective literature search, on current European guidelines, and on the authors’ clinical experience.
Results: Rheumatic inflammation of cardiac structures can manifest itself as pericarditis, myocarditis, or endocarditis. The heart valves and the intracardiac conduction system can be affected as well, leading to AV block. Functional sequelae, e.g., congestive heart failure, can arise as a consequence of any inflammatory rheumatic disease. The long-term mortality of rheumatic diseases is elevated predominantly because of the increased risk for cardiovascular comorbidities. The cardiovascular risk profile should therefore be re-evaluated regularly (e.g., at 5-year intervals) in cooperation with the patient’s primary care physician. The cardiovascular manifestations of rheumatic disease, such as pericarditis, myocarditis, and vasculitis, are treated initially with high-dose glucocorticoids and then over the long term with maintenance drugs such as methotrexate and azathioprine. Biological agents are sometimes used as well.
Conclusion: In patients with inflammatory rheumatic diseases, the elevated cardiovascular risk should be kept in mind and preventive measures should be initiated early. This subject should be further studied in controlled trials so that the treatment options for patients with cardiac involvement can be evaluated.
In Germany, approximately 1.5 million adults suffer from inflammatory rheumatological conditions (e1). The prevalences of these diseases are listed in the Table. The frequency of direct cardiac involvement and/or cardiovascular comorbidities varies between these conditions. In the past, pericarditis, myocarditis, endocarditis, and valvular heart disease were common cardiac manifestations of rheumatic disorders. Due to the advances in the treatment of rheumatoid arthritis (RA) and conditions within the spondyloarthritis (SpA) group, the prevalence of clinically relevant direct cardiac involvement—minor changes can still be visualized with modern diagnostic imaging (1)—is declining (2).
In contrast, cardiovascular comorbidities—besides musculoskeletal conditions such as osteoarthritis and osteoporosis—continue to attract increasing attention; cardiovascular comorbidities are observed in 70 to 80% of patients with RA, axial spondyloarthritis (axSpA), psoriasis arthritis (PsA), or systemic lupus erythematodes (SLE) (e2). Among patients with these conditions, the prevalences of arterial hypertension and coronary artery disease (CAD) are in the ranges of 26 to 36% and 7 to 13%, respectively (3).
Today, cardiovascular comorbidities are among the leading causes of death in patients with inflammatory rheumatological conditions (4) and there is a direct relationship between the inflammatory activity associated with these diseases and cardiovascular morbidity and mortality. The cardiovascular risk can be reduced by adequate disease control (5). The risks of CAD and cerebrovascular events are higher among RA patients by almost 60% and 50%, respectively. Accordingly, the cardiovascular mortality rate is 45% higher in RA patients compared to the general population (1707 versus 775 per 100 000 patient years) (6).
Lastly, the drugs used to treat inflammatory rheumatological conditions play a role, too. The cardiovascular risk of RA patients is dose-dependently increased by the long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, but decreased by methotrexate and TNF inhibitors (7). A cardioprotective effect was also demonstrated for hydroxychloroquine in RA und SLE patients (e3, e4). In patients with gout, colchicine has a cardioprotective effect (8).
The German Society of Rheumatology (DGRh, Deutsche Gesellschaft für Rheumatologie) issued clinical guidelines for the management of early RA (S3) and for the sequential pharmacotherapy of RA (S1) and axSpA (S3) (dgrh.de/qualitaetssicherung.html). For reasons of space, we have focused on the most important conditions.
We limited our selective literature search to the PubMed database, using as search terms the names of the diseases in conjunction with ”heart” or ”cardiac involvement”. Only selected references are listed in this article. Due to the limited data available, evidence grades could not often be reported.
Rheumatoid arthritis (RA) is the most common systemic inflammatory rheumatological condition with potential internal organ involvement. In patients with RA, signs of autoimmunity, such as rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs), but also antinuclear antibodies (ANAs), are observed. Organ involvement, for example interstitial lung disease and vasculitis, is more common in RF-positive and ACPA-positive patients (5, 10, e5). In RA, various cardiac structures may be affected (Box 1). Echocardiography frequently reveals a pericardial effusion without clinical significance (Figure) (1). Myocarditis or myocardial fibrosis are less common (11); cardiac amyloidosis is a rarity. Valvular changes, typically asymptomatic, are frequently reported. Patients with RA often suffer from impaired cardiac pump function and overt heart failure (12, 13). The cumulative incidence of heart failure among 80-year-old RA patients is at 36% almost twice has high as that among controls. While in controls “traditional” cardiovascular risk factors were responsible for the development of heart failure in the majority of cases (77%), this applied only to 54% of the RA patients (13). This difference may be explained by other RA-related risk factors such as myocarditis or heart valve defects.
RA patients have a slightly increased risk of atrial fibrillation (prevalence 3 to 4%) which has no effect on mortality (14). QT interval prolongation, a possible predictor of cardiovascular mortality in RA, was more commonly observed among RA patients (48%) than among normal controls.
Spondyloarthritis (SpA) is a family of inflammatory rheumatological conditions, sharing clinical signs and symptoms as well as a genetic predisposition (15). These are further differentiated based on prevailing clinical features or according to subtypes. The most important subtype is ankylosing spondylitis (AS, formerly known as Bechterew‘s disease), now classed in the axial spondyloarthritis disease family. The other subtypes are characterized by psoriasis, inflammatory bowel disease or preceding infection (reactive arthritis). Psoriatic arthritis (PsA) usually affects peripheral joints.
Other organs typically involved include the eyes (anterior uveitis) and, more rarely, the heart. Typical features of cardiac involvement in patients with AS (Box 2) include aortic valve disease and cardiac arrhythmia (16). The increased mortality observed in patients with AS is primarily due to cardiovascular comorbidity. The standardized mortality rate was 1.63 in men and 1.38 in women; 40% of the deaths were caused by cardiovascular disease (17).
Pathoanatomical characteristics of AS include involvement of the ascending aorta, especially of the aortic root, but also of subaortic structures, such as the membranous part of the interventricular septum and the base of the anterior mitral cusp where inflammation may lead to mitral regurgitation (18). Cardiac conduction abnormalities are also frequently observed in patients with AS (19, 20). Aortitis—today rather uncommon—can be observed in combination with typical aortic regurgitation. Its prevalences range between 3 and 18%, subject to age and disease duration. Patients with AS frequently undergo aortic valve surgery (18).
Besides the focal destruction of histological structures in the tunica media, the characteristic histopathological features of aortitis include thickening of the intima and adventitia as well as vascular obliteration (21). In addition to the potential thickening of the aorta and aortic valve, the fibrotic changes may extend below the aortic valve to form a subaortic bump.
The prevalence of significant cardiac conduction abnormalities, especially of high-degree atrioventricular (AV) blocks with clinically relevant bradyarrhythmia, is increased among AS patients (5%); this complication is associated with HLA (human leukocyte antigen) B27. In almost all cases, the AV node, which is located above the HIS bundles, is involved. These patients usually require pacemaker treatment (19, 20). AV blocks may also occur in otherwise healthy HLA-B27-positive individuals, usually in combination with aortic regurgitation. HLA-B27 positivity is more common among patients with pacemakers than in the general population (19).
In contrast, the prevalence of cardiac valve disease or conduction abnormalities is not increased among patients with PsA. Years ago, similar HLA-B27-associated aortic valve and AV node abnormalities were reported for patients with reactive arthritis (at that time referred to as Reiter‘s syndrome).
Today, the incidence and clinical relevance of acute rheumatic fever and even cardiac involvement in poststreptococcal reactive arthritis are regarded as being low (22).
There are only limited data available on the vascular, gastrointestinal or renal risks associated with NSAID treatment in patients aged <50 years with AS and PsA. However, an increase in risk is likely, especially among older patients and patients with relevant risk factors (heart failure, renal failure, history of ulcers). Yet, the risk among patients receiving short-term NSAID treatment (23) or constantly high NSAID doses is not increased (24). Two independently conducted studies with AS patients (17, 25) showed that not the intake of high NSAID doses, but of low doses was associated with increased mortality. These results indicate that there may also be beneficial effects of NSAIDs that should be taken into account in the overall evaluation of the use of NSAIDs in patients with chronic inflammatory disease.
Connective tissue disorders
Manifestations of systemic lupus erythematosus, scleroderma (progressive systemic sclerosis [PSS]), idiopathic inflammatory myopathy (IIM), including dermatomyositis and polymyositis, and mixed connective-tissue disease (MCTD) are found on various structures of the heart, representing a key differential diagnosis for endocarditis, myocarditis and pericarditis. However, the diagnosis of connective tissue disorders relies more on non-cardiac manifestations, such as skin changes and arthritis, in addition to the detection of autoantibodies (ANA, ENA, anti-dsDNA antibodies) which can be specific for some conditions.
Myocarditis occurs along with SLE and PSS in 10% and with IIM in 25% of cases (26). Regional wall motion abnormalities represent the first echocardiographic sign of myocarditis. The gold standard for the reliable diagnosis of myocarditis is endomyocardial biopsy. As a non-invasive technique, cardiac magnetic resonance imaging (cardiac MRI) can reveal signs of myocarditis (e.g. regional edema, late enhancement, wall motion abnormalities) at an early stage.
Cardiac involvement in PSS in the form of myocarditis and myocardial fibrosis with arrhythmia and potential right-sided heart failure in patients with pulmonary hypertension (scleroderma heart disease) is indicative of an unfavorable prognosis (27). Apart from routine cardiological investigations, right heart catheterization is indispensable for the quantitative assessment of pulmonary hypertension.
Pericarditis can occur with any connective tissue disorders; for example, it is found in 25 to 39% of SLE cases (e6, e7). Mitral valve involvement is typical of nonbacterial verrucous endocarditis (Libman–Sacks). In case of SLE-associated valvular deposits, antiphospholipid antibody levels should be measured.
In pregnant patients, anti-SS-A/Ro autoantibodies are associated with an increased risk of congenital heart block. In rare cases (approx. 2%), this conduction system dysfunction of the fetal heart is irreversible.
Vasculitis is characterized by cellular inflammation of the blood vessel wall which may cause ischemia and necrosis of down-stream tissues or organs as well as bleeding. Anti-neutrophil cytoplasmic antibodies (ANCAs) are found in patients with granulomatosis with polyangiitis (GPA/Wegner), microscopic polyangiitis (MPA) and in some patients with eosinophilic granulomatosis with polyangiitis (EGPA/Churg–Strauss), while no autoantibodies are present in patients with giant-cell arteritis (GCA/Horton) and Takayasu arteritis (TA).
Altogether, direct cardiac manifestations of the various types of systemic vasculitis are at 5 to 25% comparatively rare (28, e8). Pericarditis, myocarditis, endomyocardial fibrosis, vasculitis-related coronary ischemia, valve regurgitation, and/or arrhythmia may also occur (28, e9).
Malignant hypertension is a characteristic feature of panarteritis nodosa (PAN), a condition frequently associated with hepatitis-B virus (HBV) infection. In patients with TA, typically younger adults, heart involvement (aortic regurgitation, aortic aneurysm, vasculitis-related ischemia, pump failure) occurs more frequently than in patients with GCA (e9).
Cardiac involvement in rare rheumatic diseases
The most common (20 to 30%) cardiac manifestation in adult Still‘s disease is pericarditis (e10) which is usually accompanied by fever and polyserositis.
In patients with Behçet’s disease, cardiac manifestations are frequently observed (7–46%; e11), mainly in the form of pericarditis, including cases of constrictive pericarditis with hemorrhagic tamponade. Intracardiac thrombi, mostly in the right atrium, are the first manifestation of Behçet's disease in >50% of patients (e11). Coronary vasculitis as well as aortitis with aneurysmal dilation and aortic regurgitation may also occur—as is also observed for the rare relapsing polychondritis (e12). Aortic valve replacement is the most common cardiac surgery procedure undergone by patients with Behçet's disease (e13).
Secondary (AA) amyloidosis may, although rarely, develop in patients with longstanding and inadequately treated inflammatory rheumatological conditions (e14); in these cases, AA amyloid deposits can cause heart failure (e14).
The risk of major cardiovascular events (all cause caridovascular mortality, myocardial reinfarction, heart failure, re-revascularization due to ischemia) is higher in RA than in other rheumatic diseases (29). CHD prevalence in RA is at 16.6% higher compared to controls (odds ratio 1.35); the incidence rate of cardiovascular events is 7.8 per 1000 RA patient-years (30). In 80% of RA patients, at least one modifiable traditional cardiovascular risk factor is present (31). Arterial hypertension is more common among RA patients (57%); this may also apply to type 2 diabetes, but here the increase is not so clear. Among RA patients, the prevalences of increased body mass index, LDL cholesterol levels and smoking are within the normal range (31).
The prevalences and incidences of cardiovascular events are elevated in patients with AS and PsA (25, 32). Patients with psoriasis more frequently suffer from metabolic syndrome (e15). The increased mortality among AS patients is primarily due to cardiovascular comorbidity and the increased prevalence of risk factors (33). AS patients more often undergo coronary bypass surgery (e16).
Likewise, arteriosclerotic processes are induced and accelerated in patients with connective tissue disorders. Myocardial infarction in a young person can be indicative of an underlying connective tissue disorder. Due to their increased life expectancy, arteriosclerotic vasculopathy now manifests more frequently in these patients. It is important to provide advice and treatment for traditional risk factors—even though in only about half of the cases they are causing the disease. In SLE patients, it is critical to diagnose CHD at an early stage. Electron-beam CT (EBCT) and multidetector CT (MDCT) can be used to detect increased coronary calcium deposits (34); cardiac MRI is regarded as the best non-invasive technology to demonstrate inflammatory changes (35).
Recommendations for the management of cardiovascular comorbidities have been issued by the European League Against Rheumatism (EULAR) (36, Box 3). These should be followed to facilitate early intervention. The use of high-dose statins appear to reduce the risk of developing rheumatoid arthritis (e17). In patients with RA, statins reduce mortality by 20% (e18).
Antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are associated with the occurrence of necrotizing myopathy and the use of statins. However, this condition is rare and necrotizing myopathy also occurs in persons who never received such treatment (e19). The vast majority of patients treated with statins do neither develop anti-HMGCR antibodies nor signs and symptoms of myopathy (e20).
In some RA patients treated with the interleukin-6 receptor inhibitor tocilizumab, hypercholesterolemia occurred, but was not associated with an increased incidence of cardiovascular events; most likely because the anti-inflammatory effect of this drug outweighed the negative effect of increased cholesterol levels (e21).
Management and treatment of cardiovascular manifestations
In principle, whenever patients with certain rheumatic conditions, such as lupus erythematosus and polymyositis, present with increased disease activity, the cardiac manifestations of these diseases, such as pericarditis and myocarditis, should be taken into consideration and the corresponding diagnostic work-up should be initiated.
For some rheumatic diseases, such as scleroderma, routine follow-up echocardiography—for example, once per year—is recommended to enable the early detection of pulmonary arterial hypertension; the screening for this condition also relies on the heart failure marker NT-proBNP (e22). In long-term AS patients, echocardiography should be performed at 1- to 2-year intervals to facilitate early diagnosis of aortic-valve disease.
The initial treatment of direct inflammatory manifestations of rheumatological conditions, such as pericarditis, myocarditis and vasculitis, involves the use of high-dose glucocorticoids (37) and disease-modifying antirheumatic drugs, such as methotrexate (MTX) and azathioprine, among others. There are no controlled studies on cardiac involvement in rheumatic diseases available.
MTX is one of the few drugs with proven survival benefits in RA patients, primarily achieved by reducing cardiovascular mortality (38). In severe cases, biologicals, such as rituximab and tocilizumab, have been used successfully (39, 40). In adult Still‘s syndrome, interleukin-1 receptor antagonists were effective in treating myocarditis (e23).
Other manifestations and comorbidities are treated according to standard practice in cardiology.
Conflict of interest statement
Prof. Krüger has received lecture fees from Abbvie.
Prof. Manger has received consultancy fees from MSD and UCB and fees for a lecture or meeting preparation from Abbvie, MSD, Pfizer, and Roche.
Prof. Specker has received lecture fees from Roche.
Prof. Schneider has received reimbursement of meeting participation fees and travel expenses from MSD and Chugai.
Prof. Schneider and Prof. Braun received fees for a publication related to the topic.
Prof. Trappe declares that no conflict of interests exists.
Manuscript received on 3 May 2016; revised version accepted on 18 January 2017.
Translated from the original German by Ralf Thoene, MD.
Prof. Dr. med. Jürgen Braun
44649 Herne, Germany
For eReferences please refer to:
|1.||Corrao S, Messina S, Pistone G, Calvo L, Scaglione R, Licata G: |
Heart involvement in rheumatoid arthritis: systematic review and meta-analysis. Int J Cardiol 2013; 167: 2031–8 CrossRef MEDLINE
|2.||Turesson C: Extraarticular rheumatoid arthritis. Curr Opin Rheumatol 2013; 25: 360–6 CrossRef MEDLINE|
|3.||Krüger K: Therapie kardialer Risikofaktoren. Z Rheumatol 2016; 75: 173–82 CrossRef MEDLINE|
|4.||Nurmohamed MT, Heslinga M, Kitas GD: Cardiovascular comorbidity in rheumatic diseases. Nat Rev Rheumatol 2015; 11: 693–704 CrossRef MEDLINE|
|5.||Avina-Zubieta JA, Choi HK, Sadatsafavi M, et al.: Risk of cardiovascular mortality in patients with rheumatoid arthritis: a metaanalysis of observational studies. Arthritis Rheum 2008; 59: 1690–7 CrossRef MEDLINE|
|6.||Sparks JA, Chang SC, Liao KP, et al.: Rheumatoid arthritis and mortality among women during 36 years of prospective follow-up: Results from the Nurses’ Health Study. Arthritis Care Res (Hoboken) 2016; 68: 753–62 CrossRef MEDLINE PubMed Central|
|7.||Roubille C, Richter V, Starnino T, et al.: The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis 2015; 74: 480–9 CrossRef MEDLINE PubMed Central|
|8.||Solomon DH, Liu CC, Kuo IH, Zak A, Kim SC: Effects of colchicine on risk of cardiovascular events and mortality among patients with gout: a cohort study using electronic medical records linked with Medicare claims. Ann Rheum Dis 2016; 75: 1674–9 CrossRef MEDLINE PubMed Central|
|9.||Zink A, Albrecht K: How frequent are musculoskeletal diseases in Germany? Z Rheumatol 2016; 75: 346–53 CrossRef MEDLINE|
|10.||Kelly CA, Saravanan V, Nisar M, et al.: Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics—a large multicentre UK study. Rheumatology (Oxford) 2014; 53: 1676–82 MEDLINE MEDLINE|
|11.||Kobayashi Y, Giles JT, Hirano M, et al.: Assessment of myocardial abnormalities in rheumatoid arthritis using a comprehensive cardiac magnetic resonance approach: a pilot study. Arthritis Res Ther 2010; 12: R171 CrossRef MEDLINE PubMed Central|
|12.||Myasoedova E, Crowson CS, Nicola PJ, et al.: The influence of rheumatoid arthritis disease characteristics on heart failure. J Rheumatol 2011; 38: 1601–6 CrossRef MEDLINE PubMed Central|
|13.||Crowson CS, Nicola PJ, Kremers HM, et al.: How much of the increased incidence of heart failure in rheumatoid arthritis is attributable to traditional cardiovascular risk factors and ischemic heart disease? Arthritis Rheum 2005; 52: 3039–44 CrossRef MEDLINE|
|14.||Kim SC, Liu J, Solomon DH: The risk of atrial fibrillation in patients with rheumatoid arthritis. Ann Rheum Dis 2014; 73: 1091–5 CrossRef MEDLINE PubMed Central|
|15.||Braun J, Sieper J: Ankylosing spondylitis. Lancet 2007; 369: 1379–90 CrossRef|
|16.||Lautermann D, Braun J: Ankylosing spondylitis—cardiac manifestations. Clin Exp Rheumatol 2002; 20 (6 Suppl 28): S11–5 MEDLINE|
|17.||Bakland G, Gran JT, Nossent JC: Increased mortality in ankylosing spondylitis is related to disease activity. Ann Rheum Dis 2011; 70: 1921–5 CrossRef MEDLINE|
|18.||Roldan CA, Chavez J, Wiest PW, Qualls CR, Crawford MH: Aortic root disease and valve disease associated with ankylosing spondylitis. J Am Coll Cardiol 1998; 32: 1397–404 CrossRef|
|19.||Bergfeldt L, Edhag O, Vedin L, Vallin H: Ankylosing spondylitis: an important cause of severe disturbances of the cardiac conduction system. Prevalence among 223 pacemaker-treated men. Am J Med 1982; 73: 187–91 CrossRef|
|20.||Bergfeldt L, Insulander P, Lindblom D, Moller E, Edhag O: HLA-B27: an important genetic risk factor for lone aortic regurgitation and severe conduction system abnormalities. Am J Med 1988; 85: 12–8 CrossRef|
|21.||Bulkley BH, Roberts WC: Ankylosing spondylitis and aortic regurgitation. Description of the characteristic cardiovascular lesion from study of eight necropsy patients. Circulation 1973; 48: 1014–27 CrossRef MEDLINE|
|22.||van der Helm-van Mil AH: Acute rheumatic fever and poststreptococcal reactive arthritis reconsidered. Curr Opin Rheumatol 2010; 22: 437–42 CrossRef MEDLINE|
|23.||Aminoshariae A, Kulild JC, Donaldson M: Short-term use of nonsteroidal anti-inflammatory drugs and adverse effects: An updated systematic review. J Am Dent Assoc 2016; 147: 98–110 CrossRef MEDLINE|
|24.||Kroon FPB, van der Burg LRA, Ramiro S, et al.: Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis). Cochrane Database Syst Rev 2015; 17: CD010952 CrossRef|
|25.||Haroon NN, Paterson JM, Li P, Inman RD, Haroon N: patients with ankylosing spondylitis have increased cardiovascular and cerebrovascular mortality: a population-based study. Ann Intern Med 2015; 163: 409–16 CrossRef MEDLINE|
|26.||Mavrogeni S, Dimitroulas T, Kitas GD: Multimodality imaging and the emerging role of cardiac magnetic resonance in autoimmune myocarditis. Autoimmun Rev 2012; 12: 305–12 CrossRef MEDLINE|
|27.||Ferri C, Valentini G, Cozzi F, et al.: Systemic Sclerosis Study Group of the Italian Society of Rheumatology (SIR-GSSSc). Systemic sclerosis: Demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore) 2002; 81: 139–53 CrossRef|
|28.||Pagnoux C, Guillevin L: Cardiac involvement in small and medium-sized vessel vasculitides. Lupus 2005; 14: 718–22 CrossRef MEDLINE|
|29.||Ogdie A, Yu Y, Haynes K, et al.: Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: apopulation-based cohort study. Ann Rheum Dis 2015; 74: 326–32 CrossRef MEDLINE PubMed Central|
|30.||Houri Levi E, Watad A, Whitby A, et al.: Coexistence of ischemic heart disease and rheumatoid arthritis patients—a case control study. Autoimmun Rev 2016; 15: 393–6 CrossRef MEDLINE|
|31.||Chung CP, Giles JT, Petri M, et al.: Prevalence of traditional modifiable cardiovascular risk factors in patients with rheumatoid arthritis: Comparison with control subjects from the multi-ethnic study of atherosclerosis. Semin Arthritis Rheum 2012; 41: 535–44 CrossRef MEDLINE PubMed Central|
|32.||Essers I, Stolwijk C, Boonen A, et al.: Ankylosing spondylitis and risk of ischaemic heart disease: a population-based cohort study. Ann Rheum Dis 2016; 75: 203–9 CrossRef MEDLINE|
|33.||Szabo SM, Levy AR, Rao SR, et al.: Increased risk of cardiovascular and cerebrovascular diseases in individuals with ankylosing spondylitis: a population-based study. Arthritis Rheum 2011; 63: 3294–304 CrossRef MEDLINE|
|34.||Manger K, Kusus M, Forster C, et al.: Factors associated with |
coronary artery calcification in young female patients with SLE. Ann Rheum Dis 2003; 62: 846–50 CrossRef MEDLINE PubMed Central
|35.||Lin K, Lloyd-Jones DM, Li D, et al.: Imaging of cardiovascular complications in patients with systemic lupus erythematosus. Lupus 2015; 24: 1126–34 CrossRef MEDLINE PubMed Central|
|36.||Agca R, Heslinga SC, Rollefstad S, et al.: EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2017; 76: 17–28 CrossRef MEDLINE|
|37.||Duru N, van der Goes MC, Jacobs JW, et al.: EULAR evidence-based and consensus-based recommendations on the management of medium to high-dose glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 2013; 72: 1905–13 CrossRef MEDLINE|
|38.||Krause D, Schleusser B, Herborn G, Rau R: Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis. Arthritis Rheum 2000; 43: 14–21 CrossRef|
|39.||Lutman C, Finocchiaro G, Abate E, Milo M, Morassi P, Sinagra G: Purulent pericarditis in rheumatoid arthritis treated with rituximab and methotrexate. J Cardiovasc Med (Hagerstown) 2014; 15: 880–2 CrossRef MEDLINE|
|40.||Yoshida S, Takeuchi T, Sawaki H, Imai T, Makino S, Hanafusa T: Successful treatment with tocilizumab of pericarditis associated with rheumatoid arthritis. Mod Rheumatol 2014; 24: 677–80 CrossRef MEDLINE|
|e1.||Memorandum. Rheumatologische Versorgung von akut und chronisch Rheumakranken in Deutschland. Herausgegeben von der Kommission Versorgung der Deutschen Gesellschaft für Rheumatologie, Juni 2008. www.dgrh.de/?id=8878 (last accessed on 10 February 2017).|
|e2.||Deutsches Rheumaforschungszentrum (DRFZ) Berlin: Daten der Kerndokumentation 2013. www.dgrh.de/fileadmin/media/Forschung/Versorgungsforschung/ErwachsenenKerndok/Standardpraesentation_2013_extern.pdf (last accessed on 10 February 2017).|
|e3.||Sharma TS, Wasko MC, Tang X, et al.: Hydroxychloroquine use is associated with decreased incident cardiovascular events in rheumatoid arthritis patients. J Am Heart Assoc 2016; 5: e002867.|
|e4.||Jung H, Bobba R, Su J, et al.: The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum 2010; 62: 863–8 CrossRef MEDLINE|
|e5.||Quismorio FP, Beardmore T, Kaufman RL, Mongan ES: IgG rheumatoid factors and anti-nuclear antibodies in rheumatoid vasculitis. Clin Exp Immunol 1983; 52: 333–40 MEDLINE PubMed Central|
|e6.||Badui E, Garcia-Rubi D, Robles E, et al.: Cardiovascular manifestations in systemic lupus erythematosus. Prospective study of 100 patients. Angiology 1985; 36: 431–41 CrossRef MEDLINE|
|e7.||Crozier IG, Li E, Milne MJ, Nicholls MG: Cardiac involvement in systemic lupus erythematosus detected by echocardiography. Am J Cardiol 1990; 65: 1145–8 CrossRef|
|e8.||Hazebroek MR, Kemna MJ, Schalla S, et al.: Prevalence and prognostic relevance of cardiac involvement in ANCA-associated vasculitis: eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis. Int J Cardiol 2015; 199: 170–9 CrossRef MEDLINE|
|e9.||Knockaert DC: Cardiac involvement in systemic inflammatory diseases. Eur Heart J 2007; 28: 1797–804 CrossRef MEDLINE|
|e10.||Gerfaud-Valentin M, Sève P, Iwaz J, et al.: Myocarditis in adult-onset still disease. Medicine (Baltimore) 2014; 93: 280–9 CrossRef MEDLINE PubMed Central|
|e11.||Geri G, Wechsler B, Thi Huong du L, et al.: Spectrum of cardiac lesions in Behçet disease: a series of 52 patients and review of the literature. Medicine (Baltimore) 2012; 91: 25–34 CrossRef MEDLINE|
|e12.||Dib C, Moustafa SE, Mookadam M, Zehr KJ, Michet CJ Jr, Mookadam F: Surgical treatment of the cardiac manifestations of relapsing polychondritis: overview of 33 patients identified through literature review and the Mayo Clinic records. Mayo Clin Proc 2006; 81: 772–6 CrossRef MEDLINE|
|e13.||Mogulkoc N, Burgess MI, Bishop PW: Intracardiac thrombus in Behçet‘s disease: a systematic review. Chest 2000; 118: 479–87 CrossRef|
|e14.||Lachmann HJ, Goodman HJ, Gilbertson JA, et al.: Natural history and outcome in systemic AA amyloidosis. N Engl J Med 2007; 356: 2361–71 CrossRef MEDLINE|
|e15.|| Haroon M, Gallagher P, Heffernan E, FitzGerald O: High prevalence of metabolic syndrome and of insulin resistance in psoriatic arthritis is associated with the severity of underlying disease. |
J Rheumatol 2014; 41: 1357–65 CrossRef MEDLINE
|e16.||Hollan I, Saatvedt K, Almdahl SM, et al.: Spondyloarthritis: a strong predictor of early coronary artery bypass grafting. Scand J Rheumatol 2008; 37: 18–22 CrossRef MEDLINE|
|e17.||Tascilar K, Dell‘Aniello S, Hudson M, Suissa S: Statins and risk of rheumatoid arthritis: a nested case-control study. Arthritis Rheumatol 2016; 68: 2603–11 CrossRef MEDLINE|
|e18.||Schoenfeld SR, Lu L, Rai SK, Seeger JD, Zhang Y, Choi HK: Statin use and mortality in rheumatoid arthritis: a general population-|
based cohort study. Ann Rheum Dis 2016; 75: 1315–20 CrossRef MEDLINE
|e19.||Allenbach Y, Drouot L, Rigolet A, et al.: French Myositis Network. Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin. Medicine (Baltimore) 2014; 93: 150–7 CrossRef MEDLINE PubMed Central|
|e20.||Mammen AL, Pak K, Williams EK, et al.: Rarity of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects. Arthritis Care Res (Hoboken) 2012; 64: 269–72 CrossRef MEDLINE PubMed Central|
|e21.||McInnes IB, Thompson L, Giles JT, et al.: Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Ann Rheum Dis 2015; 74: 694–702 CrossRef MEDLINE PubMed Central|
|e22.||Thakkar V, Stevens W, Prior D, et al.: The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study. Arthritis Res Ther 2013; 15: R193.|
|e23.||Luconi N, Risse J, Busato T, et al.: Myocarditis in a young man with adult onset Still‘s disease successfully treated with Il-1 blocker. Int J Cardiol 2015; 189: 220–2 CrossRef MEDLINE|
|e24.||Conroy RM, Pyörälä K, Fitzgerald AP, et al.: SCORE project group. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003; 24: 987–1003 CrossRef|