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Home , Cardiovascular disease

CME Rheumatological and immunological disorders – I

Cardiac involvement with the severity of RA 1. The reasons for peripheral oedema and hepatic or this remain unclear. RHD, although gastrointestinal congestion may occur in common, rarely has haemodynamic constrictive . In tamponade, in rheumatoid consequences 2. Ischaemic disease symptoms and can rapidly develop (IHD) is a more likely cause; recent and require emergency intervention. disease studies suggest similarities of inflam- Pericardial rub occurs in 30– 40% of matory pathogenic mechanisms in RA clinical cases. Other signs (, and , and an increased ectopy, diminished ) are George Kitas MD PhD FRCP , 1,3,4 non-specific. and Consultant/Clinical Senior Lecturer in prevalence of IHD in RA . Kussmaul’s sign (rise in height of jugular Rheumatology, Dudley Group of Hospitals NHS Trust and University of Birmingham pulsation during inspiration) may occur. Range and clinical presentation In constriction, a pericardial knock may Matthew J Banks MRCP, of cardiac pathology in be heard due to early cessation of Specialist Registrar/Research Fellow, rheumatoid University of Birmingham ventricular filling. Constriction associ- ates with high jugular and a Paul A FRCP, Professor of Pericardial disease prominent y descent of early ventricular Rheumatology, University of Birmingham The commonest cardiac of filling; in tamponade, the y descent is RA is . It is found in 30–50% diminished, leaving a prominent x Clin Med JRCPL 2001;1:18–21 of autopsy cases 5–7 and in up to 30% by descent. and con- 8,9. It is commoner in striction can co-exist (effusive- male, seropositive patients with active constrictive disease), and this should be Background RA, but can occur in seronegative and suspected if pericardiocentesis fails to quiescent RA or before the onset of rectify haemodynamic compromise 11. The relationship between joint inflam- synovitis. Histopathology shows chronic mation and heart disease was first and . The peri- Non-specific suggested by Bouillaud in 1836. In 1891, cardial fluid is usually a clear exudate Charcot described endocardit is and with high and lactate dehydroge- Non-specific endocarditis is found in pericarditis in ‘ chronic rheumatis m’, nase, low glucose, and containing mainly 9–70% of autopsy cases. Echo- differentiating cardiac disease in 10. crystals can be cardiographic studies show a high preva- (rheumati c heart seen in persistent effusions; they also lence of valvular thickening, but clinical disease) from that in other forms of occur in tuberculou s pericarditis. disease is rare 8,9. The frequency of valve rheumatism (rheumatoid heart disease Staphylococcal pyopericardium has also involvement is similar to rheumatic heart (RHD)). It is now clear that cardiac been described in RA, so infection is an disease (mitral, aortic, tricuspid, pathology is common in rheumatoid important differential diagnosis. Only pulmonary). Non-specific inflammation arthritis (RA) (T able 1). This may be 2–4% of patients have symptoms, and and fibrosis cause thickening and calcifi- important. Cardiovascu lar mortality fewer than 0.5% experience haemo- cation, mainly in the base of the valve accounts for 40–50% of all in RA; dynamic compromise 2. The commonest and the valve ring, but this rarely has it is increased and occurs earlier than in symptom is dull central or sharp haemodynamic consequences. The most the general population and may associate pleuritic . Dyspnoea, distinctive lesions are rheumatoid granu- lomata within the valve leaflets which can cause incompetence. Most patients Table 1. Pathological, echocardiographic and clinical prevalence of rheumatoid heart have no symptoms because the left disease. ventricle (L V) can adapt to significant AutopsyEchocardiography Clinical mitral or aortic regurgitation without (%) (%) (%) decompensating. The effect on ventric- ular performance is mainly defined by Pericarditis 11–50 20–40 1–4 the rapidity of onset of regurgitation; in 30 rare rare severe cases, lesions can develop over a Focal, non-specific 4–30 – – Diffuse, necrotising rare – – few days and cause rapid LV failure. Granulomatous 3–5 – – Amyloid infiltration rare – – Conduction system disease unknown – rare Myocarditis Endocarditis Myocarditis is found in up to 30% of Valvular disease 6–50 30–40 rare autopsy cases 5–7. It can be diffuse or Coronary 15–20 – rare Any cardiac lesion 30–50 30–50 1.6–6 focal, non-specific or pathognomonic nodular rheumatoid myocarditis. Its

18 Clinical Vol 1No 1January/February 2001 CME Rheumatological and immunological disorders – I clinical significance is unknown. The endocarditis, cor pulmonale or are insensitive and non-specific first-line overwhelming majority of patients are constrictive pericarditis. investigations. Echocardiography allows asymptomatic. However, the compact evaluation of both cardiac anatomy and anatomy and relationship of the atrio- Ischaemic heart disease function, and may be helpful in several ventricular node to the aortic root and situations8,9,16: interventricular septum make it Myocardial imaging under • pericarditis (fluid and thickening) vulnerable to damage from inflam- pharmacological stress detects IHD in • imminent tamponade (diastolic mation of adjacent structures and can about 50% of RA patients, a prevalence collapse) to conduction defects. Complete double that of matched controls 18. This is constriction (preserved LV function has been reported in RA reflected in the incidence of MI and heart • but abrupt termination of and penicillamine-induced myositis 12,13. failure as causes of cardiovascular mor- ventricular filling) tality in RA 1. Alarmingly, more than half valvular lesions (grading of Arteritis of RA patients with IHD have no • ischaemic symptoms. Classical cardio- regurgitation and serial assessment Arteritis is present in up to 20% of vascular risk factors appear to be of LV end-diastolic dimension) autopsy cases, affecting mainly medium important, but RA, like , confers • and small intramyocardial 5–7. significant extra risk 18. The long-term • assessment of LV systolic and This may lead to patchy myocardial significance of this is obvious, but diastolic function. necrosis due to microinfar ction or strategies to prevent it are yet to be In cases of constriction, computed ischaemia. Severe arteritis of the epi- established. tomography (CT) scanning is useful to cardial vessels has been reported and confirm pericardia l thickening, and tends to be non-occlusive. Its relation- Investigation of cardiovascular helps to differentiate constrictive peri- ship to (MI) is involvement in rheumatoid from restrictive controversial 14,15. arthritis (Table 2). Cardiac catheteris ation is essential if pericardectomy is considered. Myocardial dysfunction Overall cardiovascular risk in RA, as in testing provides evidence of other conditions, can be assessed on the ischaemia, but may be impossible or Several processes operating alone or in basis of history, , and difficult due to physical disability. A tandem may lead to myocardial dysfunc- ECG. A range of other investigations is useful alternative is nuclear perfusion tion in RA. may be one of also available to identify specific cardiac imaging under pharmacological stress. the main causes of increased cardio- pathologies, assess their effects and allow This may show ischaemia, whether due vascular mortality in RA, particularly targeted treatment. These should be used to epicardial or small vessel abnormali- 1 in men . Diastolic L V dysfunction on judiciously, and they require collabora- ties, and inform the need for further Echo-Doppler, found in 30– 40% of RA tion between rheumatologists and invasive investigati on 18,19. Coronary 16 patients without overt heart disease , cardiologists. angiography will reveal epicardial is thought to be an early sign of IHD or ECG and chest X-ray are useful, but disease, but can neither differentiate heart failure and has adverse prognostic significance. Restriction due to amyloid can lead to diastolic heart failure; in the Table 2. Differential diagnostic features between constrictive pericarditis and past it was found in 10–20% of rheuma- restrictive cardiomyopathy. toid , but is now rare. Pancarditis and small vessel can lead to Diagnostic feature Constrictive Restrictive pericarditis cardiomyopathy systolic pump failure 17, while pulmonary fibrosis can cause right ventricula r S3 Gallop Absent May be present failure. Overall, however, heart failure in Pericardial knock May be present Absent RA, as in the general population, is more Palpable systolic apical impulseAbsent May be present likely to be the result of atherosclerotic Pulsus paradoxus May be present May be present disease. Symptoms of myocardial dys- Pericardial Present 50% Absent function such as dyspnoea are unusual in CT scan, MRI, RA, possibly due to reduced physical echocardiography Thickened pericardiumNormal activity, while signs are non-specific. Equal RV and LV Patients suddenly developing overt heart diastolic filling pressures Usually present LV>RV failure should be investigated for many Rate of LV filling 80% in first half of 40% in first half of possible causes, including acute MI or diastole diastole hypertensive heart disease, but also CT = computed tomography; MRI = magnetic resonance imaging; LV = left ventricle; RV = right ventricle. vasculitis, valvular disease/bacterial

Clinical Medicine Vol 1No 1January/February 2001 19 CME Rheumatological and immunological disorders – I

Key Points Conclusion There is an urgent need for further Cardiovascular disease causes almost half of all deaths in rheumatoid arthritis (RA) research into the causes, significance and prevention of IHD in RA. At present, it Cardiovascular mortality is greater and occurs earlier in RA than in the general population would be sensible to suggest that practising rheumatologists should assess Rheumatoid heart disease is commonly found at autopsy or by echocardiography, and correct the modifiable cardio- but is rarely clinically apparent vascular risk factors of their patients, and RA associates with a higher prevalence of ischaemic heart disease have a high index of suspicion and a low threshold for cardiology referral and investigation. between arteritis and atherosclerosis nor laceration, and should be performed by detect smaller vessel involvement. experienced hands under echocardio- References may provide his- graphic guidance. Extensive pericardial 1Manzi S, Wasko MCM. Inflammation- tological diagnosis and allow prompt resection should be considered in all mediated rheumatic and athero- treatment in myocarditis or diffuse patients with cardiac compression, if sclerosis. Ann Rheum Dis 2000;59:321–5. vasculitis17. Other investigatio ns that they will tolerate thoracotomy. 2Escalante A, Kaufman R, Fransisco P, may be useful in experience d hands Quisimorio FP Jr, Beardmore TD. Cardiac compression in RA. Semin Arthritis Rheum include: Valve lesions 1990;20:148–63. • 67Gallium scanning 3Pasceri V, Yeh ETH. A tale of two diseases. (inflammation) 17 Valve replacement depends on the lesion, Atherosclerosis and rheumatoid arthritis. its clinical and haemodynamic effects, and Circulation 1999;100:2124–6. stress echocardiography (ischaemia) • the patient’s state. The optimum time for 4Kitas GD, Banks MJ, Bacon PA. Accelerated electron-beam CT (coronary atherosclerosis as a cause of cardiovascular • this procedure is before development of calcification) in rheumatoid arthritis. Pathogenesis irreversible L V dysfunction but after the 1998;1:73–83. • cardiac magnetic resonance imaging. risk of significant L V damage outweighs 5Sokolof L. The heart in rheumatoid the operative risks. Pre-operative cardiac arthritis. Am Heart J 1953;45:635–43. catheterisation is essential to confirm 6Cathcart ES, Spodick DH. Rheumatoid Treatment of cardiac heart disease. N Engl J Med 1962;266: complications in rheumatoid echocardiographic findings and exclude 959–64. arthritis coexistent . In 7Bonfiglio T, Atwater EC. Heart disease in milder cases or patients unsuitable for patients with seropositive rheumatoid The majority of cardiac complications in valve replacement, medical treatment with arthritis; a controlled autopsy study. Arch 124 RA are silent and do not require vasodilators, angiotensin-convert ing Intern Med 1969; :714–9. 8Bacon PA, Gibson DG. Cardiac involvement symptomatic treatment. enzyme inhibitors and diuretics may be in rheumatoid arthritis. An echocardio- appropriate. There is no evidence for graphic study. Ann Rheum Dis 1974;33: using steroids or SAARDs in treating 20–4. Pericarditis valve lesions. Bacterial endocarditis 9MacDonald WJ Jr, Crawford MH, Klippel JH, Zvaifler NJ, O’Rourke RA. Echo- should be actively excluded if there is Silent pericarditis is benign in the long cardiographic assessment of cardiac term, without progression to constric- rapid deterioration in the condition of a structure and function in rheumatoid tion. Symptomatic pericarditis without valve. arthritis. Am J Med 1977;63:890–6. haemodynamic upset is treated with 10 Travaglio A, Anaya J-M. Rheumatoid non-steroidal anti-inflammatory drugs pericarditis: new immunopathological Fulminant coronary aspects. Clin Exp Rheumatol 1994;12:313–6. or steroids, but abrupt cessation of vasculitis/myocarditis 11 Hancock EW. Subacute effusive-constrictive steroids may result in rapid deteriora- pericarditis. Circulation 1971;43:183–92. tion. The course of aggressive pericarditis Fulminant coronary vasculitis and/ or 12 Ahern M, Lever JV. Complete heart block in is unfavourable. Compression due to myocarditis presenting with congestive rheumatoid arthritis. Ann Rheum Dis effusion or constriction associates with heart failure are usually diagnosed at 1983;42:389–95. 13 Christensen PD, Sorensen KE. 2 up to 37% mortality , and steroids or post-mortem . There is no consensus as to Penicillamine induced polymyositis with slow-acting antirheumatic drugs the best treatment. Steroids have been complete heart block. Eur Heart J 1989; (SAARDs) have little influence on such the mainstay of therapy, but they are also 10:1041–4. disease. Pericardiocentesis may be life- recognised to provoke coronary arteritis. 14 Voyles WF, Searles RP, Bankhurst AD. saving in tamponade, but re-accumula- More aggressive regimens involving Myocardial infarction caused by rheuma- toid vasculitis. Arthritis Rheum 1980;23: tion is common despite systemic or cyclophosphamide may be useful, but 860–3. intrapericardial steroids. This procedure have not been formally evaluated. 15 Morris PB, Imber MJ, Heinsimer JA, Hlatky has a risk of myocardial or coronary Fortunately, such cases are rare. MA, Reimer KA. Rheumatoid arthritis and

20 Clinical Medicine Vol 1No 1January/February 2001 CME Rheumatological and immunological disorders – I

coronary arteritis. Am J Cardiol 1986;57: 689–90. The real connective tissue diseases 16 Corrao S, Salli L, Arnone S, Scaglione L, et al. Echodoppler abnormalities in patients Paul Wordsworth MA MB FRCP, Professor of Clinical Rheumatology, University of Oxford with rheumatoid arthritis without clinically evident cardiovascular disease. Eur J Clin Dorothy Halliday MB MRCP, British Heart Foundation Clinical Research Fellow Invest 1996;26:293–7. 17 Slack D, Waller B. Acute congestive heart Clin Med JRCPL 2001;1:21–4 failure due to the arteritis of rheumatoid arthritis. Early diagnosis by endomyocar- dial biopsy. 1986;6:477–81. Rheumatologists and immunologists, in The first to be well studied was osteoge- 18 Banks MJ, Flint EJ, Bacon PA, Kitas GD. particular, are familiar with the connec- nesis imperfecta in which the diversity of Rheumatoid arthritis is an independent risk tive tissues as a battlefield for a wide clinical phenotypes correlates well with factor for ischaemic heart disease. Arthritis variety of inflammatory diseases, many the involving Type I collagen. Rheum 2000;43:S385. of which are covered in this issue. The Briefly, substitutio ns of cysteine for 19 Banks MJ, Kitas GD. Patients’ physical dis- ability in RA may influence doctors’ per- heritable disorders of connective tissue glycine in the critical central core of the ceptions of suitability for risk assessment of constitute a second, less familiar group collagen triple helix significantly impair coronary heart disease. Br Med J 1999; which in recent years has yielded many formation of the classic triple helix of 319:1266–7. of its mysteries to the techniques of mol- a chains, and lead to overmodification ecular biology. Classification and accu- of the mature collagen by excessive Address for correspondence: rate diagnosis of these conditions , glycosylation and hydroxylation. This Dr G D Kitas, Department of affecting a wide variety of mesenchymal type of (‘ dominant negative’ ) Rheumatology, Dudley Group of tissues, have benefited significantly from may reduce the amount of normal Hospitals NHS Trust, advances in basic science. A brief review collagen by 7/8ths and lead to severe phe- The Guest Hospital, Tipton Road, is able only to scratch the surface of this notypes (lethal or severely deforming). Dudley, West Midlands DY1 4SE. fascinating group of conditions which In contrast, mutations that create an E-mail: [email protected] have been extensively reviewed else- effective null allele (eg premature stop where1,2. Examples of disorders affecting codons) reduce the amount of normal the hard and soft musculoskeletal system collagen by smaller amounts and cause will be used to illustrate general points. milder forms of disease. Similar attempts at classification based on the underlying biochemical and genetic defects have Skeletal dysplasias been possible in the chondrodysplasias Skeletal dysplasias may be divided into (Table 1). The major cartilage collagen those that affect bone (eg osteogenesis (more than 90%) is T ype II. A large imperfecta) or the cartilage component number of mutations have now been of the bones (chondrodysplasias) 3. The described in the gene COL2A1, identi- latter can be separated into those pre- fying a family of chondrodysplasias 4. dominantly affecting the epiphyses or These conditions are associated not only the metaphyses. Together with the pres- with abnormalities of the epiphyses but ence or absence of spinal involvement, also frequently of theeye (T ype II col- these simple descriptions form the basis lagen is a major constituent of vitreous of a clinical classification system: humour). • epiphyseal dysplasia • metaphyseal dysplasia Soft connective tissues • spondyloepiphyseal dysplasias, etc. disorders The presence of skeletal disproportion The heritable disorders of the soft con- and its distributi on can be useful nective tissues are best exemplified by the clinically, for example: heterogeneous Ehlers-Danlos syndrome • rhizomelic short limbs in (EDS), characterised broadly by exces- achondroplasia sive skin elasticity, joint hypermobility and bruising, and the Marfan syndrome. • relatively short trunk in spondyloepiphyseal dysplasia. Ehlers-Danlos syndrome Several distinct families can be recog- nised within the skeletal dysplasias based Although 10 classic forms of EDS are on the underlying genetic abnormalities. described, many patients cannot be

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