Myocardial and conduction system disease \200 In SLE myocarditis, immuno \202 uorescence demonstrates granular deposition of immunoglobu lin and complement component, suggesting immune complex disease. Deposits are predominantly in the wall of myocardial blood vessels. In giant cell myocarditis, multicellular giant ce lls are prominent in the in \201 ltrate. Abnormalities of depolarization and repolarizatio n of pacemaker tissue and myocytes together with abnormal autonomic tone may result from th e effects of autoanti- bodies (e.g. anti-Ro) binding to the tissues, or of other circulatin g in \202 ammatory mediators, which may have excitatory and/or cytotoxic effects on excita ble tissues. In SSc, patchy myocardial \201 brosis promotes the develop- ment of re-entra nt tachycardias. Drugs may also contribute to arrhythmias, e.g. hydroxy- chloroquine is ass ociated with QT prolongation and refractory ventricular arrhythmias. Rarely sulphasalazine is associated with causing a cardiomyopathy. Conduction tissue may be in \201 ltrated by m ononuclear cells or disrupted by vasculitis of arterial supply in RA. Antibodies (e.g. anti -Ro antibodies) speci \201 c for cardiac conducting tissue may also bind to cardiac myocyt es and disrupt the function of calcium channels. In SSc, \201 brosis of the sino-atrial n ode and other con- ducting tissue underlies the high incidence of conduction disturbance. Valvular disease \200 In RA mitral and aortic valve regurgitation are common echocardiogram \201 ndings, but si gni \201 cant in a minority. In SLE, Libman-Sacks endocarditis is a verrucous endocarditis of valve lea \202 ets, papillary muscle, and/or endocardium. Valvular disease occurs in a bout 50% of SLE patients with antiphospholipid antibodies. Exclude infective endocarditis ( IE). In APLS valvular disease is estimated to occur in about a third by transthoracic (TTE) and 80% by transoesopha- geal echocardiogram (TOE). Only 5% patients require surgery. Ex clude IE. Cardiac conduction defects, aortic valve incompetence and cardiomegaly occur in A S. Anatomic evidence of aortic valve involvement can be seen in up to 20% AS patients, but few have valvular dysfunction. About 50% patients with isolated aortic valve incompetence a re HLA B27 positive. In rheumatic fever 70% of patients have valvulitis and mitral stenosis is the commonest sequelae. This is rare in the developed world. Valvular disease \200 In SLE and APLS, deposition of autoantibodies, including anti-endothelial antibodies, anti- phospholipid antibodies, and immune complexes is believed to be responsible for contributin g to endocardial in \202 ammation and valvular disease. In APLS, intravalvular capillary t hrombosis or super \201 cial thrombosis on luminal surface of valve lea \202 ets have bee n reported. Fibrosis and calci \201 cation are thought to be sequelae of chronic damage/in \202 ammation. In AS, aortic incompetence results from in \202 ammation and dilatation o f the aortic root. Coronary artery disease (CAD) \200 Coronary artery disease (CAD) \200 In RA, the risk of myocardial infarction (MI) is increased 2-fold. Silent MI is more commo n and recurrence of cardiac events is higher in RA compared with controls. Treatment with m ethotrexate (MTX) appears to be associated with a decreased cardiovascular mortality and mo rbidity. This probably reflects the association of plaque instability and vasculitis with a ctive RA. CAD occurs in 10% SLE patients (risk 4 \200\2238-fold of controls). In APLS CAD occurs in 5%. In RA, traditional risk factors are increased and contribute to risk of CAD, e.g. systemic in \202 ammation contributes to atherogenic lipid profiles and insulin resistance, reduced mobility in patients with arthritis increases the incidence of obesity; decreased exercise increased weight and some drugs (NSAIDs, glucocorticoids [GCs], le \202 unomide) promote development of hypertension. Also in RA, circulating in \202 ammatory mediators, e.g. CRP and TNFA may cause direct endothelial damage. CD4+CD28-T cells are increased in RA and some other patients with unstable angina; they have been implicated in plaque destabilization. In SLE, circulating inflammatory mediators may be directly involved in endothelial damage. Anti-phospholipid or anti-B2GPI antibodies have been reported to bind to endothelial cells. Pulmonary arterial hypertension (PAH) Refer to \200\230The Chest \200\231 in the chapter o n Organ involvement in rheumatological disease. (Refer to \200\230The chest and also see S Sc, p. 264 \200\223272.) Aortitis Takayasu \200\231s arteritis, AS, GCA, and relapsing polychondritis are all associ ated with aortic root/arch involvement. Pulmonary arterial hypertension Refer to \200\230The Chest \200\231 in the chapter on Orga n involvement in rheumatological disease (Refer to \200\230The Chest \200\231 and also see SSc, p. 264 \200\223272.) THE HEART 68 \200 Cardiac auscultation for murmurs. Check for signs of IE \200\223 fever, splinter hemorrhag es, splenomegaly. Aortitis Aortitis may result from vasculitis in the vasa vasorum of the adventitia or, in G CA, as a result of a local immune response generated by over-reactivity of dendritic cells resident in the adventitia. In \202 ammation may give rise to disintegration of the aortic media, with aneurysm forma- tion, or \201 brosis with resultant stenosis of the aorta or arteries originating from it. Coronary artery disease (CAD) CAD can present as central tight chest pain and/or dyspnoea o n exertion. \200 The incidence of silent MI is increased in RA and SLE patients relative to controls. Left v entricular dysfunction must be considered and the cause identi \201 ed, i.e. ischaemia, my ocarditis, or valvular dysfunction. On examination look for signs of arrhythmias, cardiac f ailure, hypertension, and hypercholesterolaemia. Risk factors \200 Traditional risk factors for ischaemic heart disease (smoking, hypertension, hyperlipidaemi a, family history, obesity) also apply to RA and SLE patients, and are likely to contribute to ischaemic heart disease (IHD) in all patients with rheumatological disease. Lupus antic oagulant and anti-B2GPI are risk factors for MI in SLE patients. Left heart valvular diseas e is a risk factor for stroke, and possibly epilepsy, in patients with APLS. Anti-Ro antibo dies in pregnancy confer about a 2% risk of CHB (15 \200\22320% if the mother already has a n affected child). HLA-B27 is a risk factor for aortitis. Pulmonary arterial hypertension (PAH) Refer to \200\230The Chest \200\231 in the chapter o n Organ involvement in rheumatological disease. (Refer to \200\230The Chest \200\231 and a lso see SSc, p. 264 \200\223272). Aortitis Aortitis might be \200\230silent \200\231 or present with chest pain, radiating t o the back. In the examination assess radial and carotid pulses; listen for subclavian bruit and aortic incompetence. Measure BP in both arms (may be discrepant), and there may be pulse delay be tween radial pulses or radio-femoral delay. Clinical features Pericardial disease \200 Pericarditic pain is classically positional, precordial, and relieved by sitting forward. D yspnoea with pericardial effusion raises the possibility of tamponade. Fever and tachycardi a are common. Pericardial rub occurs in the early stages but is lost as fluid accumulates \200\223 a stage that is associated with reduced heart sounds. Development of tamponade is indicated by raised jugular venous pressure (JVP) with a sharp rise and y descent. Kussmaul \200\231s sign, pulsus paradoxus, and reduced pulse volume are also detectable. Cardiac signs Kussmaul \200\231s sign (Adolf Kussmaul 1822 \200\2231902) Normally, the JVP falls with inspiration (reduced pres- sure in the expanding thoracic cavity). Where there i s impaired right ventricle \201 lling (e.g. restrictive pericarditis, pericardial effusio n, tamponade), JVP can rise with inspiration (Kussmaul \200\231s sign). \200 Pulsus paradoxus (PP) PP is an exaggeration of the normal variation in the pulse during the inspiratory phase of respiration, in which the pulse becomes weaker as one inhales and str onger as one exhales. It is a sign that is indicative of several conditions including cardi ac tamponade, peri- carditis, chronic sleep apnoea, and obstructive lung disease (e.g. asth ma, COPD). The paradox in PP is that one can detect extra beats on auscultation during insp i- ration, when compared with the radial pulse. It results from an accentuated decrease of the blood pressure. PP has been shown to be predictive of the severity of cardiac tamponade . Myocardial and conduction system disease Cardiomyopathies of all causes may present with dy spnoea, orthopnoea, and palpitations. \200 Heart failure is associated with tachycardia, reduced pulse volume, elevation of the JVP, g allop rhythm, hyper- dynamic, and/or displaced apical impulse. Left ventricular failure is usually associated with signs of pulmonary oedema or pleural effusion. Right heart failure is associated with raised JVP, pitting oedema of the ankles/legs; a pulsatile liver. The pu lse rate and rhythm should be carefully assessed in patients with a history of palpitations . Manual (rather than automated) blood pressure measurement may reveal hypertension, hypote nsion, or a pulsus alternans. CHB in utero may manifest with a fetal bradycardia. PP is quanti \201 ed using a blood pressure cuff and stethoscope, by measuring the variati on of the pressure in systole with respiration. PP is an inspiratory reduction in systolic pressure >10 mmHg. Causes include tamponade, pericardial effusion, asthma, tension pneumothorax, PE, SVC obstruction. Pulsus alternans The arterial pulse waveform has alternating strong and weak beats. It is a lmost always indicative of left ventricu- lar systolic impairment and carries a poor progno sis. Valvular disease Valve problems can present with palpitations, clinical features of cardiac failure or syncopal episodes (e.g. with aortic stenosis). \200 \200 Fevers and sweats and \200\230new \200\231 murmurs may indicate IE. Pulse character and vo lume should be carefully assessed. Blood pressure assessment may reveal wide pulse pres- su re in aortic regurgitation. Figure 3.10 Key \201 ndings in valve disease in rheumatology patients CHAPTER 3 Organ involvement in rheumatological disease 69 Pericardial biopsy is indicated if MTB is still suspected, but not con \201 rmed after per icardiocentesis (particularly relevant in patients treated with anti-TNFA agents). Endomyoc ardial biopsy may rarely be required to distinguish constrictive pericarditis from restrict ive cardiomyopathy. Patchy disease can be missed. Biopsy should only be done if supported b y appropriate pathol- ogy expertise. Cardiac catheterization is used to assess end-diastoli c pressures in the RV and LV in the investigation of constrictive pericarditis. Screen for autoimmune, infective, and malignant diseases. Include: FBC, renal function, liver function tests, serum ACE and calcium (sarcoidosis), ferritin (very high in Adult Still \200\231s), lactate deyhydrogenase (leukemia, lym- phoma) blood/urine/sputum cultures, ANA & ENAs, RF, anti-CCP antibodies (RA), Igs, ANCA, and complement components C3 and C4. Chronic aortic insuf \201 ciency/regurgitation causes an early diastolic and decresendo mu rmur, which is best heard at aortic area when the patient is seated and leans forward with breath held in expiration. The murmur is usually soft and seldom causes thrill. Chronic mitral regurgitation typically causes a pansys- tolic murmur (usually high-pitched) heard at the apex radiating to the axilla and is associated with an apical thrill and 3rd heart sound. Patients with mitral valve prolapse (e.g. Marfan syndrome) often have a mid- t o-late systolic click and a late systolic murmur Signs in PAH (e.g. in SSc) Altered heart sounds, such as a widely split S2 or 2nd heart sou nd, loud P2, (para)sternal heave, possible S3 or 3rd heart sound, and pulmonary regurgitati on. Other signs include an elevated JVP, peripheral oedema, ascites, hepatojugular re \202 ux, and clubbing. Myocardial and conduction system disease \200 \200 \200 Investigations Pericardial disease \200 Troponin-I is a speci \201 c indicator of myocardial damage. Ferritin \200\223 if adult S till \200\231s suspected. Serum ACE, PTH and plasma and 24 h urinary calcium if sarcoidosis suspected (and 1,25-dihydroxyvitamin D). Thyroid function tests in AF or sinus tachycardia . ECG: in acute pericarditis - saddle-shaped ST elevation. Subsequently, the ST segments norm alize but T waves \202 atten and the amplitude of the QRS complex alternates (QRS alterna ns). Echocardiography shows pericardial \202 uid, thickening and calci \201 cation. Tamp onade is suggested by diastolic com- pression of right heart chambers, lack of inspiratory col- lapse of inferior vena cava and swinging of the whole heart. Doppler assessment of dia stolic \202 ow patterns may suggest constrictive pericarditis. ECG. \200 Annual ECGs are recommended in all rheumatological patients at risk of myocardial and condu ction tissue disease; this includes apparently unaffected offspring of mothers with anti-Ro antibodies. 24-h Holter monitoring is used to evaluate patients with intermittent palpitat ions. Echocardiography \200 Shows nodules, dilation of chambers, and hypertrophy of chamber walls and estimates functio n (e.g. LVEF). A sparkling pattern can indicate amyloid. Global hypokinesis suggests myoc arditis in associated disease. \200 Cardiovascular MR \200 Can be used to evaluate LV function, myocardial perfusion, and distinguish causes of cardio myopathy. T2 values indicate abnormal myocardial relaxation. Other investigations \200 Anti-microbial antibody titres (e.g. CMV, EBV, in \202 uenza, hepatitis C, Coxsackie B, Bo rrelia burgdorferia, Chlamydia pneumonia); elevated IgM indicates acute infection; elevated IgG is evidence for previous exposure. Exercise stress testing for suspected ischaemia oft en not possible due to locomotor issues \200\223 use other non-invasive test such as MIBI, stress echo or MR perfusion. Serial fetal echocardiography should be performed in mothers with anti-Ro antibodies; a recommendation is for weekly scans between 16 \200\22326 weeks o f gestation and alternate week scans from 28 \200\22334 weeks). SAP (serum amyloid P) scan should be performed if the diagnosis of amyloid is considered. Endomyocardial biopsy if myo carditis is suspected. Samples should be sent for PCR for microbial DNA or RNA (enterovirus , adenovirus, echovirus, HSV, CMV, EBV, HIV, Borelia, MTB, Chlamydia pneumonia). Figure 3.11 CT chest showing pericardial effusion in RA CXR reveals increased cardiothoracic ratio in cardiac failure and prominent upper lobe pulm onary veins in pulmonary venous hypertension. Cardiac enzymes should be measured to assess for a myocardial infarction or myocarditis. Pericardiocentesis should be considered when pu rulent, tuberculous, or malignant effusion is suspected. MR is useful for loculated effusio n, haemopericardium, or constrictive pericarditis. MR also evaluates severity of valvular r egurgitation. CT can also be used to assess pericardial anatomy and may be used to guide as piration of small effusions. THE HEART 70 Pulmonary arterial hypertension Refer to \200\230The Chest \200\231 in the chapter on Orga n involvement in Rheumatological Disease (Refer to \200\230The Chest \200\231 and also see SSc, p. 264 \200\223272). Dallas criteria for classi \201 cation of (PCR -ve) myocarditis Initial biopsy \200 Myocarditis myocyte necrosis, degeneration, or both in the absence of signi \201 cant coro nary artery disease, with adjacent in \202 ammatory in \201 ltrate \201 brosis. Bord erline myocarditis inflammatory infiltrate too sparse or myocyte damage not apparent. No my ocarditis. Aortitis \200 \200 Echocardiography. MR appearances of aortitis in Takayasu \200\231s arteritis have been desc ribed. It may be possible to discriminate appearances of Takayasu \200\231s from aortitis i n other condi- tions though clarifying studies are required. 18Fluorodeoxyglucose positron emission tomography (18FDG-PET) is used in some specialist centers to char- acterise GCA an d Takayasu \200\231s arteritis, but its precise role in diagnosis and monitoring, particula rly in GCA, remains to be clari \201 ed. Mild to moderate uptake of 18FDG tracer in vessel walls in atherosclerotic disease can occur and, especially in the elderly, this can confus e the picture further \200\223 leading to false positive results. Care in reporting is ess ential and interpretation should be made in light of other clinical information. Subsequent biopsy \200 \200 \200 On-going myocarditis \201 brosis. Resolving myocarditis \201 brosis. Resolved myo carditis \201 brosis. The in \202 ammatory in \201 ltrate is sub-classi \201 ed by domi- nant cell type (lymph ocytic, neutrophilic, giant cell, granulomatous or mixed), severity (mild, moderate, severe ) and distribution (focal, con \202 uent or diffuse). Valvular disease \200 Echocardiography (both TTE and TOE) is used to screen for valve lesions in predisposing con ditions (e.g. aortic regurgitation in AS) or on the \201 nding of a new murmur (e.g. susp ected rheumatic fever). Also use TTE/TOE to seek vegetations in suspected IE and in APLS (L ibman-Sacks endocarditis; TOE is more sensitive than TTE). Blood cultures \200\223 multipl e sets to exclude IE. Treatment Pericardial disease Refer to cardiologist if pericarditis is associated with comp romised cardiac performance. \200 Analgesia: either NSAIDs (beware increased risk of peptic ulcer disease in RA, and of oesop hageal dysmotility in SSc) or course of GCs. Treat underlying condition, usually with high- dose oral or pulsed intravenous GCs, initially, followed by intro- duction of GC-sparing im munosuppression. Therapeutic pericardiocentesis temporary drain in tamponade. Pericardia l fenestration in recurrent tamponade. Intra-pericardial triamcinolone and oral colchicine have been used in large, recurrent effusions. Resection of the pericardium is required in r are cases of constrictive pericarditis. \200 Myocardial and conduction system disease Common themes in the management of myocardial dise ase are: \200 Management of cardiac failure with diuretics, ACE inhibitors, nitrates, and, if required, i notropic support. Monitor potassium especially carefully in patients with renal disease, an d those on GCs or mycophenolate mofetil. Management of arrhythmias by conventional means, s ince no RCTs have been performed on patients with arrhythmias in inflammatory Rheumatologic al disease: \200 Figure 3.12 TTE: apical four-chamber view demonstrating vegetations in Libman-Sacks endocar ditis. Coronary artery disease \200 \200 \200 ECG for typical signs of ischaemia. Troponin I. In patients who are unable to exercise, str ess TTE can be performed using sympathomimetic agents. For example, a dobutamine stress tes t has a sensitivity of 74% and specificity of 70% for ischemia-induced wall motion abnormal ities). Vasodilators (dipyridamole or adenosine) can also be used. Non-invasive assessment includes stress nuclear echo or MR, or multi-detector (MD) CT. Coronary angiography remains the gold standard for the visualization of the coronary arterial tree. Dobutamine MR has a greater sensitivity (86%) and spe- ci \201 city (86%) for ischaemic-related wall motion d efects than dobutamine transthoracic echocardiography. SVT \200\223 use verapamil-type calcium channel blockers or B-blockers; for AF digoxin and other rate-controlling agents as per NICE guidance; AV nodal ablation may used to control ventricular response rate in patients with AF or atrial \202 utter, and is successful in >80%; in sinus tachycardia treat underlying cause (e.g. hyper- thyroidism or active in \202 ammatory disease); otherwise use B-blockers; for recurrent ventricular \201 brillati on (outside the con- text of acute MI), consider an implantable cardioverter de \201 brill ator; CHAPTER 3 Organ involvement in rheumatological disease 71 disease, e.g. RA and SLE. An algorithm for cardiovascular risk reduction in RA and SLE has been proposed. ventricular tachycardia (VT) \200\223 involve cardiology team urgently! Sustained, symptom atic, drug-resistant, monomorphic VT, re-entrant VT, and occasionally severely symptomatic premature ventricular contrac- tions, can be treated with radiofrequency ablation. Rheumatoid arthritis (RA) \200 Optimize control of disease activity, with minimal use of GCs. MTX treatment appears to red uce cardiovascular risk. Use of anti-TNFA agents may also reduce risk of cardio- vascular e vents, but may exacerbate severe CCF. Antimalarials may have anti-atherogenic activity and can be used in combination with other DMARDs. Use NSAIDs only when necessary and discuss po tential cardiovascular risks with patient. COX2 selective NSAIDs increase cardiovascular di sease risk and use should be discussed on an individual basis. Aspirin should also be used carefully, since RA is associ- ated with 5-fold increase in the risk of gastrointestinal h emorrhage. Monitor and modify traditional risk factors, including smoking, hypertension, hy perlipidaemia, obesity, diabetes mellitus, and hypothyroidism. A cardiovascular risk reduct ion algorithm has been proposed (see resources). \200 Prevention of mural thrombus with anticoagulants. Control of underlying condition. For chro nic in \202 amma- tory conditions, this includes high-dose GCs (usually pulsed intravenous methylprednisolone) in the early stages, followed by introduction of immunosuppressants su ch as azathioprine, mycophenolate mofetil, cyclophos- phamide, ciclosporin, tacrolimus, or sirolimus. Intravenous immunoglobulins are sometimes used (beware of volume overload in car diac failure), although evidence for their ef \201 cacy is anecdotal only. \200 Management of speci \201 c conditions \200 Viral myocarditis. Supportive treatment, but if there are concerns, involve cardiologist. C ardiac amyloid. Increase immunosuppression to reduce progression. Poor prognosis once con \201 rmed. Cardiac nodules. There is no evidence that immuno- suppression alters nodules. S urgery may occasionally be indicated. Sinus tachycardia in SLE may respond to GCs. Incomple te CHB in utero may respond to \202 uorinated GCs (dexametasone or betametasone), which c ross the placenta. Some studies suggest that betametasone i s preferable since high-dose de xametasone may be neurotoxic. Complete CHB may require pacing ( 33% within the \201 rst w eek post-partum). Refer to cardiologist. Prophylactic treatment of pregnant women with anti -Ro antibodies (even those with previous children with CHB) is not currently recommended be cause of the risk of spontaneous abortion, growth retardation, stillbirth and, possibly, ne urotoxicity with dexametasone. De \201 brillator and/or pacemaker implantation may be requ ired for a range of conduction disturbances, e.g. recurrent VT, bradyarrhythmias. Maintain a low threshold for referral of patients with myocardial and conduction system disease to c ardiologists; remember ischaemia is often silent in RA and SLE. Systemic Lupus erythematosus (SLE) \200 \200 \200 Optimize control of disease with minimal use of GCs. Antimalarials may have anti-atherogeni c and anticoagu- lant activity, and can be used alone or in combination with other immunosu ppressants. Aspirin prophylaxis may be bene \201 cial. A cohort study suggested that aspir in was associated with a 70% reducton in cardiovascular mortality. Monitor and modify tradi - tional risk factors, as for RA. Antiphospholipid syndrome (APLS) As for SLE but aspirin antimalarials are used in patien ts who have not had frank thromboembolic disease. Warfarin antimalarials are used in pat ients who have. Table 3.5 Recommendations for anti-TNFA use in RA patients with congestive cardiac failure Scenario Recommendation RA with no history of CCF No echocardiographic screening required. Valvular disease \200 RA with mild CCF (NYHA class I and II) Doppler echocardiography prior to anti-TNFA. Aspirin has been suggested for APLS patients with asymptomatic valvular disease, but the ev idence base is lacking. Consider the risk-bene \201 t ratio. Prophylactic antibiotics are not recommended by cur- rent guidelines. Valve replacement surgery is occasionally indicate d. Refer to cardiology for assessment. If LVEF >50% then treat following informed discussion and monitor with TTE. Avoid anti-TNFA. Consider using Rituximab. RA with severe CCF (NYHA class III and IV) Investigate and treat CCF. Coronary artery disease (CAD) General measures in CAD include nitrates, aspirin, statins, a nd anti-hypertensives, to maintain blood pressure <140/85. \200 Stop anti-TNFA and investigate and treat CCF. Development of CCF while receiving anti-TNFA treatment. Other conditions \200 \200 The UK Primary Care Quality and Outcomes Framework (QOF) for cardiovascular risk reduction, sets targets for blood pressure and lipids, which are less stringent than other recognized national guidelines. Furthermore more stringent guidance (e.g. Joint British Society guide lines) takes no account of the increased risk associated with inflammatory rheumatological For Kawasaki Disease \200\223 refer to Chapter 9, Vasculitis. Sarcoidosis \200\223 refer to section on Chapter 18, p. 512, Sarcoidosis in miscellaneous rheumatological disease. The frequency of CAD and other cardiovascular disease is increased in a number of in \202 amm atory rheumatologi- cal conditions. Careful management of conventional THE HEART 72 cardiovascular risk factors is recommended (BP, lipids, smoking), as well as screening for hyperglycaemia and hypothyroidism. NICE Clinical Guideline CG64: Prophylaxis against infec- tive endocarditis (www.nice.org). Further reading Bidani AK, Roberts JL. Immunopathology of cardiac lesions in fatal Pulmonary arterial hypertension Refer to both section on SSc (p. 264 \200\223272), and the section on \200\230The Chest \200\231 in Chapter 3, p. 54 systemic lupus erythematosus. Am J Med 1980; 69: 849 \200\22358. Hall FC, Dalbeth N. Disease modi \201 cation and cardiovascular risk reduction: two sides of the same coin? Rheumatol 2005; 52: 3678 \200\2239. JBS2. Joint British Societies \200 \231 guidelines on prevention of cardiovas- Aortitis Treat underlying in \202 ammatory disease since dilatation of aorta increases the risk of vessel rupture. cular disease on clinical practice. Heart 2005: 91: 1 \200\22352. Khanna D, McMahon M. Anti-tumor necrosis factor alpha therapy and heart failure. Arthritis Rheum 2004; 50: 1040 \200\22350 Resources British Heart Foundation information online. Available at: www.bhf.org.uk/default .aspx Cardiovascular risk reduction algorithm for patients with RA and SLE. Available at: w ww.medschl.cam.ac.uk/ medtools/chd1.php Panoulas et al. Algorithm for management of hyperte nsion in RA. 2008; see references. Maisch B, Pankuweit S, et al. Invasive techniques \200\223 from diagnosis to treatment. Rheumatology 2006; 45: iv32 \200\22338. Maksimovic R, Seferovic PM, et al. Cardiac imaging in rheumatic diseases. Rheumatology 2006; 45 iv26 \200\22331. Panoulas VF, Metsios GS, et al. Hypertension in rheumatoid arthritis. Rheumatol 2008; in press. Rosenstein ED, Zucker MJ, Kramer N. Giant cell myocarditis: most fatal of autoimmune diseas es. Semin Arthritis Rheum 2000: 30: 1 \200\22316. Seferovic PM, Ristic AD, et al. Cardiac a rrhythimias and conduction disturbances in autoimmune rheumatic diseases. Rheumatol 2006; 4 5: iv39 \200\22342. Assessment tools New York Heart Association (NYHA) Functional Classi \201 cation system Slobodin G, Naschitz JE, et al. Aortic involvement in rheumatic diseases. Clin Exp Rheumatol 2006; 24: S41 \200\2237 Soltesz P, Szekanecz Z., et al. Cardiac manifestations in antiphos- Class Patient symptoms pholipid syndrome. Autoimmun Rev 2007; 6: 379 \200\22386. I No limitation of activity. Ordinary physical activity does not cause undue fatigue, palpita tion, or dyspnoea. Tincani A, Rebaioli CB, et al. Heart involvment in systemic lupus erythematosus, anti-phosp holipid syndrome and neonatal lupus. Rheumatology 2006: 45: iv8 \200\22313 II Slight limitation of activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnoea. Van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis. An extraarticular feature o f rheumatoid arthritis? Arthritis Rheum 2002; 46: 862 \200\22373. III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activit y causes fatigue, palpitation, or dyspnoea. Voskuyl AE. The heart and cardiovascular manifestations in rheuma- toid arthritis. Rheumatology 2006; 45: iv4 \200\2237 Weyand CM, Gornzy JJ. Medium and large-vessel vasculitis. N Engl J IV Symptomatic at rest. Any physical activity increases fatigue, palpitation, or dyspnoea. Med 2003; 349: 160 \200\2239. Guidelines Joint British Societies \200\231 guidelines on prevention of cardio- vascular di sease in clinical practice (see refs). This page intentionally left blank THE KIDNEY 74 The kidney Renal involvement in rheumatological disease is a signi \201 cant cause of morbidity and p redictor of mortality. These complications can arise as a result of the direct effects of t he disease or as a result of the treatment. Diseases with particularly strong associations with kidney involvement include: systemic lupus erythematosus (SLE), systemic vasculitides, rheumatoid arthritis (RA), systemic sclerosis, Beh et \200\231s disease, anti-phospholipi d antibody syndrome (APLS), Sj gren \200\231s syndrome (SS) and sarcoidosis. Medica- tions commonly used in rheumatological diseases and commonly associated with renal complications include: non-steroidal anti-inflammatory drugs (NSAIDs), D-penicillamine, and gold. HSP is seen primarily in children aged 3 \200\22315 years with an annual incidence of appro ximately 20/100 000 children. HSP is uncommon in adults. HSP is slightly more common in mal es. Renal disease complicates approximately 20% of cases of cryoglobulinemia (50% have a ne phritic syndrome). Nephritis is a very rare complication of RA and may result from a focal mesangial lesion, a rheumatoid vasculitis or from D-penicillamine treatment. Etiology/pathophysiology The nephritic syndromes result from perturbation of the glomerular endothelium resulting in red blood cells leaking into the urinary space (causing haematuri a and cel- lular casts), and obstruction of the capillaries from either endocapillary proli feration or the proliferation of extra- capillary components of the glomerulus (see Plate 3 5). Obstruction of the capillary lumens leads to renal dysfunction and hypertension. Rheumatological diseases that affect the kidney can present as any one of several syndromes . Major renal syndromes include the nephritic syndrome, the nephrotic syndrome, tubulointer stitial nephritis, and acute or chronic renal failure. Nephritic syndromes (glomerulonephritis) De \201 nition The nephritic syndrome is characte rized by new onset or worsening hypertension, acute renal failure and abnormalities of urin e sediment, primarily glomerular hae- maturia, cellular casts and non-nephrotic range prote inuria (<3.5 g/day). Renal dysfunction is an insensitive marker of renal involvement due to the inherent large reserve of renal function in most people. Also, nephrotic range protein uria does not exclude a nephritic syndrome. SLE \200 Renal involvement in SLE is characterized by immune complex deposition. Immune complexes ar e composed of DNA-anti-DNA and may include composites of nucleosomes, C1q, chromatin, and o ther nuclear antigens. The pattern of deposition of immune complexes largely determines the phenotype of the renal disease. Large and anionic immune complexes deposit in the subendot helial and mesangial compartments of the glomerulus, and subsequent activation of the immun e systems provokes a proliferative glomerular lesion the severity of which is determined by the amount deposited. Severe proliferative lesions are char- acterized by dysmorphic haema turia, red blood cell casts, proteinuria, hypertensions, and eventually renal dysfunction. Kidney involvement in SLE may be due to specific subclasses of IgG in speci \201 c patient s. IgG1 and IgG3 autoantibodies more avidly fix complement, and are more commonly associate d with severe renal lesions. Rheumatological diseases associated with the nephritic syndrome include proliferative lupus nephritis, anti-neutrophil cytoplasm antibody associated vasculitis [(AAV), which include Wegener \200\231s granulomatosis (WG), microscopic polyangiitis (MPA) and Churg \200\223Str auss syndrome [CSS]), Henoch \200\223Sch nlein purpura (HSP), cryoglobulinemic vasculitis and, rarely, RA or Beh et \200\231s disease. The nephritic syndrome results from immunolog ical lesions of the glomerulus in these diseases. Epidemiology \200 75% of patients with SLE will have abnormalities of urinalysis at some point. 16% of patien ts in large European cohorts have signi \201 - cant proteinuria at diagnosis of SLE and 35 % will develop proteinuria within 10 years of diagnosis. Renal involvement in drug-induced lupus is rare. ANCA associated vasculitis (AAV) has a an overall inci- dence of 10 \200\223 14 per million in Europe and 80% will have some form of renal involvement but this may vary from isolated urinary abnormalities to rapidly progressive glomerulonephritis and end-stag e renal disease The incidence of AAV peaks in the 6 \200\2237th decade of life. ANCA determ ined by immuno \202 uorescence is manifest by either a cytoplasmic pattern (C-ANCA), assoc iated with reactivity to proteinase 3 (PR3-ANCA) by ELISA, or a peri-nuclear pattern (P-ANC A) associated with reactivity to myeloperoxidase (MPO-ANCA). Approximately 90% of patients with WG will have a detectable ANCA (the majority are PR3-ANCA posi- tive), while approxima tely 70 \200\22380% of patients with MPA will have a detectable ANCA (usually MPO-ANCA posi - tive). Less than 50% of patients with CSS are ANCA positive (usually MPO-ANCA). AAV \200 \200 The pathogenicity of ANCA is debated. Murine models of MPO-induced glomerulonephritis provi de the strongest evidence that ANCA are patho- genic. This evidence is supported in humans by a case report of in utero transfer of ANCA causing a pulmo- nary-renal syndrome. However , ANCA alone may be insuf \201 cient in humans to cause disease and other abnor- malities, such as a neutrophil priming event (an infection or environmental exposure), endothelial d ysfunction, B cell dysfunction, and Fc-RIIIB polymorphisms are impli- cated in the pathogen esis. Whether these abnormalities are required to initiate vasculitis or are a consequence of the vasculitic damage are unclear. \200 \200 HSP \200 Renal damage is mediated by the deposition of immune complexes, primarily immunoglobulin A1 . IgA deposition may result from increased IgA secretion following a mucosal infection and/ or abnormal glycosyla- tion of IgA. CHAPTER 3 Organ involvement in rheumatological disease 75 Cryoglobulinaemia \200 Special investigations \200 Antigen-antibody complexes are deposited in small and medium arteries including glomerular capillaries. Hepatitis C virus (HCV) is a common cause. Serum creatinine should be performed in all patients suspected of having nephritis, but are not sensitive even in cases of severe disease, as abnormalities of renal function tend to occur late in the disease course. Urinalysis demonstrating dysmorphic haematuria with prote inuria and/or cellular casts support the presence of glomerulonephritis. Quantification of proteinuria \200\223 either a 24-h urine collection or a spot morning urine protein to cre atinine ratio should be performed in patients with suspected nephritis and dipstick positiv e proteinuria. Blood tests aim to determine the cause of nephritis and should include hepat itis B, hepatitis C, HIV, ANCA, anti-glomerular basement membrane antibodies, ANA, anti-DNA antibodies, extractable nuclear antigens, APL antibodies, RF, complement levels, protein e lectrophoresis, and cryoglobulins. Anti-double stranded DNA antibodies and hypocomple- ment emia occur frequently in patients with SLE. ANCA indirect immunofluorescence, and an ELISA for PR3 and MPO antibodies should be done in all cases. A negative test does not exclude a diagnosis of vasculitis. A renal biopsy should be used to con \201 rm the diagnosis whenev er possible, since no serological or urine labora- tory work are suf \201 ciently sensitiv e and speci \201 c. A renal biopsy will also provide prognostic information and is used to stratify treatment (see color plates). Risk factors \200 Patients of black African or Hispanic descent are more likely to have lupus nephritis, and it is more likely to follow a severe course. AAV patients with nasal Staphylococcus aureus carriage are at higher risk of relapse. A1-antitrypsin de \201 ciency is associated with a more severe course. The NA1 polymorphism of the FcG-RIIIB allele also appears over- repres ented in patients with severe AAV. AAV may result as a complication of medications used in hyperthyroidism, such as propylthiouracil or more rarely with the use of hydralazine or min ocycline. Exposure to silica has also been associated with the development of AAV. HSP occu rs rarely in the summer and is commonly preceded by an upper respiratory tract infection. Key features in the history Features associated with the nephritic syndrome. \200 New onset hypertension or hypertension that has become increasingly dif \201 cult to contr ol. Hypertension may be severe and present as an emer- gency (headache, visual changes, che st pain, dyspnoea). Advanced and chronic renal failure is associated with fatigue, anorexia , and pruritis. Abnormalities of the urinalysis: haematuria and cellular casts and sub-neph rotic levels of proteinuria. Cellular casts are often missed in routine urine samples, but are quite speci \201 c for a nephritic process. The protean manifestations of renal dysfun ction or a systemic immunological process are often mistaken for an infection. Patients com monly report being treated with antibiotics for upper respiratory or urinary tract infectio ns repeatedly with no improvement in their symptoms. This is particularly true of patients with abnormalities of the urinalysis, but without a docu- mented microbiologic diagnosis. E xtra-renal manifestations of systemic diseases are often more pronounced during periods whe n the kidneys are also involved. Treatment Supportive treatment for all patients with nephritis includes the management of v olume status, electrolyte abnormalities, and hypertension. Renal replacement ther- apy in t he form of dialysis or renal transplantation may be required for patients with advanced ren al failure. The treat- ment of lupus nephritis is usually predicated by renal biopsy \201 ndings. \200 Class I and II lesions typically have an excellent renal prognosis even without treatment a nd are not speci \201 - cally treated. Proliferative lupus nephritis (Class III and IV) is