Arthralgia: Is mainly due to hypertrophic osteoarthropathy. In patients with R l L shunt, m egakaryocytes bypass the pulmonary circulation and become trapped in systemic vascular beds , promoting new bone formation. Haemoptysis is common. Most episodes are self-limiting and precipitated by infection. Diffe rentiation from pulmonary embolism may be dif \201 cult. Try to keep the patient calm and ensure adequate BP control. Give high- \202 ow oxygen by mask. If there is clinical suspic ion of infection (fever, sputum production, leukocytosis, raised C-reactive protein (CRP), etc.) start broad-spectrum antibiotics. Ventilation \200\223perfusion (VQ) scan may help in the diagnosis of pulmonary embolism but is often equivocal. Avoid aspirin and NSAIDs as th ese exacerbate the intrinsic platelet abnormalities. There is anecdotal evidence for the us e of low-dose IV heparin, dextran 40 (500 mL IV infusion q4 \200\2236h), Arvin (reduces plasma \201 brinogen by cleaving \201 brin), or low-dose warfarin therapy for reducing thrombotic tendency in these patients. Severe pulmonary hemorrhage may respond to aprotinin or tranexamic acid. Breathlessness may be due to pulmonary oedema or hypoxia (increased shunt) secondary to che st infection or pulmonary infarction. Do not give large doses of diuretics or nitrates as t his will drop systemic pressures and may precipitate acute collapse. Compare CXR to previou s \201 lms to try to assess if there is radiological evidence of pulmonary oedema. The JV P in patients with cyanotic CHD is typically high and should not be used as a sole marker o f heart failure. Overall, patients need a higher \201 lling pressure to maintain pulmonar y blood \202 ow. Give high- \202 ow oxygen by mask. Start antibiotics if there is a clin ical suspicion of infection. Give oral diuretics if there is evidence of pulmonary oedema o r severe right heart failure. Monitor haematocrit and renal function closely for signs of o ver-diuresis. Effort syncope should prompt a search for arrhythmias, in particular ventricular tachycardi a (VT) (Holter monitor), severe valve disease, or signs of overt heart failure. Treat as ap propriate. Chest pain may be secondary to pulmonary embolism or infarction (spontaneous thrombosis), p neumonia, ischaemic heart disease, or musculoskeletal causes. It requires careful evaluatio n with the conventional diagnostic modalities already described. This page intentionally left blank 617 Chapter 13 Multisystem disorders Coronary artery disease in patients with rheumatologic diseases 618 Rheumatoid arthritis 620 Systemic lupus erythematosus 622 Antiphospholipid syndrome 624 Neo natal lupus 625 Systemic sclerosis 626 Pulmonary hypertension and connective tissue disease s 626 Polymyositis and dermatomyositis 627 Mixed connective tissue disease 627 Sj gren \200\231s syndrome 627 Takayasu arteritis 628 Giant cell (temporal) arteritis 629 Kawasaki disease 630 Small- and medium-vessel vasculitis 632 Small vessel vasculitis 632 Ankylosing spondylitis 634 Marfan syndrome 636 Ehlers \200\223Danlos syndrome 640 Rheumatic drug thera py and the heart 642 Erectile dysfunction 644 Chronic kidney disease as a cardiovascular ri sk factor 646 CKD: which examinations are appropriate? 648 Side-effects of cardiological in vestigations in patients with CKD 649 Prevention and treatment of cardiovascular sequelae in renal patients 650 618 CHAPTER 13 Multisystem disorders Coronary artery disease in patients with rheumatologic diseases Origins \200 Atherosclero sis, thrombosis, arteritis, vasospasm Epidemiology Systemic lupus erythematosus (SLE) \200 The prevalence of ischaemic heart di sease (IHD) is 6 \200\22310 % (true prevalence of subclinical disease not known). Women with SLE are overall 5 \200\2236 times more likely to have a myocardial infarction (MI) than non-lupus women of similar age. Rheumatoid arthritis (RA) \200 Incidence 4.8 \200\2235.9/1000 person-years. Patients with RA are 2 \200\2233 times more likely than matched controls to have a MI, after controlling for traditional risk factors. Epicardial disease is more common than microvascular disease. \200 Patients with acute co ronary syndrome (ACS) have a twofold recurrence rates risk and mortality compared with age- and sex-matched controls. Coronary arteritis is uncommon; it affects epicardial and small/ medium-sized intramyocardial arteries and usually presents as ACS. In \202 ammation and atherogenesis \200 There is evidence that in \202 ammation has a f undamental role in the initiation and progression of atherosclerosis. Increased risk of IHD cannot be fully explained by traditional atherogenic risk factors (hypertension, hyperlipidaemia, diabetes mellitus, smoking, obesit y, sedentary lifestyle). Disease or treatment-related risk factors: elevated homocysteine, glucocorticoid use, renal disease (SLE), seropositive disease (RA), and non-steroidal anti-in \202 ammatory drug (N SAID) use (probably by increasing blood pressure). Differential diagnosis of chest pains \200 IHD: maintain lower than normal threshold for investigating and appreciate it as a cause in younger patients Primary coronary artery thrombosis (antiphospholipid syndrome) \200 Upper gastrointestina l problems associated with NSAID use \200 Costochondritis \200 Osteoporotic rib/vertebr al fracture \200 Pleuropericarditis \200 Large-vessel vasculitis causing aortic dissect ion or aneurysm Management \200 Physician awareness and patient education \200 Manage traditional risk factors: aggressive blood pressure control, lipid- lowering agents, smoking cessation CAD IN PATIENTS WITH RHEUMATOLOGIC DISEASES 619 Individualized aerobic exercise program \200 Disease-speci \201 c potential risk factors : reduce homocysteine levels (consider folate supplementation), minimize glucocorticoid use , recognize thrombotic potential; consider antiphospholipid antibodies See Table 13.1. Table 13.1 Cardiac manifestations of rheumatic diseases e s a e s i d m e t s y s n o i t c u d n o C t o o r l a i d r a c o y M l a i d r a c i r e P y r a n o r o C r a l u v l a V e s a e s i d e s a e s i d e s a e s i d e s a e s i d e s a e s i d c i t r o A Ankylosing spondylitis + + + + + + + Beh et \200\231s disease + + + + Churg \200\223Strauss syndrome + + Giant cell arteritis + + + + + Kawasaki \200\231s disease + + + Neonatal lupus erythematosus + + + Polyarteritis nodosa + Polymyositis/dermatomyositis + + + Reiter \200\231s syndrome + Rheumatoid arthritis + + + + + + + + Adult Still \200\231s disease + + + + + Systemic lupus erythematosus + + + + + + + + + Systemic sclerosis + + + + + + Takayasu \200\231s arteritis + + + + + + + + Wegener \200\231s granulomatosis + Taken from Manzi S, Kao AH, Wasko MM Oxford Textbook of Rheumatology , Chapter 1.3.4 The ca rdiovascular system. Oxford: Oxford University Press. 620 CHAPTER 13 Multisystem disorders Rheumatoid arthritis \200 RA is a multisystem in \202 ammatory autoimmune disease charac terized by a symmetrical and progressive deforming, peripheral arthropathy. Prevalence 1 % ; male:female = 1:3, peak onset in the \201 fth decade. Clinical features \200 Constitutional symptoms such as fever, malaise and fatigue \200 Symmetrical polyarthritis with insidious or abrupt onset \200 Early morning and rest stif fness \200 Subcutaneous nodules \200 Pleuritis, interstitial lung disease, intrapulmona ry nodules \200 Scleritis, episcleritis, dry eyes Cardiac disease Coronary artery disease \200 See b p. 618. Pericarditis \200 50 % of ca ses have a benign \201 brinous pericarditis with effusions seen in 40 % of cases on echocardiography 1 \200\2232 % of cases are symptomatic \200 Usually independent of disease duration and m ay precede it \200 Cardiac tamponade and constrictive pericarditis are rare \200 Respon ds to treatment with steroids and disease-modifying drugs Myocardial and endocardial granul omas \200 Found in more than 50 % of patients with subcutaneous nodules \200 Rarely, th ey compromise cardiac function through mitral valve deformity and regurgitation Rarely, they cause conduction problems like \201 rst-degree (commonest), left bundle branch, and complete heart blocks Myocarditis \200 20 % of patients with severe disease have a diffuse myocarditis with non speci \201 c in \202 ammatory in \201 ltrates, myocyte necrosis, and \201 brosis \200 May rarely cause biventricular failure, arrhythmias, and conduction problems Ventricular function may also be compromised by secondary amyloidosis Valvular disease \200 Non-speci \201 c valvitis producing \201 brotic, hyalinized valv es with occasional incompetence. The aortic valve is affected more commonly than the mitral valve Treatment \200 Immunosuppressive therapies such as disease-modifying anti-rheumatic drugs (DMARDs) (e.g. methotrexate), Anti-TNF (tumor necrosis factor) therapies and rituximab Early intensive treatment (often with combinations of therapies) to tightly control disease activity prevents joint damage and progression to disability RHEUMATOID ARTHRITIS 621 RA predictors of coronary artery disease \200 Older age of disease onset \200 Early cor ticosteroid therapy \200 Longstanding disease ( > 10 years) \200 Active extra-articular disease \200 Active erosive and nodular disease \200 Vasculitis \200 High serum titr es of rheumatoid factor \200 High levels of haptoglobin \200 Erythrocyte sedimentation rate (ESR) > 55 mm/h. 622 CHAPTER 13 Multisystem disorders Systemic lupus erythematosus \200 Multisystemic autoimmune disease affecting predominatel y women; female:male = 9:1, peak onset in 20s and 30s, Prevalence per 100 000 estimated at 35 in Caucasian and 177 in African-Caribbean individuals in the UK 1 Associated with accelerated atherosclerosis (see b p. 212) \200 Pulmonary hypertension ma y occur though more frequent in scleroderma and mixed connective tissue disease (see b p. 627) Pericarditis \200 Symptomatic pericarditis occurs in approximately 25 % of SLE sufferers at some point in their disease. Autopsy studies show pericardial disease in 61 \200\223100 % . The pericardial \202 uid is usually exudative. Pericarditis is commonly associated with pleurisy and/or pleural effusion. It is frequently associated with active disease in other organs, so full assessment of dise ase activity is required, including urinalysis, urine protein/creatinine ratio, anti-dsDNA, and complement levels. \200 Unusually for SLE, the C-reactive protein (CRP) is usually h igh, and there may also be a fever. Rub is rarely audible; diagnosis is con \201 rmed by electrocardiography (ECG) or ECHO. Complications such a pericardial tamponade and constrictive pericarditis are rare, and invasive therapy is not usually required. \200 There is usuall y a prompt response to prednisolone therapy; this may suggest the need for escalation of ot her disease-modifying therapy. Myocarditis \200 Myocarditis is a vasculopathy rather than true myositis; creatine kinase (CK) is usually normal. Diagnosis is usually clinical, based on global ventricular hypokinesis in the context of ac tive disease. Myocardial biopsy, despite the risk of sampling error, remains the gold stand ard for diagnosis. Prevalence by echocardiography is 1 \200\22320 % . \200 Clinically apparent disease usual ly requires high-dose corticosteroid therapy and escalation of therapy to include other immunosuppressive therapy (such as pulse d cyclophosphamide) in addition to standard heart failure therapy. Valvular heart disease \200 Valve abnormalities are found in 28 \200\22374 % , most commo nly of the mitral valve followed by the aortic valve. Other valves and endocardial surfaces may also b e affected. It may cause valve regurgitation; stenosis is rare. Libman \200\223Sack \200\231s (verrucous) endocarditis occurs in 4 \200\22343 % of cases; i t is more frequently found in those with antiphospholipid antibodies. SYSTEMIC LUPUS ERYTHEMATOSUS 623 Valve lea \202 et thickening occurs in 19 \200\22352 % of cases, with associated regurgita tion in 73 % . There is no evidence for the use of immunosuppression or anticoagulation therapy despite the association with complications. Conduction defects \200 Conductions defects can be detected in up to 5 % of patients but complete heart block is restricted to case reports. 624 CHAPTER 13 Multisystem disorders Antiphospholipid syndrome \200 This is an acquired autoimmune thombophilia that causes bo th arterial and venous thrombosis and pregnancy morbidity. Diagnosis requires the detection of anti-cardiolipin, anti- B 2 -protein antibodies, or lupus anticoagulant, con \201 rmed after 12 weeks to ensure persistence. It may be primary or secondary to other connective tissue diseases, particularly SLE. Valvular disease \200 Valve abnormalities are found in 30 \200\22332 % of cases, particul arly those with peripheral arterial thromboses. Vegetations occur in 6 \200\22310 % and thi ckening in 10 \200\22324 % . As with SLE, the mitral valve is most frequently affected, followed by the aortic valve. There is no evidence for immunosuppression or anticoagulation. Thrombotic disease \200 Although rare, MI may occur due to primary thrombotic disease despite normal angiography. Pulmonary veno-occlusive disease may cause pulmonary hypertensi on. A micro-angiopathic cardiomyopathy has also been described. NEONATAL LUPUS 625 Neonatal lupus \200 Neonatal lupus is associated with the transplacental transmission of anti-Ro antibodies and anti-La antibodies. It is not limited to women with lupus, and frequently the mothers have other connective tissue diseases or are asymptomatic. The predominant manifestations are photosensitive neonatal lupus rash and congenital heart block, but other organs may be involved. With the exception of heart block and myocardial disease, the disease resolves with the clearance of maternal antibodies. Congenital heart block \200 Congenital heart block occurs in approximately 2 % of the off spring of anti-Ro antibody-positive mothers, with a recurrence rate in subsequent pregnanci es of around 17 % . There is frequently associated myocardial disease. \200 It usually presents between 18 an d 30 weeks of gestation. \200 Early mortality occurs in approximately 20 % . \200 Compl ete heart block is irreversible, 1st- and 2nd-degree heart block may respond to therapy. Be tamethasone or dexamethasone should be considered. First-degree heart block detected in utero frequently resolves spontaneously. Pre-emptive therapy is not recommended, \202 uorinated steroids and beta-s timulation may be bene \201 cial in fetuses that are compromised. 626 CHAPTER 13 Multisystem disorders Systemic sclerosis \200 Systemic sclerosis is characterized by scleroderma proximal to th e metacarpal phalangeal joints, Raynaud \200\231s, oesophageal dysmotility, calcinosis, and telangectasia. Limited systemic sclerosis : scleroderma is con \201 ned to the face and distal limbs in 7 0 % of cases; associated with anti-centromere antibodies. Diffuse systemic sclerosis : pati ents are more likely to develop lung, cardiac, and renal disease and have a poorer prognosi s in 30 % of cases. Associated with anti-Scl70 antibodies. Following therapeutic advances (particularly for renal hypertensive crisis), cardiac disease and pulmonary hypertension have become more prominent causes of de ath, with pulmonary hypertension second only to pulmonary \201 brosis. Cardiac disease \200 Myocardial \201 brosis is found in 50 \200\22380 % of cases in aut opsy studies and in 2/3 of cases using delayed enhanced magnetic resonance imaging (MRI). No immunomodulatory therapy has been shown to alter the progression of myocardial \201 brosis. It is associated with atrial and ventricular arrhythmias, cardiac failure and sudden death. Pulmonary hypertension and connective tissue diseases \200 Pulmonary arterial hypertensio n is the most frequent cause of death in systemic sclerosis (occurs more frequently in limi ted systemic sclerosis). It also occurs in the other connective tissue diseases, predominantly mixed connective tissue disease and SLE. In addition to pulmonary vascular disease, patients are also at risk of pulmonary hypertens ion secondary to interstitial lung disease or veno-occlusive disease related to the antipho spholipid syndrome. \200 Patients at high risk, namely ribonucleoprotein (RNP)-positive m ixed connective tissue disease and systemic sclerosis should be screened annually for pulmo nary hypertension by echocardiography and lung function testing (including transfer factor) . Due to the high pregnancy mortality in women with pulmonary hypertension, RNP-positive patients and those with systemic sclerosis should also be screen ed before conception. In contrast to systemic sclerosis, there are some retrospective data to suggest that a prop ortion of patients with SLE and mixed connective tissue disease may respond to cyclophospha mide therapy. Thus, in addition to the therapies discussed on b p. 622, immunosuppressive t reatment should be considered in these patients. SJ \226GREN \200\231S SYNDROME 627 Polymyositis and dermatomyositis \200 Cardiac disease is the main cause of death in polym yositis (PM) and dermatomyositis (DM) after malignancy and interstitial lung disease. Howev er, it is unclear whether this is due to accelerated atherosclerosis or myocarditis. 25 % of cases have myocarditis at post-mortem, with microscopic interstitial \201 brosis, non-speci \201 c in \202 ammatory in \201 ltrates, and necro sis. Ventricular function is usually preserved. However, disease that is severe enough to c ause cardiac failure is rare. Conducting tissues may be affected, producing non-speci \201 c ST- and T-wave changes, atr ial arrhythmias, and atrioventricular and bundle branch block. These are more commonly seen in children. \200 Clinically apparent pericarditis is rare but is seen in 25 % on echocardiography. Cor pulmonale may occur secondary to primary lung disease or pulmonary hypertension. Overt myocarditis should be treated using steroids and immunosuppressive drugs. Mixed connective tissue disease \200 This group of patients has high-titre anti-RNP antib odies and clinical features of scleroderma, SLE, and in \202 ammatory myositis. As such, t hey may have the cardiac manifestations of any of these connective tissue diseases. Pericar ditis is the commonest cardiac manifestation, found in 10 \200\22330 % patients. Pulmonary hypertension has a prevalence of approximately 13 % and is a major cause of death. Patients should have annual screening for pulmonary hypertension. Sj gren \200\231s syndrome \200 This predominantly affects the exocrine glands, causing dry eyes and dry mouth secondary to lacrimal and salivary gland disease. Anti-Ro and anti-La antibodies are a hallmark of the disease, and as such there is a small risk of congenital heart block in the offspring of affected women. However, heart block in Sj gren \200\231s patients is rare. \200 Clinically apparent cardiac disease is rare as a manifestation of Sj gren \200\231s syndrome. However, subclinical diastolic function and asymptomatic pericarditis may be common. 628 CHAPTER 13 Multisystem disorders Takayasu arteritis \200 This is an idiopathic, segmental, granulomatous, large-vessel vas culitis predominantly involving the aorta and its branches. UK incidence: 0.15/million; 80 \200\22390 % female in their 2nd/3rd decade. \200 Symptoms are non-speci \201 c and symptoms include fever, fatigue, weight loss, myalgia, arthralgia, and rash, frequent at onset. Limb claudication, abdominal pain, and syncope are due to arterial disease producing end-organ ischaemia. Investigations \200 Arterial biopsy is not usually feasible; thus imaging is core to diag nosis. \200 Imaging demonstrates the characteristic stenoses, occlusions, and/or aneurysms of the aorta and its primary branches. Arteriography is usually diagnosic but invasive \200\224 cannot assess arterial wall thickness. Magnetic resonance angiography (MRA) and/or computed tomography (CT) angiog raphy is usually used. Ultrasound is also helpful. Positron emission tomography (PET) may s how increased uptake in active disease. Bloods are non-speci \201 c; there are usually raised in \202 ammatory markers. \200 Ec hocardiogram is used to assess the ventricles, aortic root, and valve. Cardiac complications \200 Heart failure from central hypertension due to stenotic lesion s \200 Aortic regurgitation secondary to aortitis \200 Angina and MI from ostial or cor onary arterititis. Treatment \200 High-dose steroids; additional agents used include methotrexate, azathiopr ine, le \202 unomide, and anti-TNF therapy, but evidence is limited. Balloon angioplasty/stenting or surgery may be complicated by restenosis due to ongoing in \202 ammation. GIANT CELL (TEMPORAL) ARTERITIS 629 Giant cell (temporal) arteritis \200 This is characterized by granulomatous large- and me dium-vessel vasculitis occurring in individuals aged (cid:116) 50 years. Incidence is 1/500 in this age group Features: visual disturbance/loss, jaw claudication, and temporal headaches. Polymyalgic symptoms may be present High in \202 ammatory markers \200 Temporal artery biopsy is diagnostic but may be norma l due to patchy involvement Cardiac complications \200 Aortitis and aortic valve disease may occur. \200 Thoracic a neurysms are a late complication occurring in approximately 10 % of cases and may progress to dissection. \200 Coronary artery involvement is also re cognized. Treatment \200 High-dose steroids. Two randomized controlled trials (RCTs) assessing methotrexate had con \202 icting results. Retrospective data suggest low-dose aspirin may reduce the risk of cranial ischaemic events and visual loss. 630 CHAPTER 13 Multisystem disorders Kawasaki disease \200 There is arteritis of large, medium, and small arteries, particular ly the coronary arteries. UK incidence: 78/100 000 children; 90 % at <10 years (peak 18 \200\22324 months in USA and 6 \200\22312 months in Japan). Male > female. It is more common in childr en of Far-East descent. Clinical features Acute stage (days 1 \200\22311): High fever, irritability, non-exudative bilateral conjunctivitis (90 % ), iritis (70 % ), perianal erythema (70 % ), acral erythema and oedema that impede ambulation, strawberry tongue, lip \201 ssures, hepatic, renal, a nd gastrointestinal dysfunction, myocarditis, pericarditis, mitral and, rarely, aortic regu rgitation, and cervical lymphadenopathy (75 % ). Subacute stage (days 11 \200\22330): Persistent irritability, anorexia, conjunctival infect ion, decreased temperature, thrombocytosis, acral desquamation, and aneurysm formation. Convalescent/chronic phase (after 30 days): Aneurysm expansion, possible MI, and resolution of smaller aneurysms (60 % of cases). Investigations \200 Blood abnormalities are non-speci \201 c: raised in \202 ammatory m arkers (ESR, CRP), normocytic anemia, granulocytosis, thrombocytosis (weeks 2 \200\2233), a nd thrombocytopaenia (with severe coronary disease), mild transaminitis (40 % ) and raised bilirubin (10 % ). Echocardiogram to detect coronary aneursyms (4 % with intravenous immunoglobulin (IVIG) the rapy, 20 \200\22325 % untreated or aspirin alone), impaired cardiac function, valvular hear t disease, and pericardial effusions. Perform at diagnosis, 2 weeks, and 6 \200\2238 weeks after diagnosis in uncomplicated cases. In patients with aneurysms, serial monitoring with echocardiography. \200 In chronic dise ase, stress testing, angiography, spiral CT, and/or cardiac MRI may be required to assess or monitor disease. Treatment \200 Aspirin 30 \200\223100 mg/kg daily for 4 days, and thereafter, 3 \200\2235 mg/kg daily. If no coronary aneurysms, treatment can be stopped after resolution of in \202 ammation. As there is a risk of Reye \200\231s syndrome, annual in \202 uenza vaccine should be given if there is long-term use. Intravenous gammaglobulin (2 mg/kg) within 10 days of onset of symptoms. Further courses may be tried in resistant cases. Consider in patients presenting later if there are aneurysms or ongoing in \202 ammation. In refractory disease, other agents such as methylprednisolone or in \202 iximab (an anti-TNF agent) may also be considered. KAWASAKI DISEASE 631 In chronic disease, in patients with giant aneurysms, due to the risk of coronary thrombosi s, anticoagulation or additional platelet therapy should be considered. In a small minority of patients, coronary artery bypass surgery (CABG), percutaneous corona ry intervention (PCI), or valvular heart surgery is required. Differential diagnosis of Kawasaki disease: diseases and disorders with similar clinical \201 ndings \200 Viral infections (e.g. measles, adenovirus, enterovirus, Epstein \200 \223Barr virus) Scarlet fever \200 Staphylococcal scalded skin syndrome \200 Toxic shock syndrome \200 Bacterial cervical lymphadenitis \200 Drug hypersensitivity reactions \200 Stevens \200\223Johnson syndrome \200 Juvenile rheumatoid arthritis \200 Rocky Mountain spotted fever \200 Leptospirosis \200 Mercury hypersensitivity reaction (acrodynia). 632 CHAPTER 13 Multisystem disorders Small- and medium-vessel vasculitis \200 Polyarteritis nodosa and Churg \200\223Strauss v asculitis affect medium and small vessels. Both may be complicated by coronary artery involvement or myocarditis, which are poor progn ostic factors for survival. The presence of cardiac disease is an indication for cyclophosphamide therapy. Churg \200\223Strauss syndrome \200 This is systemic vasculitis characterized by allergic rhinitus, late-onset asthma, blood eosinophilia, and eosinophilic pulmonary in \201 ltrat es. Cutaneous and peripheral nerve involvement is common. Peak onset is at 38 years, but it can occur throughout adulthood, and is usually preceded by a prodromal allergic phase. Anti-neutrophil cytoplasmic antibodies (ANCA) are present in 38 \200\22359 % patients, usually of the myeloperoxidase subtype. Polyarteritis nodosa \200 ANCA-negative vasculitis. \200 Characterized by mesenteric ar teritis (abdominal pain, weight loss), livedo reticularis, renal involvement (hypertension) , and peripheral nerve involvement. Hepatitis B surface antigen positive in 30 % of cases; hepatitis C and hairy cell leukemia are also implicated in a subset of cases; these patients require different therapeutic regi mes. Selective angiography remains the gold standard for diagnosis. Small vessel vasculitis ANCA-positive vasculitis \200 Wegener \200\231s granulomatosis, a nd microscopic polyangiitis are small- vessel ANCA-positive vasculitides. Pauci-immune glomerulonephritis is common in both. \200 Wegener \200\231s granulomatosis rarely causes pericarditis and coronary arteritis (10 \200\22320 % cases ante-mortem); they can cause MI and sudden death. Microscopic polyangiitis may be complicated by coronary artery involvement or myocarditis, which have a major effect on the prognosis. This page intentionally left blank 634 CHAPTER 13 Multisystem disorders Ankylosing spondylitis \200 Incidence 0.1 \200\2231 % ; 1 \200\2232 % amongst human leuco cyte antigen (HLA)- B27-positive individuals. 10 \200\22320 % of \201 rst-degree relatives positive for HLA-B 27 develop the disease. Male:female = 3:1. Usually seen in northern Europeans. Onset is in late adolescence/early adulthood. Other seronegative spondyloarthropathies include reactive arthritis (Reiter \200\231s syndr ome), and those in association with psoriasis and in \202 ammatory bowel disease. Cardiac involvement \200 Usually manifests late; occasionally precedes overt joint diseas e \200 Aortic regurgitation (1 \200\22310 % ) causes: (1) ascending aortitis (1 \200\2231 0 % cases); (2) aortic valve \201 brosis causing cusp thickening, nodularity, and shortening Anterior mitral valve lea \202 et thickening, rarely causing mitral regurgitation Fibrosis of the aortic and mitral valve junction producing subaortic bump on echocardiography \200 Pericarditis (<1 % of cases) \200 Myocardial \201 brosi s causing systolic and diastolic dysfunction on echocardiography. May progress to dilated cardiomyopathy. Myocardial function may be furthe r compromised by secondary amyloidosis Atrioventricular node conduction problems with complete heart block Clinical features \200 Systemic features: malaise, fever and weight loss \200 Insidious low back pain progressing proximally in a relapsing \200\223remitting pattern Chronic pain and morning stiffness ( > 70 % cases); fatigue (65 % cases); reduced mobility (47 % cases). Depression (20 % cases, especially females) and neurological de \201 cits \200 Acute unilateral iritis (25 \200\22330 % cases) \200 Chest tightness and breathless ness from restricted chest movements Imaging \200 Imaging of sacro-iliac joints (plain X-ray, MRI, bone scan): erosions and sclerosis of sacroiliac joints (sacro-iliitis) Squared-off vertebral bodies and syndesmophytes culminating in the bamboo spine Bloods \200 No diagnostic tests; there may be elevated ESR and CRP (75 % of cases) Treatment \200 NSAIDs, steroids, immunosuppressants, including anti-TNF \200 Specialist treatment for complications. May require spinal or cardiac surgery This page intentionally left blank 636 CHAPTER 13 Multisystem disorders Marfan syndrome Epidemiology \200 This is one of the commonest single gene mutation disea ses. Incidence is 1/ 5000 to 1/10 000. There are no known geographical, racial, or sex predilections. \200 It is diagnosed prena tally through to adulthood. Pathology \200 Autosomal dominant point mutations in \201 brillin-1 gene on chromosome 15. Over 200 are described. Phenotype is highly variable due to varying genotype expression. Fibrillin-1 glycoprotein is an integral component of micro \201 brils in connective tissue s. The structural integrity of ocular, skeletal, cardiovascular, and other tissues is compr omised. Ghent criteria for diagnosis \200 Index case \200\224 no contributory family or genetic history, major criteria in at least two different organ systems plus involvement of a third organ system. Alternatively, contributory family or genetic history, one major organ syste m criterion plus involvement of a second organ system. Relative of index case \200\224 major criterion in family history, major criterion in organ system plus involvement of a second organ system. Imaging \200 Radiographs, CT, and MRI to assess the axial skeleton, hips, hands, and feet. Echocardiography and MRI scan to assess the mitral and aortic valves, aortic root, and ascending aorta. If the measured aortic root dimension is greater than tha t expected from a normogram by 1.18 times, there is root dilatation. Slit-lamp examination looking for retinal detachment, superolateral lens dislocation, catar acts, severe myopia, and open-angle glaucoma. Globe ultrasound and keratometry to assess th e cornea. Genetic testing \200 Genetic testing has a limited role in diagnosis; it is used primaril y to diagnose family members if a mutation is known. Linkage analysis is used in families w ith several affected relatives. Treatment \200 B -blockers (possibly calcium-channel blockers) delay and attenuate aortic root dilation Antibiotic chemoprophylaxis for bacteraemia-prone procedures \200 Surgery for aortic root and valve disease, skeletal and ocular complications \200 Gentle exercise Prognosis \200 Life expectancy is about two-thirds of normal. \200 Cardiovascular death in over 90 % of cases is due to aortic dissection or heart failure. MARFAN SYNDROME 637 Ghent criteria for Marfan syndrome Skeletal system involvement (two major or one major and two minor criteria) Major criteria Minor criteria 1. Pectus carinatum 1. Moderately severe pectus excavatum 2. Pectus excavatum requiring surgery 2. Joint hypermobility 3. Reduced upper to lower segment ratio or arm span to height ratio > 1.05 3. High arched palate with teeth crowding 4. Wrist and thumb signs 5. Scoliosis exceeding 20 o or 4. Facial appearance (dolichocephaly, malar hypoplasia, down-slanting palpabral \201 ssures, retrognathia) or spondylolisthesis 6. Elbow extension <170 o 7. Medial displacement of the medial malleolus causing pes planus, or 5. Enophthalmos 8. Protrusio acetabulae Ocular system involvement (one major or two minor criteria) Major criteria Minor criteria 1. Ectopia lentis 1. Abnormally \202 at cornea 2. Axial globe lengthening 3. Iris or ciliary muscle hypoplasia Cardiovascular system involvement (one major or one minor criterion only) Major criteria Minor criteria 1. Mitral valve prolapse with or without mitral regurgitation 1. Ascending aortic dilation involving at least the sinuses of Valsalva with or without aor tic regurgitation and 2. Main pulmonary artery dilatation 2. Ascending aortic dissection 3. Mitral annulus calci \201 cation 4. Descending thoracic or abdominal aortic dilatation or dissection Pulmonary system involvement (requires one minor criterion) 1. Spontaneous pneumothorax or apical blebs Skin and integument involvement (requires one of the following): 1. Striae atrophicae without marked weight change, pregnancy, or repetitive stress, or 2. Recurrent or incisional herniae (Continued) 638 CHAPTER 13 Multisystem disorders Dural involvement (one major criterion) 1. lumbosacral dural ectasia A contributory family or genetic history (one major criterion) 1. Parent, child, or sibling meeting diagnostic criteria independently 2. Known \201 brillin-1 mutation or 3. Presence of haplotype around \201 brillin-1 inherited by a descendent known to be asso ciated with unequivocally diagnosed Marfan syndrome in the family This page intentionally left blank 640 CHAPTER 13 Multisystem disorders Ehlers \200\223Danlos syndrome Epidemiology \200 1 in 5000 live births; incidence is abou t 1 in 400 000 \200 Typically presents between childhood and early adulthood \200 No ra cial or sex bias is known. Pathology \200 Inherited (autosomal dominant or recessive and X-linked recessive) defects in synthesis and metabolism of different types of collagen producing connective tissue def ects A new form has recently been described due to a de \201 ciency of tenascin-X (extracellula r matrix protein) with normal collagen Six subtypes: classic, hypermobile, vascular, kyphoscoliosis, arthrochalasia, and dermatosparaxis. There is much overlap between types in up to 50 % case s. Clinical features \200 Joint hypermobility, skin hyperextensibility, tissue fragility, an d poor wound healing. Patients classically get \200\230cigarette paper \200\231 scarring o ver the knees. Mitral valve prolapse is seen in classic, hypermobile, and vascular forms. A minority of pa tients progress to severe mitral regurgitation requiring surgery. Recent echocardiographic studies suggest cardiac defects are less frequent than previously thought, although coronar y artery aneurysm can be devastating. Aortic root ectasia with dilated sinuses of Valsalva is also seen. Rarely, severe or progre ssive and aortic root replacement is exceptional. \200 The vascular form also exhibits pr ominent veins, low weight, short stature, spontaneous pneumothorax, and rupture of medium- and large-sized arteries and bowel perforation. Joints are affected less frequently. The sk in is fragile but not hyperextensible. Differential diagnoses include Marfan syndrome, Menkes kinky hair disease, Williams syndrome, Stickler syndrome, cutis laxa, and pseudoxanthoma elasticu m. Treatment \200 There is no speci \201 c medical therapy. High-dose vitamin C may provide some bene \201 t there are but no controlled studies Patient education and preventive strategies. Avoid excess and repetitive lifting, and contact sports Avoid suturing wounds if possible \200 Regular eye and dental assessments \200 Antibiot ic chemoprophylaxis for mitral valve prolapse \200 Genetic counseling; there is a limited role for genetic testing EHLERS \200\223DANLOS SYNDROME 641 Prognosis \200 Increased mortality in vascular form. Median age is 50 years, with death from spontaneous arterial and gastrointestinal rupture. Other forms usually have normal life expectancy, with increased morbidity from recurrent di slocations, poor wound healing, and scarring. 642 CHAPTER 13 Multisystem disorders Rheumatic drug therapy and the heart Only rheumatic drug therapies with speci \201 c relev ance to the cardiovas- cular system are considered here. NSAIDs and cyclo-oxygenase (COX)-2 inhibitors \200 A 2006 meta-analysis of clinical trial s found that selective COX-2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high-dose regimens of ibuprofen and diclofenac, but high-dose n aproxen is not associated with such an excess. 1 Associated with a tenfold risk of symptomatic heart failure in patients with a history of cardiac disease (and doubling of risk in those without). 2 Glucocorticoids \200 Avoided for long-term control of disease activity in view of adverse side-effect pro \201 le. High-dose steroid is associated with adverse effects on the cardiovascular system: endothelial dysfunction, impaired glucose tolerance and hypertension . Association of steroids with atherosclerosis is not clear. Some studies have shown a protec tive effect of low-dose steroid. It may be that by reducing in \202 ammation they have pro tective effects. Anti-TNF therapies (e.g. adalimumab, etanercept, in \202 iximab) \200 Immunosuppressive/ immune-modulatory effect. \200 Anti-TNF therapy is contraindicated in patients with New Y ork Heart Association (NYHA) class III or IV heart failure. Patients who develop new-onset heart failure while on anti-TNF therapy should have therapy discontinued and be evaluated for other causes of heart failure , keeping in mind that underlying diseases themselves may be causative. Zoledronic acid \200 In a double blind placebo-controlled RCT of 3889 participants, serio us atrial \201 brillation occurred more frequently (50 vs. 20) in the zoledronic acid gro up compared with controls. 3 1 Kearney, PM, Baigent C, Godwin J, et al. (2006). Do selective cyclo-oxygenase-2 inhibitor s and traditional non-steroidal anti-in \202 ammatory drugs increase the risk of atherothr ombosis? Meta-analysis of randomized trials. BMJ (Clin Res ed) 332(7553): 1302 \200\2238. 2 Page J, Henry D (2000). Consumption of NSAIDs and the development of congestive heart fail ure in elderly patients: an underrecognized public health problem. Arch Intern Med 160 (6): 777 \200\22384. 3 Black D, Delmas P, Eastell R, et al . (2007). Once yearly zolendronic ac id for treatment of postmenopausal osteoporosis. N Engl J Med 356 : 1809 \200\22322. RHEUMATIC DRUG THERAPY AND THE HEART 643 Peri-operative management of anti-TNF \200 British Society of Rheumatology guidelines rec ommend withholding treatment with anti-TNF for patients with RA 2 \200\2234 weeks prior to major surgery. Treatments may be restarted postoperatively if there is no evidence of infection and once wound healing is satisfactory. Interrupting immune-suppression may trigger \202 ares of disease. \200 Flares of rheuma toid arthritis can often be managed with oral/