Examination features \200 \200 Inspiratory stridor with large airway obstruction. Monophonic (tracheal) inspiratory wheeze , associated with a bovine cough may indicate tracheomalacia in relapsing polychondritis (r are). Expiratory polyphonic wheezing indicates bronchospasm. High-pitched, end-inspiratory basal squeaks, in the absence of wheezing, are characteristic of obliterative bronchiolitis (usually with RA). \200 Lung parenchyma \200 \200 Cough: usually persistent and non-productive. Exertional dyspnoea. Examination features \200 Finger clubbing occurs in 70% of patients with pulmo- nary \201 brosis. Reduction in che st expansion in severe disease. Inspiratory crepitations: basal in pulmonary fibrosis assoc iated with RA, SLE, systemic sclerosis (SSc), Sj gren \200\231s syndrome, DM, and PM. Figure 3.2 Right sided pleural effusion in SLE. \200 HRCT chest Ankylosis of costochondral and costovertebral joints is visible (AS). Pleural th ickening alone or in the presence of a pleural effusion can be detected. Pulmonary vasculature and lymphatics \200 \200 Shortness of breath, particularly on exertion. Haemoptysis. Pleural aspirate and Abrams pleural biopsy. \200 In RA and SLE, the pleural \202 uid is usually an exudate (protein >30 g/l). RA associate d pleural effusions can become a sterile empyema, characterized by a reduced glucose concen - tration (<30 mg/dl), elevated lactate dehydrogenase (LDH), and cholesterol levels, high t itre RF and low pH. SLE effusions have a raised glucose level (>60 mg/dl) and the pleural \202 uid/serum glucose ratio is >0.5. Note that in right heart failure, secondary to pulmo nary hyperten- sion, the pleural \202 uid may be a transudate. For all pleural aspirates request microscopy, culture and sensitivity and in patients who are immunosuppressed, espec ially with anti-TNFA, request a Ziehl \200\223Nielsen stain for acid-fast bacilli, mycobact erial cultures, and consider other assays, including PCR. The pleural biopsy should be cult ured in addition to histological assessment. Request cytology where malignancy, including l ymphoma, is suspected. Examination features \200 Signs of right heart strain may be evident in PAH (large a and v waves in JVP, paraster nal heave, right ventricu- lar gallop rhythm, loud P2, pansystolic murmur loudest over left sternal edge). Right heart failure (elevated JVP, peripheral pitting oedema) occurs in dec ompensated PAH. Systolic waves in the JVP and a pulsatile liver indicate tricuspid regurgit ation. Parotid enlargement and palpable lymphadenopathy (cervical, axillary, and/or inguina l) may be present in cases of Sj gren \200\231s syndrome or sarcoidosis, in which hilar ly mphadenopathy can be demonstrated by radio- logical imaging. Investigations Chest wall and pleura Lung function tests: spirometry Measures such as the f orced vital capacity (FVC) and total lung capacity (TLC) are used to detect a restrictive d efect, which may be attributable to chest wall, pleural or \201 brotic T-spot assay if M. tuberculosis (MTB) is suspected. This assay of the patient \200\231s T c ell responses to mycobacterial antigen, ESAT-6, is particularly useful for discriminating CHAPTER 3 Organ involvement in rheumatological disease 59 Table 3.3 Lung function test: spirometry, characteristics in disease associated with rheuma tological conditions Lung involvement FEV1 N or d d FVC d FEV1/FVC N or i d TLC d RV N or d N or i i TLCO N or d N or d d KCO N or i N Chest wall/pleura N or d N or d d N or i N or i d Bronchiectasis N or d N or d N d or i i OB N d N or d N d ILD N or i d i Alveolar hemorrhage N N N d Pulmonary vascular N N N N N FEV1: Forced expiratory volume in 1 second; FVC: Forced vital capacity, TLC: Total Lung Cap acity; RV: Residual Volume; TLCO: Gas Transfer Factor; KCO: Gas transfer factor adjusted fo r lung volume (KCOc is also corrected for Hb) HRCT (Figures 3.4 \200\2233.6) Lung windows enable the detection of parenchymal disease. Gr ound glass change represents alveolitis (NSIP, LIP, DAD), pulmonary hemorrhage, or infectio n (PCP, viral). Reticulations, traction bronchiectasis, honeycomb- ing, and architectural d istortion are found in the presence of \201 brosis. Septal thickening, centrilobular nodu les, and cysts are features of LIP, whereas consolidation occurs with organizing pneumonia. between exposure to MTB and BCG (the latter lacks expression of the ESAT-6 antigen). Arterial blood gasses For assessment of oxygenation and the presence of hypercapnic respira tory failure. Airways Lung function tests: spirometry In healthy individuals, the FEV1/FVC ratio is usual ly 75%, falling to 65% in those aged over 70 years. In obstructive ventilatory defect, the FEV1/FVC ratio is <70%, whereas a ratio >80% indicates restrictive lung disease. Upper air way obstruction is suggested by FEV1(L)/PEFR(l/min) ratio >10 (e.g. in RP). Other imaging modalities \200 18FDG-PET and MR with gadolinium may be used to determine neurological and cardiac involvem ent in sarcoidosis. Serial peak expiratory \202 ow rate (PEFR) measures. PEFR should be measured on at least three occasions throughout the day, including an early morning reading to assess for diurna l variation and are used to diagnose reversible obstructive airways disease. Upper panel: Airflow obctructions as occurs with airways disease, e.g. obliterative bronchi olitis. Flow [L/s] F/V ex 10 Flow-volume loop (Figure 3.3) Used to investigate upper ( \201 xed or variable) or lower a irway obstruction, or restrictive disease. 5 Vol [L] 0 1 2 3 4 5 6 HRCT Lung windows can be used to examine abnormal airway architecture, e.g. bronchiectasis, tracheomalacia. Expira- tory images are helpful in the detection of air trapping, as occur s with small airways disease. Obliterative bronchiol- itis is characterized by a \200\230m osaic attenuation pattern \200\231 on HRCT, whereas \200\230tree in bud \200\231 typi \201 es follicular bronchiolitis. HRCT may also be used to examine the larynx for signs of cricoarytenoiditis, subluxation, or deformity. Middle panel: Restrictive ventilatory defect as seen with fibrosing ILD, pleural, or chest wall involvement. F/V ex Flow [L/s] 6 4 2 Sputum analysis Microscopy, culture, and sensitivities, including Ziehl \200\223Nielsen sta in for acid-fast bacilli, mycobacterial cultures and, possi- bly, PCR analysis should be re quested in patients at risk of MTB. Vol [L] 0 0.5 1.0 1.5 2.0 2.5 3.0 2 Lower panel: Fixed extrathoracic upper airway obstruction. Fiber optic bronchoscopy Used to determine the presence of tracheal stenosis. Endobronchial sarcoid granulomas have a characteristic cobblestone appearance. Airway abnormalities shou ld be biopsied for histological assessment. F/V ex Flow [L/s] 10 5 Vol [I] Lung parenchyma Lung function tests: spirometry The transfer factors (TLCO and KCO) measure the ef \201 ciency of gas exchange. The KCO is corrected for lung volume and KCOc correct ed for both lung volume and hemoglobin concentration. 0 1 3 4 5 6 2 Figure 3.3 Patterns of Flow-volume loops (In each panel, the arrow indicates normal \202 ow volume loop). THE CHEST 60 A video-assisted thoracoscopic surgical (VATS) lung biopsy may be required for diagnosis (i f atypical features on HRCT) for other ILDs and pulmonary vasculitis. Other useful investigations \200 Serum ACE, serum, and 24-h urinary calcium may be elevated in sarcoidosis. ACE levels are i ncreased in 60% of patients and are in \202 uenced by ACE gene polymor- phisms. Its role i n diagnosis and management of sarcoidosis remains controversial. Avian and aspergillus prec ipitins in those with appropri- ate clinical history or suggestive radiological features. Pulmonary vasculature and lymphatics Lung function tests: spirometry. If the KCO is decreas ed disproportionately compared to lung volume (e.g. TLC or FVC), this may re \202 ect a pu lmonary vascular defect. Figure 3.4 HRCT showing pulmonary \201 brosis (UIP) in a patient with SLE. CXR (Figure 3.7) Hilar and paratracheal lymphadenopathy can be detected. CXR is used to sta ge sarcoidosis. \200 \200 \200 \200 Stage 1: bilateral hilar lymphadenopathy. Stage 2: lymphadenopathy and parenchymal disease. Stage 3: parenchymal disease alone Stage 4: \201 brosis. Figure 3.5 HRCT showing NSIP in a patient with SSc-related ILD. Figure 3.7 CXR showing stage 1 sarcoid. Figure 3.6 HRCT showing LIP in Sj gren \200\231s Syndrome. Ventilation-perfusion scan (Figure 3.8) This is the investigation for a suspected pulmonary embolus in a patient with a normal plain CXR. Oesophageal manometry, barium swallow and gastroscopy to assess for aspiration and upper GI tract involvement. Other CT examinations CT pulmonary angiogram (CTPA) is used for a suspected pulmonary embol us in patients with pre-existing pulmo- nary disease and/or an abnormal plain CXR and to id entify pulmonary artery aneurysms. Mediastinal windows can assess for hilar and mediastinal lymphadenopathy. Fiber optic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy \200 Differential cell count of BAL provides diagnostic and prognostic information. BAL neutroph ilia in the pres- ence of \201 brosis is associated with a poor prognosis. Lymphocytic la vages are found with cellular NSIP, OP, LIP, and sarcoidosis. The presence of eosinophils ( >5%) may be associated with drug-induced pneumonitis. A blood- stained lavage signi \201 e s pulmonary hemorrhage. Transbronchial biopsies have a diagnostic yield >85% for sarcoidosi s when multiple lung segments are sampled. Echo and right heart catheterization studies Used to evaluate pulmonary hypertension both a t rest and with exercise. CHAPTER 3 Organ involvement in rheumatological disease 61 cardiac disease, or discharged within 6 weeks for an exacerbation of chronic lung or cardia c disease). SpO2<92% at rest or use of supplemental oxygen at sea level indicates the need for in- \202 ight oxygen. Patients with infectious mycobacterial disease must not travel b y public air transportation until rendered non-infectious. ECG is used to detect signs of r ight heart strain (right axis deviation, dominant secondary R wave in V1); P pul- monale, r ight bundle branch block and atrial conduction abnormalities, such as atrial \201 brillat ion, may also occur. Echocardiography is used as a screening test for PAH, signs of which i nclude right ventricular dilatation or hyper- trophy and tricuspid regurgitation (TR). If T R is present, it is possible to measure the peak pulmonary artery systolic pressure indirec tly with Doppler echocardiography. Right heart catheterization is used to measure pulmo- na ry artery pressure to enable diagnosis, assess patient response to vasodilators and facilit ate monitoring of pulmonary arterial hypertension. Figure 3.8 Ventilation/perfusion (V/Q) scan from patient with APLS showing multiple areas o f impaired perfusion. Treatment In all cases exposure to exacerbating factors should be reduced or stopped. \200 Stop smoking. \200 Minimize/remove occupational or recreational exposures. \200 Stop pneumotoxic drugs. \200 Review other drugs that may be exacerbating respira- tory disease (e.g. GCs and NSAIDs in left ventricular failure; immunosuppressants in bronchiectasis, pn eumonia and empyema). Assess need for supportive measures including O2, analgesia and the n eed for ventilatory support. In \202 uenza and pneumococcal vaccinations should be con- si dered for patients who are either immunosuppressed or have pulmonary disease. Figure 3.9 CTPA demonstrates a saddle embolus (arrowed). Other pulmonary or related assessments \200 Pulse oximetry: non-invasive assessment of oxygen saturation of hemoglobin. Blood gasses: Chest wall and pleura Costochondritis/enthesitis Topical administration of NSAID gel may pr ovide local relief. Oral NSAIDs. Judicious use of manubriosternal and SCJ GC injection in S APHO. Type II respiratory failure Normal Type I respiratory failure SSc hidebound chest The patient may be advised to perform daily deep breathing exercises, b ut there is no evidence base that this or phar- macological intervention affects the SSc pr ogression. 35 \200\22345 35 \200\22345 \211 45 H+ (nmol/l) PO2 (kPa) 10 \200\22313.3 <8.0 4.8 \200\2236.1 <8.0 PCO2 (kPa) <6.6 22 \200\22326 >6.6 SLE shrinking lung There are no speci \201 c treatments, although GCs, high-dose inhaled B -agonists, and theophylline have been tried. Generally, the prognosis is good \210\222 (mmol/l 22 \200\22326 92 \200\223100 >26 Plasma HCO3 O2 saturation (%) <92 <92 Myositis-related chest wall/diaphragmatic weakness. Treatment is of the underlying conditio n, plus the provision of chest physiotherapy to aid clearance of retained secre- tions. Non -invasive ventilation may be required if there is evidence of hypercapnic respiratory failu re, as may occur following an acute presentation of myositis. FBC: investigation for anemia is important in the breathless patient. Exercise tests: the 6 -min walk test is often used as a serial assessment of function in patients with known ILD and/or PAH. Note that patients with rheumatological conditions may be limited by musculoske letal pathology. Sleep studies: overnight oximetry to assess for evidence of oxygen desatur ation. Detailed polysonography is required for obstructive sleep apnoea and sleep disorders . Fitness to \202 y assessments: hypoxic challenge should be performed in patients with r esting sea level SpO2 92 \200\22395% who have an additional risk factor (hypercapnia, FEV1< 50%, restrictive lung disease, cerebrovascular or Pleural effusions Review other evidence of RA disease activity (e.g. DAS28, CRP, ESR) or SL E disease activity (e.g. BILAG, SLEDAI, ESR, C3 and C4, CRP (CRP often rises in SLE serosit is, in the absence of infection). In the presence of active disease, adjust or change immun osuppressive regimen to control systemic symptoms. Thoracocentesis with a chest drain is THE CHEST 62 supports this. Although a small study (45 patients), cyclo- phosphamide followed by azathio prine compared to GCs alone failed to reveal any different between the two randomized arms. required for large effusions or those refractory to medical treatment. Consider pleurodesis and/or pleurectomy for recurrent, non-infective effusions. Empyema Thoracocentesis with a chest drain together with appro- priate antibiotic treatment of the underlying infection. The presence of pleural thickening (>1 mm on CT images) or an extensively loculated effusion may indicate the need for surgical intervention. Review und erlying rheumatological disease activity and assess the nature of and reasons for immunosup pression (e.g. neutropaenia, lymphopenia, hypogammaglobulinaemia). Review the use of conven tional and biologic immunosuppressants. SLE and RA associated ILD There are no placebo-controlled trials of therapy. One small, ope n-labeled study of prednisolone treatment (60 mg/day for 4 weeks) showed resolution or impr ove- ment of symptoms in >60% of patients. Based on a series of case reports, treatment reg imes involve a trial of GCs with an immunomodulatory agent, including cyclophos- phamide, m ethotrexate, azathioprine, MMF, and rituximab (used for GC-resistant LIP). The role of anti -oxidant ther- apy in rheumatological disease associated UIP is unknown. Congenital/acquired scoliosis, kyphosis and pectus excavatum Physiotherapy to aid draining of secretions from hypoven- tilated regions and to retard progression of deformity. If spin al deformity is progressive, refer to spinal surgeon for assessment. Lung parenchyma: other diseases Sarcoidosis Treatment is usually determined by stage of pul monary disease and organ involvement. \200 L fgren \200\231s syndrome (stage 1 disease) symptoms are treated with NSAIDs. In these pa tients, >90% will undergo spontaneous resolution. Inhaled GCs are used for airways involvem ent (cough, wheeze, endobronchial sarcoidosis). A 3-month trial of oral GCs is required whe n there is ILD (stage 2, 3 or 4 disease). If lung function improves, taper the GC dose to 5 \200\22315 mg/day and treat for at least 12 months. GC-sparing agents including methotrexa te, azathioprine and MMF have all been used in refractory disease. One RCT of anti-TNFA tre atment showed modest improve- ment in FVC at 6 months. Airways Cricoarytenoid arthritis, laryngeal destruction, tracheomalacia Maintaining adequat e ventilation is the mainstay of treatment. Tracheostomy is required if there is signi \201 cant laryngeal involvement. Surgery or the insertion of airway stents has been describ ed to relieve severe air \202 ow obstruction. Chest physiotherapy is important to aid with clearance of secretions. Steroids and immunosuppression have been used in the management o f acute in \202 ammatory episodes. Proximal airway stenosis Control the systemic disease with immunosuppressive treatments. Ad ditional measures include dilatation and local injections of long-acting GCs to the involve d sites of the trachea, performed via rigid or \202 exible bronchoscopy. If there is seve re air \202 ow obstruction, airway stents or tracheostomy may be necessary. Drug-induced pneumonitis The most important treatment is stopping the offending drug and su pportive measures (oxygen). GCs may have a role in methotrexate induced pneumonitis and eos ino- philic diseases. Folinic rescue is often used when there is suspicion of underlying fo late de \201 ciency. Bronchiectasis Physiotherapy with postural drainage and appropriate antibiotic regimes form the basis of treatment. Inhaled corticosteroids and long-acting B-agonists are helpful for obstructive airways disease. Rheumatoid nodules Treatment is aimed at controlling the underlying systemic disease. Pulmonary hemorrhage Respiratory supportive therapy including mechanical ventilation may be required if there is evidence of respira- tory failure. \200 Follicular bronchiolitis Antibiotics and inhaled GCs are of no proven bene \201 t. Oral GC s have varying results (see obliterative bronchiolitis). Treatments are directed for either the remission- induction or maintenance phase according to disease severity as determined by the European Vasculitis Study Group (EUVAS). Remission -induction phase: \200 Obliterative bronchiolitis This responds poorly to oral or inhaled GCs. Macrolides (clarith romycin) and immunosuppressants including cyclo- phosphamide, sirolimus and mycophenolate m ofetil (MMF) have been used with limited success. Overall prognosis is poor. limited disease: use a single agent, e.g. GCs, azathioprine or methotrexate; early generali zed disease \200\223 use oral GCs and cyclo- phosphamide or methotrexate; active generaliz ed disease \200\223 pulses of IV GCs and cyclophosphamide; severe disease \200\223 as for active generalized disease plus plasma exchange therapy; refractory disease \200\223 if t he above treatments fail, consider in \202 iximab, rituximab, antithymocyte globulin or IV IG. In one study, in \202 iximab induced remission in 88% of patients but it was associate d with a high rate of infection (21%) and disease relapse (20%). In a small Lung parenchyma (ILD) The decision to treat is often challenging and should be based on the evaluation of disease severity (as determined by extent of disease on HRCT and TLCO), long itudinal disease behavior (change in FVC) and the histological type of ILD. There are few d ata from few therapeutic trials in these patients. SSc One open-label prospective and two retrospective analyzes suggest that MMF is associate d with reduced progression of ILD in SSc. A pilot study of MMF given with methylpred- nisol one pulses followed by low-dose prednisolone CHAPTER 3 Organ involvement in rheumatological disease 63 Prognosis/natural history Pulmonary involvement in Rheumatological Disease is invariably as sociated with signi \201 cant mortality. \200 study with rituximab, remission was induced in all 11 patients and 8 of them had undetectab le ANCA titres. Larger, randomized controlled studies are required to assess these treatmen ts further. The histological type of ILD is the most important predictor of early mortality, with patte rns characterized by \201 brosis (UIP, \201 brosing NSIP) having a worse prognosis than those demonstrating cellular disease (cellular NSIP, LIP, OP). RA patients with UIP type I LD have a survival similar to those with idiopathic pulmonary \201 brosis (50% 3-year mor tality). Diffuse alveolar hemorrhage that is associated with SLE has a 50% in hospital mort ality. The development of PAH is associated with signi \201 cant mortality, particularly i n SSc. In Beh et \200\231s disease, pulmonary artery aneurysm formation has a poor prognos is, with a 2-year mortality of 30%. Maintenance phase once clinical remission has been established for 3 \200\2236 months. Usua l maintenance therapy consists of low dose GCs with azathioprine or meth- otrexate. If into lerant, consider second line agents MMF, cyclophosphamide or le \202 unomide. Septrin (to treat Staph. aureus infection) has been shown to reduce the rate of relapses. AASV cavitating lung lesions Exclude infection and treat as above. Anti-TNFA therapies and rituximab have shown promising results. Infections \200 \200 Treat pneumonia with appropriate antibiotics. Supportive measures including oxygen, analges ia, and chest physiotherapy may be required. Treat atypical mycobacterial disease or MTB in accord- ance with British Thoracic Society or American Thoracic Society guidelines. Referr al to respiratory physician is recommended. For aspiration pneumonia, lifestyle measures (a void large meals, and elevate the head of the bed) in addition to re \202 ux treatment (PP I or ranitidine) and gastric motility stimulants are used. Monitoring disease activity In addition to clinical assessment, the monitoring of lung dise ase activity involves serial CXRs, lung function tests (the rate of decline of FVC is of pr ognostic importance in ILD), 6-minute walk tests and echocardiogram. Transplantation should be considered for those with progressive ILD or PAH (TLCO <35%) in w hom the systemic disease is well controlled. Pulmonary vasculature and lymphatics PAH Secondary to AICTDs Supportive treatments include warfarin, diuretics, digoxin, oxygen, and lifestyle advice. \200 Resources Respiratory physiotherapy resources are available from the British Thoracic Socie ty website. Available at: http:// www.brit-thoracic.org.uk Information related to drug indu ced lung diseases. Available at: www.pneumotox.com/base.php?fich=new&lg=en For SSc-related PAH, bosentan, sildena \201 l, prostanoids and sitaxsentan are used (see p . 269 \200\223270). For other AICTDs, immunosuppress if evidence of active disease. Small, randomized studies of cyclophosphamide alone or in combination with GCs have shown a fall i n pulmonary artery pressure. Patients with positive vasodilator challenge during right hear t catheterization studies might bene \201 t from a calcium channel blocker. Otherwise trea tment pathways are as for SSc-related PAH. Assessment tools New York Heart Association (NYHA) Functional Classi \201 - cation system. Class Patient symptoms I No limitation of activity. Ordinary physical activity does not cause undue fatigue, palpita tion, or dyspnoea. Secondary PAH Optimize treatment for the underlying lung disease. Supportive treatments as above. II Slight limitation of activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation or dyspnoea. III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activit y causes fatigue, palpitation or dyspnoea. Pulmonary embolism Anticoagulate with warfarin; however, the duration of treatment and inte nsity of anticoagulation remains contro- versial. Beware of the development of aneurysms in patients with Beh et \200\231s syndrome (see below). Aspirin is a useful alternative in t his group. Hydroxychloroquine may be added to the anticoagulant regime of patients with in \202 ammatory rheumatological disease and thromboem- bolic disease, since there is some ev idence that it has anti- coagulant effects. IV Symptomatic at rest. Any physical activity increases fatigue, palpitation, or dyspnoea. Guidelines British Thoracic Society (BTS) Guidelines for management of the Interstitial Lun g Diseases (new version available 2008), Pulmonary hypertension, TB and Fitness to \202 y . Avail- able at: http://www.brit-thoracic.org.uk/guide- line-download.html American Thorac ic Society (ATS) guidelines for the man- agement of mycobacterial disease. Available at: ht tp:// www.thoracic.org Pulmonary arterial aneurysm A combination of prednisolone and cyclophosphamide therapy is u sed, although there are no RCT data on which to base management. Anticoagulation carries a signi \201 cant risk and should be used only after systemic immunosuppres- sives have been started. Embolization is limited by the size and number of aneurysms. ICD-10 codes \200 J99.1 Respiratory disorder in diffuse CTD (DM, PM, SS, SLE, WG). J99.0* Rheumatoid lung dis ease. Lymphoma Refer to hematologist for appropriate management. THE CHEST 64 J99.8* Respiratory disorders in ankylosing spondylitis or cryoglobulinaemia. M95.5 Acquired deformity of chest and rib. Gerbino AJ, Goss CH, Molitor JA. Effect of mycophenolate mofetil on pulmonary function in s cleroderma-associated interstitial lung disease. Chest 2008; 133: 455 \200\22360 Hoyles RK, Ellis RW, et al. A multicenter, prospective, randomized, double-blind, placebo-c ontrolled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathi oprine for the treatment of pulmonary \201 brosis in scleroderma. Arthr Rheum 2006; 54: 3 962 \200\22370. See also: Rheumatoid arthritis Systemic lupus erythematosus Systemic sclerosis Dermatomyosi tis Polymyositis Sj gren \200\231s syndrome ANCA-associated vasculitis Beh et \200\231s d isease Relapsing polychondritis Sarcoidosis The heart in rheumatological disease p. 197 p. 240 p. 264 p. 290 p. 282 p. 254 p. 330 p. 340 p. 346 p. 512 p. 66 Karim MY, Miranda LC, et al. Presentation and prognosis of the shrinking lung syndrome in s ystemic lupus erythematosus. Semin Arthritis Rheum 2002; 31: 289 \200\22398. Lee KS, Ernst A, et al. Relapsing polychondritis: prevalence of expiratory CT airway abnorm alities. Radiol 2006; 240: 565 \200\22373. Liossis SN, Bounas A, Andronopoulous AP. Mycophe nolate mofetil as \201 rst-line treatment improves clinically evident early sclero- derma lung disease. Rheumatol 2006; 45: 1005 \200\2238. Nihtyanova SI, Brough GM, et al. Mycophenolate mofetil in diffuse cutaneous systemic sclero sis \200\223 a retrospective analysis. Rheumatol 2007; 46: 442 \200\2235. Further reading Abraham D, Distler O. How does endothelial cell injury start? The role of e ndothelin in systemic sclerosis. Arthr Res Ther 2007; 9(Suppl 2): S2. Quismorio FP Jr, Sharma O, et al. Immunologic and clinical studies in pulmonary hypertensio n associated with systemic lupus erythematosus. Semin Arthritis Rheum 1984; 13: 349 \200 \22359. American Thoracic Society/European Respiratory Society International Multidisciplinary Cons ensus Classi \201 cation of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165: 277 \200\223304. Utzig MJ, Warzelhan J, et al. Role of thoracic surgery and interven- tional bronchoscopy in Wegener \200\231s granulomatosis. Ann Thorac Surg 2002 74: 1948 \200\22352. Vanthuyne M, Blockmans D, et al, A pilot study of myophenolate mofetil combined to intraven ous methylprednisolone pulses and oral low-dose glucocorticoids in severe early systemic sc lerosis. Clin Exp Rheumatol 2007; 25: 287 \200\22392. Ansari A, Larson PH, Bates HD. Vascular manifestations of systemic lupus erythematosus: cur rent perspective. Angiology 1986; 37: 423 \200\22332. Bayar N, Kara SA, et al. Cricoarytenoiditis in rheumatoid arthritis: radiologic and clinical study. J Otolaryngol 2003; 32: 373 \200\2238 This page intentionally left blank THE HEART 66 The heart Cardiovascular disease accounts for the majority of prema- ture mortality in several in \202 ammatory Rheumatological conditions. Pericardial, myocardial and endocardial tissues a re affected by the processes, which cause the underlying multisystem in \202 ammatory diseases; Cardiac disease may also arise as a result of coron ary or systemic/pulmonary arterial diseases. Classi \201 cation Table 3.4 Anatomical classi \201 cation of cardiac involvement in rheumatological disease Aortitis Coronary artery disease Pulmonary arterial hypertension Endocardial (valvular) disease Pericardial disease Myocardial and conduction system disease Rheumatoid arthritis (RA) +++ rare + +? + ++ rare ++ Ankylosing spondylitis (AS) + ++ + Reactive arthritis + Systemic lupus erythematosus (SLE) +++ ++ ++ ++ Neonatal lupus ++ APLS +++ Systemic sclerosis (SSc) ++ ++ + + ++ Sj gren \200\231s syndrome (SS) + + Dermato- (DM) and polymyositis (PM) + Beh et \200\231s disease + + + + Kawasaki disease +++ Wegener \200\231s granulomatosis (WG) + Churg \200\223Strauss syndrome (CSS) + + Takayasu \200\231s disease + ++ + +++ Polyarteritis nodosum (PAN) +++ +++ Relapsing polychondritis + Giant cell arteritis (GCA) +++ + + + Adult Still \200\231s disease ++ Rheumatic fever ++ +++ +++ ++ JIA ++ Haemachromatosis ++ Sarcoidosis + + ? Hereditary connective tissue disease* ++ Gout ? ? Abbreviations: APLS, antiphospholipid syndrome; JIA, Juvenile idiopathic arthritis; * e.g. Marfan syndrome, Ehlers \200\223Danlos \200 Myocarditis occurs in 10% of patients with SLE. In sarcoidosis, cardiac involvement has be en reported in >25%, but this is rarely clinically signi \201 cant. Giant cell myocardiits is rarely associated with RA, SLE, Sj gren \200\231s syndrome, GCA, and Takayasu \200\231 s arteritis. In RA, ventricular arrhythmias or sudden cardiac death may be secondary to isc haemia, nodules, amyloidosis, increased sympathetic drive, and drugs. Epidemiology Pericardial involvement Pericardial effusions occur commonly in RA, SLE, SSc, and Adult Still \200\231s disease, but most are asymptomatic. Myocardial and conduction system disease \200 Cardiomyopathy is rare in RA. Amyloid can occur in patients with persistent elevation of in \202 ammatory markers. Haemochromatosis may present with arthritis and cardiomyopathy. CHAPTER 3 Organ involvement in rheumatological disease 67 Etiology/pathophysiology Pericardial disease In SLE, deposition of immunoglobulin and compl ement C3 on pericardial tissue has been demonstrated. In SLE, sinus tachycardia, atrial \201 brillation, and atrial ectopics are the most commo n dysrhythmias. In SSc, ventricular arrhythmias occur in about a half of patients and sudde n cardiac death has been estimated to occur in 5%. Atrial arrhythmias [atrial \201 brill ation (AF), atrial \202 utter or paroxysmal supraventricular tachycardia (SVT)] are prese nt in about a fourth of SSc patients. Conduction disturbances occur in about a third of RA, SSc (bundle branch block) and SLE [ \201 rst degree atriov- entricular (AV) block] patien ts. Congenital heart block (CHB) is the most serious manifestation of neonatal lupus and oc curs in 2% of mothers with anti-Ro antibodies ( 20% in a mother with a previous, affected child). CHB is reported to be associ- ated with 20% mortality and about two-thirds of live -born children require a pacemaker. Incomplete blocks may progress postnatally. Complete CH B, once established, is irreversible. Drug-induced cardiomyopathy may occur with corticos- teroids or antimalarials. 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.