Schirmer \200\231s test (Figure 8.4) A Schirmer strip ( \201 lter paper) is tucked under t he lower eyelid and soaks up the tears. The length of staining in mm gives a measure of tea r production. Less than 5 mm wetting in 5 min denotes aqueous tear de \201 ciency (as seen in Sj gren \200\231s), 5 \200\22310 mm is equivocal, greater than 10 mm is normal (withou t anesthetic eye drop use). Tonometry All uveitis patients need their intraocular pressures checked by Goldman tonometr y. Digital tonometry (using 2 \201 ngers to press on the eyeball) is only reliable to dis tin- guish between normal pressure (<21 mmHg) and extremely high pressures (>45 mmHg). Fluo rescein angiography Is used to investigate uveitis (CMO and vasculitis) and visual loss in scleritis. May also show delayed choroidal perfusion in cases of visual loss in suspected G CA. Ocular coherence tomography (OCT) Allows 3D imaging of the retina down to the level of the choroid. Very useful for showing retinal \202 uid (CMO). Microbiology \200 Borrelia serology is rarely positive, but worth doing in endemic Lyme Disease areas. TPHA i s always worth checking as it alters treatment. If viral retinitis is suspected, then a vit reous tap should be taken and sent for PCR for varicella-zoster, CMV, Epstein Barr virus (E BV), syphilis, and toxoplasmosis. \200 THE EYE 52 dilute baby shampoo. Ocular chloramphenicol bd for 2 weeks GC eye drops when necessary. Oral doxy- cline can be used in more severe cases with rosacea. Scleritis and episcleritis \200 Episcleritis is usually self-limiting or resolves with \202 urometholone eye drops (mild GC) or oral non-steroi- dal anti-in \202 ammatory drugs (NSAIDs). It is sensible to refer to an ophthalmologist to check diagnosis unless there is a convincing and documented histor y of previ- ous episcleritis. Scleritis may resolve with an NSAID or systemic GCs (reducing course over many months). Severe cases of scleritis may need IV methylprednisolone 1 g dai ly for 3 days followed by oral GCs and GC-sparing agents. Cyclophosphamide may be needed in very aggressive cases. Urgent ophthalmology referral is required as severe scleritis cases can rapidly result in scleral melting, globe perforation, and loss of vision. PUK is treat ed along similar lines to scleritis. There is no ocular treatment for scleromalacia perfora ns (painless necrotizing scleritis in late stage RA). RA scleritis patients have an increas ed risk of mortality. Surgery \200 Cataract surgery in patients with uveitis requires ade- quate GC cover and management by an ophthalmologist with some experience of managing uveitis. Lacrimal duct plugging/ablation is useful in more severe cases of dry eye. Intraocular GC slow-release devices are being de veloped but have a high rate of secondary glaucoma. Retinovascular disease in AICTDs/vasculitis Active retinopathy in the context of an AICTD o r vasculitis should prompt a review of disease activity by both medical ophthalmologist and rheumatologist. The retina is the only part of the body, apart from the nailfolds, where c apillaries vessels can be viewed directly. \200 Care should be taken to distinguish hypertensive retinopathy from that caused by systemic v asculitis. SLE retinopathy usually has a good prognosis for vision, although a small group has an occlusive vasculopathy and cerebral vasculitis with a poor prognosis. Giant cell arteritis In suspected cases with ocular symptoms immediate ophthalmology referr al is mandatory. Also do not delay starting glucocorticoids (GCs), while waiting for an oph - thalmologist to review the patient or a biopsy. In GCA it is very unusual for any signi \201 cant visual recovery to take place once vision is lost. \200 Juvenile idiopathic arthritis \200 \200 Anterior uveitis can be asymptomatic. JIA-associated uveitis can start soon after the onset of the arthritis or may already be present at the time of diagnosis of JIA. It can be seve re with few symptoms. Referral for ophthalmological screening by a specialist experienced i n seeing children with the condition is therefore urgent. Children should be screened by an ophthalmologist according to the BSPAR protocol (see Assessment tools, below). Treatment i s challenging and children can go blind with this condition. Systemic GCs, eye drops, and m ethotrexate have been used extensively. If methotrexate is discontinued for any reason then the ophthalmologist should be informed as more frequent ocular screening is required at th is point In addition to chronic anterior uveitis, ocular damage and even blindness can be c aused by cataract, secondary glaucoma, band keratopathy and ultimately phthisis bulbi. Observational studies support the use of high dose GCs in GCA. Recently, guidelines on the management of large vessel vasculitis have been produced by EULAR (Mukter et al., 2008). In patients without ocular symptoms, oral GCs starting at 0.7 \200\2231 mg/kg (maximum dose 6 0 \200\22380 mg) should be prescribed. In patients with ocular symptoms IV methyl- predniso lone 1 g daily for 3 days should be used in addition to oral GCs. The headache should resol ve rapidly (<48 h). A recent randomized study suggested that use of IV methylprednisolone ( 15 mg/kg) for 3 days in addition to oral prednisolone 40 mg/day permitted more rapid GC tap er. Oral GCs should be tapered quickly aiming for 10 mg/day at 6 months. In patients with \202 uctuating visual loss, plasma expanders, fragmin, aspirin, lying the patient down wit h foot of bed raised, and oral acetazolamide to reduce intraocular pressure, have been trie d. Data from robust studies is lacking however. \200 Resources Assessment tools A reading chart (test with reading glasses on and record distanc e, e.g. 20 cm) or Snellen chart should be available to check visual acuities. Keratoconjunctivitis sicca Most patients bene \201 t from eye drops. There are many differ ent preparations from which to choose. \200 Hydroxychloroquine screening \200 Short-acting preparations contain polyvinyl alcohol (SnoTears, Liqui \201 lm) or carboxyce llulose (hypromellose, Tears Naturale). Longer-acting preparations contain carbomer gels (e .g. Viscotears, Geltears) or paraf \201 n (e.g. Lacrilube, Lubri-Tears); these are stickie r and patients may prefer to use them at night. Some patients are intolerant of preservativ es in aqueous drops and preservative-free Liqui \201 lm may be tolerated. Blepharitis is c ommon and frequently exacerbates the symptoms of dry eyes. Treat with daily lid hygiene cle aning eyelid margins with a cotton bud dipped in Check patient \200\231s vision is normal in each eye before starting treatment and document this. If not normal then ask them to see their high street optician (optometrist) who can provide a report on their vision and eyes. Check visual acuity annually. If vision deterior ates then stop treatment, send patient to their optome- trist who can refer on to an ophtha lmologist if new glasses are not the answer. CHAPTER 3 Organ involvement in rheumatological disease 53 See also \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 If exceeding the maximal daily dosage of 6.5mg/kg of lean body weight or in patients who ha ve taken the drug, even in recommended doses, for >6 years then annual screening by an opht halmologist is prudent. The Royal College of Ophthalmology guidelines are available free of charge at: http://www.rcophth. ac .uk/docs/publications/published-guidelines/ Oculartoxici ty2004.pdf; \200 Rheumatoid arthritis. Ankylosing spondylitis/SpA. Reactive arthritis (spondylarthropathy). Systemic lupus erythematosus. Sj gren \200\231s syndrome. Wegener \200\231s granulomatosis (ANCA-associated vasculitis). Beh et \200\231s disease. Sarcoidosis. Juvenile idiopathic arthritis. Anti-phospholipid antibody syndrome (APLS). Polyarteritis nodosa. Children with JIA should be screened for uveitis by an ophthalmologist according to the BSP AR protocol (available at: http://www.bspar.org.uk/downloads/ clinical_guidelines/BSPAR_gui delines_eye_screening_ 2006.pdf). Further reading Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclat ure (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical dat a. Results of the First International Workshop. Am J Ophthalmol. 2005; 140: 509 \200\22316. Krause L, Altenburg A, et al. Long-term visual prognosis of patients with ocular adamantia des-Beh et \200\231s disease treated with inter- feron-alpha-2a. J Rheumatol 2008; 35: 896 \200\223903. Guidelines/NICE Hydroxychloroquine Monitoring Guidelines: Royal College of Ophthalmology. A vailable at: http://www.rcophth. ac.uk/docs/publications/published-guidelines/ Oculartoxici ty2004.pdf BSPAR protocol for screening children with JIA: Available at: http://www.bspar.o rg.uk/downloads/ clinical_guidelines/BSPAR_guidelines_eye_ screening_2006.pdf. Mavrikakis I, S \201 kakis PP, et al. The incidence of irreversible retinal toxicity in pa tients treated with hydroxychloroquine: a reap- praisal. Ophthalmology. 2003; 110: 1321 \200\2236. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large v essel vasculitis. Ann Rheum Dis 2008. Epub ahead of print: doi:10.1136/ard.2008.088351. ICD-10 codes H04.1 Dry eye. H15.0 Scleritis. H15.1 Episcleritis. H20.0 Acute anterior uveit is. H20.1 Chronic anterior uveitis. H30.1 Posterior uveitis. H35.0 Retinal vasculitis. Niccoli L, Nannini C, et al. Long-term ef \201 cacy of in \202 iximab in refrac- tory pos terior uveitis of Beh et \200\231s disease: a 24-month follow-up study. Rheumatol (Ox) 200 7; 46: 1161 \200\2234. THE CHEST 54 The chest Chest disease is a significant cause of morbidity and mortality in rheumatological conditio ns, and the disease may sometimes present with respiratory symptoms. Chest involvement may occur in patients with congenital, or acquired deformity of the spine or rib cage, in RA, a utoim- mune connective tissue connective tissue diseases, anky- losing spondylitis (AS), AN CA-associated vasculitides (AASV), RP, and other systemic in \202 ammatory conditions, suc h as sarcoidosis. The management re \202 ects the location of pathology and its pathophysiology. This section will con- sider those rheumatological co nditions affecting the chest wall, pleura, airways, lung parenchyma, lung vasculature, and lymphatics. Classi \201 cation Conditions may be classified arbitrarily according to their disease ass ociations or on their anatomical basis (Table 3.2). Table 3.2 Anatomical Classi \201 cation of Lung Involvement in Rheumatological Disease Chest Wall Pleura Airways Parenchyma Pulmonary Vasculature & Lymphatics Pleurisy effusion; Empyema; Nodules PAH ILD (UIP > NSIP > OP, LIP); Drug-induced pneumonitis; Nodules; Infections \200\223 pneumon ia and tuberculosis Follicular and/or obliterative bronchiolitis; Bronchiectasis; Cricoarytenoid arthritis; Voc al fold nodules Rheumatoid Arthritis (RA) Respiratory muscle weakness Obliterative bronchiolitis Upper lobe \201 brosis Ankylosing Spondylitis (AS) Costovertebral arthritis Pleural thickening; effusion Pleurisy effusion PAH; Pulmonary embolus (APLS) ILD (NSIP or DAD > OP, UIP or LIP); Diffuse alveolar hemorrhage/ acute lupus pneumonitis. Upper airways dysfunction; Obliterative Bronchiolitis; Bronchiectasis Shrinking Lung; Costochondritis Systemic Lupus Erythematosus (SLE) PAH ILD (NSIP >> UIP > DAD); Aspiration pneumonia Systemic Sclerosis (SSc) Hidebound chest (diffuse cutaneous SSc) Pleurisy effusion Sj gren \200\231s Syndrome Bronchiectasis ILD (NSIP > LIP > OP, UIP or DAD) Lymphadenopathy; Lymphoma PAH ILD (NSIP >OP > DAD or UIP); Aspiration pneumonia Dermato- and Polymyositis (DM, PM) Respiratory muscle and diaphragm weakness Beh et \200\231s Disease Pleurisy OP Pulmonary artery aneurysm; Arterial and venous thrombosis Relapsing Polychondritis Costochondritis Laryngeal destruction; Tracheomalacia Pneumonia Systemic Vasculitides Effusion (CSS) Large airway stenoses (AASV) Hemorrhage; Cavitating lesions (AASV) Mediastinal lymphadenopathy Effusion Air \202 ow obstruction due to endobronchial sarcoidosis Pulmonary \201 brosis Bilateral hilar lymphadenopathy (L ffgren \200\231s syndrome); PAH Sarcoidosis Respiratory muscle and diaphragm weakness Pleurisy effusion Periodic Fevers Pneumonia Secondary PAH Chest wall deformity Congenital or acquired kyphosis; scoliosis; pectus excavatum Abbreviations: ILD: interstitial lung disease; UIP: usual interstitial pneumonia; NSIP: non -speci \201 c interstitial pneumonia; OP: organizing pneumonia; LIP: lymphocytic interstit ial pneumonia; DAD: diffuse alveolar damage, APLS: antiphospholipid antibody syndrome; PAH: pulmonary arterial hypertension; SSc: Systemic sclerosis; CSS: Churg Strauss Syndrome. CHAPTER 3 Organ involvement in rheumatological disease 55 ILD is less common (30%) in dermato- (DM) and poly-myositis (PM), SLE (30%), RA (20%), and Sj gren \200\231s syndrome (10%). In RA, ILD is more common in men, in late-onset disease and in those with high titre RF. In sarcoidosis, 25% will develop pulmonary \201 brosis. Epidemiology Chest wall and pleura \200 Costochondritis occurs in patients with SpAs, sarcoid, and SAPHO. The hidebound chest is a complication of truncal sclero- derma in diffuse cutaneous systemic sclerosis. Myopathy/myo sitis. Involvement of respiratory muscles occurs in about 25% of patients with inflammatory muscle diseases; this predisposes the patient to pneumonia, but is a rare cause of ventila tory failure. >50% of patients with sarcoidosis have granulomas in their muscles, but <1% a re symptomatic. The shrinking lung syndrome has been reported as a rare (<0.3%) complicat ion of SLE. Pleurisy, pleuritis, and effusions are the commonest pulmonary manifestations o f SLE, affecting up to 35%. RA pleural effusions are usually small and asymmetric, occurrin g in 5% of patients, in particular males with long- standing articular disease and those wi th subcutaneous nodules. Apical pleural thickening is an early feature of AS; effusions are rare. Up to 10% of cases of Wegener \200\231s granulomatosis (WG) will develop an effusion . Pectus excavatum is the commonest congenital chest wall deformity, affecting 1 in 300 liv e births. Scoliosis is usually idiopathic, but can be associated with neuromuscular disease s, e.g. poliomyelitis. Other parenchymal lesions \200 \200 Rheumatoid nodules are reported in up to 20% of patients. Diffuse alveolar hemorrhage is ra re, occurring in 1-5% of SLE patients. Nodular lesions are found in 55 \200\22370% of those diagnosed with ANCA-associated systemic vasculitis (AASV) and cavitating lesions occur in 35 \200\22350% of patients with WG. Pneumonia is a primary concern in patients treated with immunosuppression. In addition, some patients with SLE have an increased risk of infection with encapsulated bacteria. Aspiration pneumonia may be a complication both of oesophageal dysmotility in SSc and weak upper pharyngeal muscles in DM and PM. Pulmonary vasculature and lymphatics \200 Pulmonary arterial hypertension (PAH) due to a vascu- lopathy is most frequently occurs in limited cutaneous SSc ( 12%) and mixed connective tissue disease (MCTD), less commonly in S LE ( 4%) and APLS ( 2%), and rarely in RA and PM. Pulmonary capillaritis (small vessel vasc ulitis) is associated with RA, PM, and SLE. Thromboembolism occurs in 25% of SLE (most with APLS) patients and is a major cause of death. In Beh et \200\231s disease, the reported p revalence of pulmonary complications ranges from 1 to 8%. The pulmonary arteries are the se cond commonest site for aneurysms particularly in young men. Superior vena cava obstruction can result from thrombosis of innominate and sub-clavian veins. Although it can occur at a ny age, sarcoidosis has a peak incidence between 20 and 39 years. All racial and ethnic gro ups are affected, in particular northern Europeans (5 \200\22340/100 000) and African Ameri cans (35.5/100 000). PAH has been identi \201 ed in up to 23% of patients at rest and 43% with exertion. Airways \200 Cricoarytenoiditis occurs commonly (>25%) in RA and has been reported in SLE and in SpAs. V ocal fold lesions, including nodules and bamboo nodes, occur in RA. Recurrent laryngeal neu ropathy may occur in any condi- tion associated with mononeuritis (including SLE and small vessel vasculitides). Tracheomalacia and bronchomalacia are features of RP. A retrospective review of dynamic chest CT scans in patients with RP indicates intra-thoracic airway abnor - malities in 94% (17/18) and extra-thoracic (tracheal and proximal bronchial) involvement in 44% (8/18). Large airway stenosis. Tracheal stenosis occurs commonly in patients with WG . Follicular and/or obliterative bronchiolitis: Small airways obstructive lung disease is m ost commonly seen in RA compared with other rheumatological conditions. Bronchiectasis is f ound in RA patients with severe, chronic nodular disease. HRCT studies indicate a preva- le nce of 30% in RA and 20% in SLE patients. Etiology/pathophysiology Chest wall and pleura \200 Costochondritis in RP is characterized by recurrent, destructive in \202 ammation of carti laginous structures. Shrinking lung syndrome is attributed to diaphragmatic weakness, how ever a myopathy is present only in a third of SLE patients and muscle enzymes are normal. P hrenic nerve neuropathy, involving immune complex deposition and ischaemic lesions, has als o been reported. The etiology of congenital and acquired chest wall deformities is largely obscure. Polymorphisms in the estrogen receptor gene have been implicated in adolescent idi opathic scoliosis. Lung parenchyma Interstitial lung disease (ILD) The prevalence and clinical signi \201 can ce of ILD varies in the autoimmune connective tissues diseases. With the advent of HRCT, IL D is becoming increasingly recognized. \200 In post-mortem studies of SSc, ILD is present in up to 80%, although clinically significant fibrosis occurs in approximately 40% of patients. In SSc, anti-topoisomerase antibody (Scl -70) is associ- ated with ILD, whereas anti-centromere antibody is protective. Pleuritis and pleural effusions The presence of immune complexes, complement activation pro ducts, and immune deposits within the parietal pleura suggest an immune-mediated mechanism is a common pathway in the development of pleural disease. THE CHEST 56 LIP (lymphocytic interstitial pneumonia) Diffuse in \201 ltration of the alveolar septa by a dense poly- clonal lymphocytic in \201 ltrate. Both B and T cells are present. T cells predominate in the alveolar septum; B cells are found in the lymphoid follicles. Viral infe ctions, including EBV, may have a role in disease pathogenesis. It is important to exclude lymphoma. In RA, immune complexes are probably generated locally in the pleura, whereas they are deri ved from the circula- tion in SLE. RA-associated effusions have a high concentration of IL- 2, which suggests that a local T cell mediated immune reac- tion maybe a more important mec hanism than in SLE. Both sterile and septic empyemas have been reported in RA. Organizing pneumonia (OP) This is most frequently reported with DM or PM. Organizing granul ation tissue \201 lls the alveolar ducts and alveoli. It is a patchy process and overall the lung architecture is preserved. Although OP usually resolves, it can progress to \201 brosis. Airways \200 Dysphonia may result from synovitis/subluxation of the cricoarytenoid joint, rheumatoid nod ules of the larynx, or arteritis of the vasa nervorum of the recurrent laryn- geal and vagu s nerves. Laryngeal paralysis and destruction, and tracheomalacia are consequences of recur rent in \202 ammation of the airway wall cartilage. Upper and large airways in \202 ammat ion can occur with AASV. Tracheobronchial ulceration, intra-luminal pseu- dotumour and bron chiomalacia due to necrotizing granulomas of the cartilage result. The subglottic region of the trachea is most frequently involved, usually in younger patients. Scarring here leads to airway stenosis and obstruction. Follicular bronchiolitis is characterized by peribronch i- olar inflammation with lymphoid follicles situated between bronchioles and pulmonary art eries. External compression of the airway lumen results, leading to small airways obstructi on. Obliterative bronchiolitis occurs as a result of direct occlusion of the airway lumen b y \201 brotic tissue. The small airways proximal to the terminal bronchiole are involved. The etiology is unknown. Bronchiectasis: dilatation and thickening of the airways proximal to the terminal bronchioles occurs as a result of chronic in \202 ammation. Diffuse alveolar damage (DAD) This is a rapidly progressive form of ILD with a high mor- ta lity. It has a diffuse distribution with hyaline membrane formation, septal thickening, and organization of the air spaces. Granulomas, viral inclusions, and neutrophilic abscesses s uggest an infective etiology. Other parenchymal pathology \200 Drug-induced pneumonitis is a diagnosis made after exclusion of infection, hemorrhage, or o ther pulmonary disease, in the setting of an appropriate drug exposure history. Risk factor s include age, diabetes mellitus, pre- existing lung disease, hypo-albuminaemia, renal impa ir- ment, and use of disease-modifying anti-rheumatic drugs (DMARDs). The mechanism is unkn own. Histological patterns of NSIP, OP, granulomas, and eosinophilic in \201 l- trates hav e been reported. Rheumatoid nodules occur in the interlobular septa, subpleural regions and lung parenchyma. They can be single or multiple, can cavitate and must be differentiated f rom a pulmonary neoplasm. Caplan described multiple nodules that rapidly cavitated in 25% o f Welsh coal min- ers with RA. Other occupational dust exposures have been associated with this syndrome. Pulmonary hemorrhage occurs is due to involvement of small vessels in AASVs (WG, microscopic polyangiitis [MPA] and Churg \200\223Strauss syndrome [CSS]). Fibrinoid ne crosis, necrotizing granulomas and neutrophilic in \201 l- trates occur within the vessel walls. The resulting nodular lesions may cavitate and either resolve or repair with \201 brosis. ANCAs have been implicated in the disease pathogenesis. Infection: hyposplenic SLE patients are susceptible to encapsulated organisms. Those patients receiving anti- TNFA reg imens are at an increased risk of severe com- mon infections, atypical mycobacterial and MT B infections. Fungal colonization and aspergillomas can occur in pulmonary cavities (e.g. A S, WG). The susceptibility for, and phenotype of, sarcoid depends on both genetic and envir onmental factors. Lung parenchyma ILD associated with autoimmune connective tissue disease is classi \201 ed histologically in accordance with the ATS/ERS consenus statement. The etiology, the role o f autoanti- bodies and underlying disease pathogenesis, remains to be determined. \200 Epithelial injury is a common feature that triggers a number of inflammatory cytokine, coag ulation, and mechano-sensing cascades. This activates stem cells, epithelial to mesenchymal tran- sition, \201 brocyte recruitment from the bone marrow, and differentiation of \201 broblasts to myo \201 broblasts. Excessive collagen and extra-cellular matrix is prod uced ultimately leading to \201 brosis. NSIP (non-speci \201 c interstitial pneumonia) This is the commonest ILD associated with a utoimmune connective tissue diseases, particularly SSc. Both cellular (interstitial in \202 ammation with lymphoid aggregates and minimal \201 brosis) and \201 brotic (dense interstitial collagen deposition leading to distortion of the lung architecture) forms occu r. NSIP can be distinguished from UIP by its temporal uniformity. Etiology and pathophysiology of lung sarcoid Genetic factors Macrophage HLA class II antige ns encoded by HLA- DRB1 and DQB1, butyrophilin-like 2 (BTNL2) gene on chromosome 6p and chr omosomes 3p, 5p, 5q UIP (usual interstitial pneumonia) The characteristic histological features are architectur al destruction, \201 brosis with honeycomb formation, \201 broblas- tic foci, and a per ipheral, patchy distribution. These areas of \201 brosis are interspersed with normal lun g and connect to form a reticulum. Environmental factors Inorganic particles, metalworking, molds, mycobacterial, and propioni bacterial infections. CHAPTER 3 Organ involvement in rheumatological disease 57 In Beh et \200\231s disease, a number of mechanisms have been implicated in thrombosis, in cluding increased platelet reactivity and homocysteine levels, and reduced acti- vated prot ein C and tissue plasminogen activator levels. Granulomas CD4+ T cells interact with antigen presenting cells to form and maintain epithel oid, non-caseating granulo- mas. These activated CD4+ cells can differentiate into Th-1 lik e cells secreting IL-2 and IFN , to propagate the local cellular immune response. Sarcoid granulomas may resolve, persist or lead to fibrosis, and can, depending on their site, lead to lymphadenopathy and pulmonary hypertension. Lymphadenopathy \200 Lymphadenopathy results from recruitment and prolif- eration of lymphocytes in an adaptive immune response, as in autoimmune connective tissue diseases or due to development of epith eloid granulomas (e.g. hilar lym- phadenopathy in sarcoidosis). Lymphoma represents maligna nt transformation of lymphoid elements. This may manifest as hilar lymphad- enopathy. Appro ximately 5% of patients with Sj gren \200\231s syndrome develop lymphoma. Matrix changes Activated alveolar macrophages stimulate \201 broblast proliferation and c ollagen production via secretion of fibronectin and CCL18. Matrix metalloproteinases 8 and 9 are increased in bronchoalveolar lavage speci- mens. Sputa from these patients can contri bute to extra-cellular matrix degradation and remodeling that ultimately results in \201 brosis. Risk factors \200 \200 \200 Smoking, in particular patients with RA. Pets. Occupational exposures: asbestos, coal dust and hard metal pneumoconiosis. Pneumotoxins: azathioprine, methotrexate, cyclophos- phamide , celecoxib, sulphasalazine, leflunomide, D- penicillamine, gold, and anti-TNFA therapies \200\223 in \202 iximab, etanercept. Susceptibility to encapsulated bacterial infection (h ypo- splenism or mannose binding protein de \201 ciency in SLE). Left ventricular failure is more likely to occur in patients with accelerated atherosclerosis (SLE, RA) or with card iomyopathies, or in those patients treated with glucocorticoids (GCs). Anticardiolipin anti bodies and/or lupus anticoagulant are risk factors for thromboembolic disease and the devel opment of PAH. Anti-Jo-1 antibodies are associated with the development of ILD in DM and PM . Pulmonary vasculature and lymphatics Pulmonary arterial hypertension (PAH) Of greatest rele vance in SSc, PAH evolves following \201 brocollagenous intimal and medial arterial thick ening, alterations in the elastic lamina and luminal narrowing. \200 In SSc, endothelial injury appears to be an early event and aberrant \200\230cross-talk \200\231 between endothelia, underlying vascular smooth muscle cells and other stromal cell s orchestrates the proliferative vasculopathy and \201 brosis. Vasoconstrictive, pro-in \202 ammatory and prothrombotic endothelial products, including endothelin-1 (ET-1) and von Willebrand factor are elevated. Anti-in \202 ammatory, anti-thrombotic, vasodilators, suc h as nitric oxide are reduced. The proliferative vasculopathy serves to increase pulmo- nar y vascular resistance and to cause PAH. Anti-endothelial cell antibodies (AECA), including antibodies speci \201 c for the platelet-derived growth factor (PDGF) receptor have also b een implicated in the initiation of endothelial cell injury in SSc. The development of PAH in SSc is also associated with the presence of anti-cardiolipin antibodies. In SLE-related PAH, granular deposits of IgG and the complement protein C1q have been identi \201 ed in v essel walls, suggesting that immune deposits may be involved in the pathogenesis. In sarcoi dosis, granulomatous infiltration of the pulmonary arterioles has been observed. Secondary PAH can result from long-term sequelae of chronic hypoxia, secondary to severe airway, pare nchymal or chest wall disease. Pulmonary artery aneurysm: Histopathological features of Beh et \200\231s disease include a systemic vasculitis of all vessels of both the arterial an d venous circulations, and perivascular inflammatory infiltrates. Inflammatory thrombotic o cclusion, recanalization and fresh thrombi can be found within arterial aneurysms. Clinical features The exercise capacity of patients with rheumatological diseases is often limited by musculoskeletal disease. Hence, exertional dyspnoea may be masked. For all patie nts, assess the respiratory rate, the presence of central cyano- sis and oxygen saturations (either on air or inspired Fi02). Chest wall and pleura \200 \200 Dyspnoea from chest wall restriction. Orthopnoea and dyspnoea exacerbated by being in a bat h of water suggest diaphragmatic weakness. Chest pain needs clarifying whether it is parast ernal/para- vertebral (costochondral/costovertebral) or whether it is more diffuse and wors e on deep inspiration (pleuritic). Chest pain referred from general lower neck and upper sp inal pathology is common (e.g. degenerative disease or vertebral fracture). History of ches t wall deformity and trauma. Examination features \200 Costovertebral tenderness (costochondritis in SpAs or SAPHO). Manubriosternal and sternocla vicular joint (SCJ) tender- ness and swelling is a feature of SpAs, SAPHO, and axial sarcoi d. Reduction of chest expansion in AS, SSc, DM, PM, or SLE shrinking lung. Serial measureme nts of chest expansion are useful for monitoring thoracic restriction involve- ment in AS. Thromboembolic disease \200 In SLE/APLS, anti-phospholipid antibodies promote thrombo-embolic disease by up-regulating endothelial cell adhesion molecules, increasing expression of pro- coagulant endothelial ce ll products (tissue factor, von Willebrand factor, thromboxane A2) and decreasing anti-coag ulant products (thrombomodulin, protein C). THE CHEST 58 lung disease. In restrictive disease, the FEV1/FVC ratio is preserved or elevated (although absolute values of FEV1 decrease). FVC is used to monitor respiratory function in patients with DM or PM. Ventilatory support should be considered when FVC <50% and/or hypercapnic r espira- tory failure. Paradoxical abdominal movement occurs with diaphrag- matic weakness. Stony dull percussion note, reduced breath sounds and vocal resonance indicates pleural effusion. A pleural rub i s characteristic of in \202 ammation of pleura (pleurisy alone, or in association with pne umonia or pulmonary embolus). Respiratory muscle function testing Sniff test. Maximal inspiratory and expiratory pressure s measure respiratory muscle, including diaphragmatic, func- tion. Fluoroscopy can be used to assess for the presence of diaphragmatic weakness or paralysis. Airways \200 \200 Shortness of breath, particularly on exertion. Persistent productive cough or recurrent low er respira- tory tract infections suggests bronchiectasis. Wheeze: establish diurnal variat ion and relationship to exercise. Hoarseness may indicate arthritis of cricoarytenoid joint s or vocal fold nodules (e.g. RA). Cough is a non-speci \201 c symptom associated with dif ferent airways diseases. CXR 500 ml pleural effusion will be detectable as blunting of the costophrenic angle. Large r effusions are obvious. Raised hemidiaphragm suggests diaphragmatic weakness. 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.