Page 780 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 55 Scleroderma–Systemic Sclerosis 751

involvement is often asymptomatic and nonprogressive, yet idiopathic pulmonary fibrosis), and nintedanib (a tyrosine kinase
significant lung abnormalities can be detected in over 40% of inhibitor). 23,24
patients with sensitive lung function testing or special imaging.
In a subgroup of patients (10–20%), the disease process can Pulmonary Arterial Hypertension
lead to major pulmonary vascular disease or inflammation with PAH is detected in 8–15% of patients with SSc and may occur
progressive fibrosis and subsequent respiratory failure and death. as the sole pulmonary manifestation of the disease or in
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A recent survey reported that 35% of all SSc-related deaths were association with ILD. The natural history of PAH is highly
directly attributable to pulmonary fibrosis or interstitial lung variable. In many patients, it is clinically silent for years before
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disease (ILD), and 26% of deaths resulted from PAH. Additional it presents with exertional dyspnea and hypoxia secondary to
pulmonary manifestations of SSc include aspiration pneumo- altered gas exchange and right heart failure. It is most often
nitis, pulmonary hemorrhage, bronchiectasis, bronchiolitis a late (9–12 years after onset of Raynaud phenomenon [RP])
obliterans with organizing pneumonia, pleural reactions, and complication in patients with limited scleroderma; but PAH
pneumothorax. The risk of lung cancer is increased in patients can occur within 5 years from the disease onset, particularly
with SSc. in patients older at the time of SSc diagnosis. Risk factors for
PAH in SSc include disease onset at a later age, history of severe
Interstitial Lung Disease RP, numerous skin telangiectasias, abnormal nailfold capillar-
Nonspecific interstitial pneumonia (NSIP) is the most common ies, the presence of anticentromere, anti-U1 ribonucleoprotein
histopathological pattern in patients with SSc-related ILD (RNP), anti–U3 RNP (fibrillarin), or anti-B23 antibodies.
(SSc-ILD). The prevalence of SSc-ILD is found in 50% of Untreated, the estimated 3-year survival is approximately
those with dcSSc compared with 35% in those with lcSSc. The 50%. Although responses to current therapy are not as good
presence of topoisomerase-I autoantibodies is strongly linked among patients with SSc and PAH compared with patients
to the development of ILD, and the worst outcome is often with idiopathic PAH, there is evidence of improved survival on
seen in African Americans and Native Americans. Inflamma- modern therapy compared with historical controls. Prognosis
tory alveolitis and subsequent tissue fibrosis causes restrictive is poor among patients with PAH associated with ILD, and an
ventilatory defect and an abnormal gas exchange. Patients with even worse prognosis is associated with increased blood brain
ILD usually experience rapid initial decline in lung function natriuretic protein (BNP), echocardiographic signs of right heart
during the early period of active disease. About 20% of patients disease, and decreased diffusion capacity of the lungs for carbon
who eventually developed severe ILD (FVC ≤50%) have a fall monoxide (DLCO) on lung testing. PH can occur in SSc in the
in forced vital capacity (FVC) within 4 years of the onset of absence of PAH as a result of left heart disease or secondary
symptoms. If there is only minor impairment in FVC on lung to chronic hypoxia from severe ILD. Therefore patients need
function after more than 5 years of disease duration, then is it to undergo a right heart cauterization to confirm the presence
unlikely that the patient will ever develop severe lung fibrosis. of PAH or PH and characterize its severity. Current therapy
In early disease, most patients have no respiratory symptoms. for SSc-associated PAH is focused on supportive care, reduc-
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The most sensitive methods to detect early lung disease are tion of cardiac work load, and vasoactive drugs. Short-acting
pulmonary function testing and imaging with high-resolution prostacyclin analogues, including intravenous (epoprostenol or
computed tomography (HRCT). The presence of fibrosis and treprostinil) or inhaled (iloprost) prostaglandins, are used for
ground-glass opacities on HRCT is an indication of the activity treating severe disease. Selective and nonselective endothelin-1
of the disease process and correlates with subsequent decline in receptor inhibitors (bosentan, ambrisentan, and macitentan),
FVC. When the extent of disease defined by HRCT is <20%, the a phosphodiesterase type 5 inhibitor (sildenafil, tadalafil, and
10-year survival is reported to be 67%, whereas in the group vardenafil), and a soluble guanylate–cyclase stimulator (riociguat)
with HRCT-defined disease extent of >20%, 10-year survival is are helpful for treating milder disease. Early intervention and
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considerably poorer at 43%. Likewise, FVC of <70% is associated combination therapy may help achieve improved outcomes. In
with a poor prognosis. Biological biomarkers that can detect active relatively short-term clinical trials, each of these treatments has
alveolitis and predict disease progression are needed. The presence been shown to improve exercise tolerance and hemodynamics,
of neutrophilia in fluid obtained from bronchoalveolar lavage with variable benefit on disease progression. Early detection
(BAL) was thought to predict outcome, but neutrophilia does of PAH is important as it provides an opportunity for timely
not clearly define prognosis or response to therapy. Both Krebs intervention. A systematic detection program in which periodic
von den Lungen-6 (KL-6), a lung glycoprotein, and surfactant screening was performed in every patient with SSc detected less
protein-D (SP-D) levels are elevated in patients with SSc compared severe pulmonary vascular disease and showed better survival
with controls and higher in patients with alveolitis compared on therapy compared with that in patients managed by usual
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with those without alveolitis; thus SP-D levels are thought to clinical practice. Because of the complexity of life-threatening
be useful biomarkers of disease progression. Two multicenter PAH, it is recommended that patients be referred to experts in
clinical trials have been completed; one compared cyclophos- pulmonary medicine, especially in PAH, to manage these cases.
phamide to placebo, and the other compared cyclophosphamide Lung transplantation remains an option for carefully selected
to mycophenolate. 21,22 Both studies demonstrated statistically patients with SSc, with survival following lung transplanta-
significant stabilization or improvement of lung function along tion being similar to that of non-SSc patients with other lung
with improvement in scleroderma skin score and a variety of diseases.
clinical measures. These studies suggest that immunosuppres-
sive therapy can control active lung disease. A variety of other Cardiac Involvement
agents are now being tested in SSc-ILD, including rituximab Cardiac involvement is common, but often there are no signs
(monoclonal antibody [mAb] to CD20 on B lymphocytes), or symptoms until the heart has been severely affected. The
pirfenidone (an antifibrotic/antiinflammatory agent used in reported prevalence of heart disease varies, depending on method