Page 1015 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 72 Immunological Lung Diseases 979

the presence of keratoconjunctivitis sicca and xerostomia in a Although the 5-year survival for patients with SSc and ILD is
patient with RA and ILD should suggest this histological type. 38–45%, it is better than that of patients with IPF.
In general, ILD in RA appears more indolent than in the IIPs.
Thus because of uncertain treatment benefits and possible adverse Pulmonary Vascular Disease
effects, the decision to institute therapy should be based on Pulmonary hypertension is a frequent complication of SSc,
clinical, radiographic, and physiological deterioration. occurring in approximately 30% of patients with diffuse sclero-
derma and in 10–50% of those with limited scleroderma (Chapter
Drug-Induced Lung Disease 55). It is a major cause of morbidity and mortality in systemic
Methotrexate and gold are the two main anti-RA drugs capable sclerosis and has also become part of the diagnostic criteria for
40
of causing lung injury. Methotrexate administered weekly the disease. Pulmonary hypertension can either be associated
(10–20 mg/week) is associated with the development of interstitial with interstitial fibrosis or result from involvement of small
changes in 1–5% of patients with RA. No correlation with age, and medium-sized arteries and arterioles with smooth-muscle
sex, disease duration, or cumulative dose has been identified. hyperplasia, medial hypertrophy, and intimal proliferation
The clinical presentation is subacute, with fever, cough, and (plexogenic). Direct involvement of the pulmonary circulation
dyspnea occurring 1–5 months after initiation of the drug. Chest is more common with limited scleroderma, whereas pulmonary
radiography shows mixed interstitial–alveolar infiltrates. Non- hypertension in patients with diffuse scleroderma is more likely
specific laboratory abnormalities include leukocytosis, sometimes associated with ILD.
with mild eosinophilia, and an elevated erythrocyte sedimentation The clinical presentation is characterized by the insidious
rate (ESR). In most cases, BAL reveals a lymphocytosis. Histologi- onset of fatigue and dyspnea on exertion. Physical examination
cally, cellular NSIP is seen with areas of organizing pneumonia. and chest radiography show signs typical of pulmonary hyperten-
Noncaseating, granulomatous inflammation similar to that seen sion, whereas a decreased diffusing capacity is seen on pulmonary
in hypersensitivity pneumonitis may also be present. The primary function testing. Risk factors for developing SSc-associated
treatment of methotrexate-induced pneumonitis is withdrawal pulmonary hypertension include limited skin involvement,
of methotrexate, as well as appropriate supportive care. duration of disease greater than 10 years, onset of SSc at older
Gold-induced pneumonitis occurs in fewer than 1% of patients age, and severity and duration of RP.
with RA who are treated with gold. Dyspnea and cough usually The pathogenesis of SSc-associated pulmonary hypertension
begin after 4–6 weeks of therapy; eosinophilia occurs in a minority is poorly understood. Vascular changes occur at an early stage
of patients. Chest radiography typically reveals mixed alveolar– in SSc and include apoptosis, endothelial cell activation with
interstitial opacities with a predilection for the upper lung zone. increased expression of cell adhesion molecules, inflammatory
The histology is similar to that seen in patients with RA-associated cell recruitment, intimal proliferation, and adventitial fibrosis
ILD. Thus the differentiation of gold-induced pneumonitis from leading to vessel obliteration. Endothelial injury is reflected by
RA-associated ILD can only be established when discontinuation increased levels of soluble cell adhesion molecules, disturbances
of the medication results in remission. of angiogenesis with increased levels of circulating vascular
endothelial growth factor (VEGF), and the presence of angiostatic
Systemic Sclerosis (Scleroderma) factors. To what extent dysregulated angiogenesis in SSc-associated
SSc is characterized by excessive deposition of ECM in the skin pulmonary hypertension is driven by an inflammatory process
and internal organs, and vascular involvement (Chapter 55). or other as yet unidentified mechanisms remains unclear.
The degree of visceral organ involvement determines morbidity Treatment of SSc-associated pulmonary hypertension has been
and mortality. Pulmonary involvement occurs in 70–100% of disappointing, with no therapy showing a significant survival
patients with SSc. There is no correlation with the degree of benefit. Calcium channel blockers are not usually indicated for
extrapulmonary disease. ILD is the most common pulmonary patients with SSc-associated pulmonary hypertension, although
manifestation of SSc. Of note, with the improved mortality often used at lower doses for RP. Continuous intravenous
41
associated with renal involvement in SSc, lung disease has become epoprostenol improves exercise capacity and hemodynamics.
the most important cause of morbidity and mortality. Randomized clinical trials with phosphodiesterase inhibitors,
including sildenafil, showed a modest effect on exercise capacity,
Interstitial Lung Disease hemodynamic parameters, and functional class after 12 weeks
The incidence of ILD in SSc depends on the method of detection. of treatment. Carefully selected patients may be considered for
Autopsy studies have reported an ILD incidence of 60–100% of heart–lung transplantation but are often excluded because of
cases, whereas studies based on chest radiography have noted the risk of postoperative complications arising from SSc-related
interstitial changes in 14–66% of cases. Cough and dyspnea on gastroesophageal reflux disease (GERD) and renal dysfunction.
exertion are the most common symptoms. Physical examina-
tion reveals bibasilar rales. Radiographic findings include basal CONCLUSIONS
reticulonodular infiltrates, enlargement of pulmonary arteries,
and progressive volume loss. Pulmonary function testing reveals ILDs comprise a diverse group of disorders ranging from
restrictive lung disease, preservation of flow rates, and decreased idiopathic etiologies to those related to an underlying autoimmune
diffusing capacity. A disproportionate decrease in diffusing condition. There is likely a complex interplay between the innate
capacity compared with lung volume changes should suggest and adaptive arms of the immune system and the profibrotic
pulmonary hypertension, especially in individuals with limited pathways that lead to the development of these various disease
scleroderma (calcinosis, Raynaud phenomenon [RP], esophageal states. Future work should focus on better understanding this
dysmotility, sclerodactyly, telangiectasia [CREST] syndrome). The relationship and, more importantly, translating these findings
predominant histopathologic abnormality is NSIP. Rarely, LIP to the clinical setting. The role of standard immunosuppressive
may complicate cases of SSc associated with Sjögren syndrome. approaches with the ongoing discovery of novel approaches to