marker, an autoantibody to topoisomerase I (antitopoisomerase I, also called Scl70). Another potential pulmonary manifestation of scleroderma is disease of the small pulmonary blood vessels, producing pulmonary arterial hypertension, which is discussed in Chapter 14. This involvement appears to be independent of the fibrotic process affecting the alveolar walls. Because patients with scleroderma commonly have esophageal disease leading to gastroesophageal reflux, recurrent aspiration may play a role in the development or progression of apparent interstitial lung disease.

In addition to interstitial fibrosis, patients with scleroderma may develop pulmonary vascular disease involving the small pulmonary vessels that is independent of the interstitial process.

In polymyositis-dermatomyositis, muscles and skin are the primary sites of the inflammatory process. The interstitial lung disease of polymyositis-dermatomyositis is relatively infrequent and often has no particular distinguishing features. Patients may also have respiratory problems due to muscle disease, with weakness of the diaphragm or other inspiratory muscles. Involvement of striated muscle in the proximal esophagus may lead to difficulty in swallowing and recurrent episodes of aspiration pneumonia.

In Sjögren syndrome, a lymphocytic infiltration affects salivary and lacrimal glands and is associated with dry mouth and dry eyes (keratoconjunctivitis sicca). When patients with Sjögren syndrome have pulmonary parenchymal involvement, the histologic appearance is most commonly either NSIP or a lymphocytic infiltrate within the alveolar walls called lymphocytic interstitial pneumonia. Other lymphocytic complications of the lung can develop in patients with Sjögren syndrome, specifically either a localized nodular lesion called a pseudolymphoma or a full-fledged lymphoma.

Finally, a number of overlap syndromes, often called undifferentiated connective tissue disease, have features of several of these disorders, particularly scleroderma, lupus, and polymyositis. Patients may develop any of the complications noted with the more classic individual disorders, including parenchymal lung disease, pleural disease, and pulmonary vascular disease.

Sarcoidosis

Sarcoidosis is a systemic disorder in which granulomas, typically noncaseating, can be found in affected tissues or organ systems. An important qualification is that these granulomas occur in the absence of any exogenous (infectious or environmental) agents known to be associated with granulomatous inflammation. The lung is the most frequently involved organ, with potential manifestations including parenchymal lung disease, enlargement of hilar and mediastinal lymph nodes, or both.

Sarcoidosis is a systemic granulomatous disease that most commonly affects the lungs, the hilar and mediastinal lymph nodes, or both.

Sarcoidosis is a relatively common disorder that particularly affects young adults between the ages of 20 and 40 years. It is slightly more common in women than in men. In the United States, it is more common in the Black population than in the White population. However, this predilection is not seen throughout the world because the disease is notably prevalent in the White population of Scandinavia. Of all the disorders of unknown cause affecting the alveolar walls, sarcoidosis is the most prevalent.

Despite increasing knowledge about the cells involved in the inflammatory and granulomatous response in sarcoidosis and the identification of multiple cytokines and chemokines that appear to be involved in the pathogenesis of disease, the fundamental etiology of sarcoidosis remains as mysterious as it was when the disease was first described more than 125 years ago. It is hypothesized that sarcoidosis represents an immunologic response to an exogenous agent in a genetically susceptible individual. Multiple exogenous

FIGURE 11.4 Simplified proposed pathogenetic sequence in sarcoidosis. Ab,

antibody; Ag, antigen.

The accumulation of CD4+ lymphocytes at sites of active disease appears to result in secondary immunologic phenomena that are well recognized in sarcoidosis. First, presumably because of this concentration of activated lymphocytes in affected tissues, there is a relative depletion of CD4+ cells in peripheral blood. The depletion leads to an apparent depression of cell-mediated immunity, at least as measured by cutaneous delayed hypersensitivity (skin testing). However, patients with sarcoidosis are not unduly susceptible to opportunistic infections that characteristically affect the immunosuppressed host with impaired cellular immunity. Second, T lymphocytes in sarcoidosis nonspecifically activate B lymphocytes and the humoral immune system, leading to production of a variety of immunoglobulins and the common finding of polyclonal hypergammaglobulinemia.

The characteristic histopathologic feature of sarcoidosis is the noncaseating granuloma (see Fig. 9.2). These typically well-formed granulomas represent a collection of tissue macrophages (also called epithelioid histiocytes), multinucleated giant cells, and T lymphocytes, particularly toward the periphery or at the rim of the granuloma. In contrast to the histopathology seen in tuberculosis or histoplasmosis, the center of a sarcoid granuloma does not show evidence of frank necrosis or caseation. An alveolitis often accompanies the granulomas in the lung parenchyma or intrathoracic lymph nodes. The alveolitis is composed primarily of CD4+ T-helper lymphocytes, which are presumed to be of particular importance in the pathogenesis of disease.

FIGURE 11.5 Posteroanterior (PA) chest radiograph of stage I sarcoidosis

showing bilateral hilar and paratracheal adenopathy without apparent pulmonary

parenchymal involvement.

FIGURE 11.7 Chest computed tomography scan demonstrates micronodular pattern

in a patient with sarcoidosis.

The chest radiograph in sarcoidosis shows symmetrically enlarged hilar lymph nodes, interstitial lung disease, or both. The CT scan often shows a characteristic pattern of small peribronchovascular nodules accompanied by hilar and mediastinal adenopathy.

The course of the radiographic findings in sarcoidosis is quite variable. Over time, both the adenopathy and the interstitial lung disease may regress spontaneously. At the other extreme, the interstitial disease may progress to a condition of extensive scarring and end-stage lung disease, at which time the patient has severe respiratory compromise.

Patients often display immune system abnormalities. Clinically, these patients may have anergy, failure to respond to skin tests requiring intact delayed hypersensitivity. They also may have hypergammaglobulinemia, which is evidence of a hyperactive humoral immune system. Calcium metabolism may be abnormal in sarcoidosis, due to increased formation of the active form of vitamin D (1,25-dihydroxy-D3) by activated macrophages in granulomas. Increased amounts of the active form of vitamin D lead to enhanced calcium absorption from the gastrointestinal tract, potentially causing hypercalciuria or, less frequently, hypercalcemia.

The diagnosis of sarcoidosis can be established in several ways. When the clinical diagnosis strongly suggests sarcoidosis, tissue confirmation is sometimes unnecessary. An example of such a presentation is the patient who presents with a classic picture of Löfgren syndrome. In contrast, when the patient has other symptoms or findings or when there is a question about the diagnosis, tissue sampling usually is undertaken to look for noncaseating granulomas and rule out other causes. The lung or a lymph node in the mediastinum is generally the most appropriate source of tissue, assuming an easily accessible biopsy site such as a skin lesion or an enlarged peripheral lymph node is not available. Samples of lung tissue are frequently obtained by transbronchial biopsy through a flexible bronchoscope. Interestingly, even when

the chest radiograph shows only hilar adenopathy without obvious parenchymal lung disease, the alveolar walls and small airways are often studded with granulomas that may be seen on transbronchial lung biopsy. With the increasing use of endobronchial ultrasound during bronchoscopy, needle aspiration through the airway wall into an adjacent mediastinal or hilar lymph node has become a frequent option for obtaining cellular material to identify granulomatous inflammation. Other, more invasive ways of obtaining tissue include performing a biopsy of a lymph node in the mediastinum (via mediastinoscopy) or a thoracoscopic lung biopsy. Potential biopsy sites outside the thorax depend on the presence of apparent disease in those sites. These can include the skin, peripheral lymph nodes, conjunctiva, minor salivary glands, and liver.

In sarcoidosis, transbronchial lung biopsy through a flexible bronchoscope usually demonstrates granulomas in the lung parenchyma, even when the chest radiograph does not show interstitial lung disease.

Elevated serum levels of angiotensin-converting enzyme (ACE) have been found in a large percentage of patients with sarcoidosis. This enzyme, which normally is synthesized by vascular endothelial cells, appears to be produced in the granulomas of sarcoidosis. However, because it is not specific for sarcoidosis and often is normal in the presence of relatively inactive disease, ACE levels are not considered reliable in either diagnosing sarcoidosis or assessing its response to treatment.

The natural history of sarcoidosis is quite variable. In some patients, all clinical and radiographic manifestations resolve within 1 to 2 years. Other patients have persistent radiographic changes, either with or without persisting symptoms. In general, nearly two-thirds of patients have spontaneous remissions. A minority of patients (10%-30%) show continued progression of radiographic abnormalities, with or without additional extrathoracic disease, and may have debilitating respiratory symptoms. Clinical factors associated with a worse prognosis include age at onset older than 40 years, chronic uveitis, chronic hypercalcemia, certain genetic variants, progressive pulmonary parenchymal fibrosis, and the presence of lupus pernio, a skin lesion affecting the face. In the United States, multiple studies show that Black race and low-income status are adverse prognostic factors; the degree to which socioeconomic factors explain an association with prognosis is an area of current interest.

Pulmonary function tests are most useful for quantifying functional impairment. Spirometry, lung volumes, and diffusing capacity all are measured. Perhaps surprisingly, abnormalities on pulmonary function testing do not necessarily correlate well with the severity of the findings on chest radiography or HRCT scanning. Although a restrictive pattern is most common, some patients develop either isolated or concomitant airflow obstruction, often resulting from granulomas involving airways or from distortion of airways in patients with extensive fibrosis.

The initial treatment decision confronting the clinician is whether to institute therapy for the patient with sarcoidosis. Many patients do not require treatment, especially when the disease is not causing significant symptoms or significant functional organ involvement. The fact that the disease may improve or resolve spontaneously also complicates decisions about instituting therapy. When treatment is indicated because of symptoms and significant tissue involvement affecting organ function, first-line treatment is usually systemic corticosteroids. Because long-term treatment with systemic glucocorticoids is associated with significant adverse side effects, early consideration of steroid-sparing agents is recommended if a patient requires prolonged therapy. Commonly used nonsteroidal medications include methotrexate, azathioprine, mycophenolate mofetil, and leflunomide. In patients with refractory disease, monoclonal antibodies targeting TNF-α, particularly infliximab and adalimumab, can be employed.

The variable natural history of sarcoidosis often makes decisions about treatment difficult.

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