Disease presentation and natural history are also influenced by epidemiologic factors. White patients tend to present more often without symptoms, whereas severe multisystem disease occurs more often in blacks.^9,¹⁰ Black race has been described as conferring added mortality; however, data from population-based settings have suggested that at least part of the differential outcome may be related more to access to medical care than to inherent differences in disease behavior.¹¹^–¹³ The ACCESS study systematically characterized 736 newly diagnosed patients at ten U.S. centers.¹⁴ Organ involvement was significantly influenced by demographic variables, including age, sex, and race (Fig. 1).¹⁵

Figure 1 Demographic predictors of organ involvement in sarcoidosis.

E. nodosum, erythema nodosum. *Not including erythema nodosum.

Adapted from Baughman RP, Teirstein AS, Judson MA, et al: Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001:164:1885-1889, with permission.

PATHOPHYSIOLOGY AND NATURAL HISTORY

Sarcoid inflammation is characterized by non-necrotizing granulomas (Figs. 2 and 3). The granuloma is a compact mass of cells that walls off foreign antigens, typically microbes. Epithelioid histiocytes, together with a few multinucleated giant cells, compose the core, surrounded by an outer rim of T lymphocytes. The lymphocyte population is oligoclonal, with restricted T cell receptor repertoires, consistent with an antigen-driven process. Inflammation in sarcoidosis is dependent on persistent stimulation by CD4⁺ T cells.¹⁶ Thus, polymorphisms of the major histocompatibility complex and the T cell receptor that modulate affinity for the antigen may be responsible for development or course of the disease.¹⁷ Granulomatous inflammation that is widespread or at critical locations (e.g. A-V node) can lead to functional organ impairment. However, it is not uncommon for organ involvement to be clinically silent.

Figure 2 Non-necrotizing pulmonary granuloma.

Well-formed non-necrotizing pulmonary granuloma characteristic of sarcoidosis. The granuloma is composed of a core of epithelioid histiocytes surrounded by a rim of lymphocytes. There is a large multinucleate giant cell in the center (arrow).

Image courtesy of Carol Farver, MD.

Figure 3 Distribution of granulomas in pulmonary sarcoidosis.

The granulomas are typically found in a lymphatic distribution, coursing along the pulmonary veins (upper arrow) and the airways (lower arrow).

Image courtesy of Carol Farver, MD.

The search for a causative agent has spanned more than a century. It is still unknown whether a single agent triggers the disease or if sarcoidosis represents a stereotyped immune response to diverse etiologies. A large number of infectious and noninfectious agents have been proposed (see Box 1). Recent attention has focused most prominently on Mycobacteria spp.^18,¹⁹ and Propionibacterium acnes,²⁰ but the evidence to date has been inconclusive and sometimes contradictory.

The natural history of disease is variable. Spontaneous resolution occurs within 5 years in approximately two thirds of patients ¹⁰; over a 2-year follow-up period in ACCESS, 80% demonstrated either improvement or stability, with no requirement for treatment.¹⁵ Features believed to predict poor prognosis vary among studies (Box 2); of all the putative risk factors, no study to date has comprehensively ascertained which are independently associated with disease chronicity or progression.

Staging of pulmonary disease based on the chest x-ray (Fig. 4) allows a general prediction of outcome. For chronic sarcoidosis, there is a striking degree of heterogeneity between patients: Some have persistent inflammation, and others shift to a fibrotic phenotype. This shift is not seen in all patients, and the onset and pace of the fibrosis are likewise highly variable. Large-scale epidemiologic surveys have suggested that between 5.4% and 10% of cases are fibrotic at presentation alone. In the United States, pulmonary fibrosis is the leading cause of death in sarcoidosis, which carries a mortality rate of 1% to 5%. Other complications of pulmonary sarcoidosis include mycetomas, pleural effusions, bronchiectasis, pulmonary hypertension, endobronchial stenosis, and, rarely, bullous lung disease. Depression, chronic pain syndromes resembling fibromyalgia, and sleep apnea are prevalent in sarcoidosis patients.

Figure 4 Common chest radiograph stages of sarcoidosis, as classified by the Scadding method (see text).

SIGNS AND SYMPTOMS

Sarcoidosis can affect any organ, although the lungs are involved in up to 95% of patients (Fig. 5). Other organ systems commonly affected include the skin, eyes, and lymphoreticular system. Estimates of organ involvement are confounded by the method of discovery, referral bias, and the sensitivity of diagnostic modalities. Why different organs are differentially affected in various patients is unclear. Manifesting symptoms are organ dependent, but the most common ones include fatigue, arthralgias, diffuse pain syndromes, cough, dyspnea, wheezing, chest discomfort, rash, photophobia, scleritis, decreased visual acuity, weight loss, and fever.

Figure 5 Percentage of overt organ involvement.

Occult involvement is in parentheses.

In the lungs, important differential diagnostic possibilities include granulomatous infections, idiopathic interstitial pneumonias, hypersensitivity pneumonitis, and asthma. Cutaneous manifestations are protean.²¹ Ultimately, one quarter of patients develop at least one dermatologic feature. Erythema nodosum is associated with acute onset of disease and confers a good prognosis. Lupus pernio is a chronic plaquelike induration of the face, usually appearing with violaceous discoloration of the cheeks, lips, nose, and ears (Fig. 6). It can erode into cartilage or bone, causing permanent disfigurement. Lupus pernio generally portends chronic, multisystem sarcoidosis, is more common in older African-American and West Indian women, and is notoriously difficult to treat. Other skin lesions include plaques, maculopapular eruptions, hypo- or hyperpigmented patches, subcutaneous nodules, and alopecia (Fig. 7).